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1. A method of testing for the occurrence of a state associated with the generation of volatile components comprising: a) providing a gaseous sample potentially containing said volatile components; b) exposing a single sensor device to said sample, said sensor device being capable of generating an output signal in response to a range of different volatile components; c) determining a plurality of parameters of the output signal, and correlating the plurality of determined parameters with predetermined parameter patterns associated with one or more states whose occurrence is to be detected. 2. A method according to claim 1 wherein the sensor device is an electrical device having a sensor element whose electrical resistance is affected by exposure to volatile components. 3. A method according to claim 1 wherein said sensor is an electrical device having a semiconductor sensor element. 4. A method according to claim 3 wherein said element is a metal oxide semiconductor (MOS) element. 5. A method according to claim 3 wherein said element is an organic semiconducting polymer element. 6. A method according to claim 5 wherein said element is based on polypyrrole or polyaniline. 7. A method according to claim 1 wherein said sensor is a surface acoustic wave device that is responsive to volatiles in the sample. 8. A method according to claim 7 wherein said acoustic wave device is modified with a chemical layer that forms the sensor element. 9. A method according to claim 1 wherein the state to be detected is a disease state. 10. A method according to claim 9 wherein the disease state affects at least one of: the urinary tract; the gastrointestinal tract; the respiratory system; soft tissues; skin; auditory and olfactory system; circulatory system; and the central nervous system. 11. A method according to claim 1 wherein the volatile components are generated by microorganisms, and step (a) includes a first step of obtaining a sample of material potentially containing the microorganisms and culturing it under conditions such that the microorganisms would generate the components. 12. A method according to claim 1 wherein the volatile components are generated by body processes, and step (a) includes a first step of obtaining a sample of material potentially containing the volatiles of interest. 13. A method according to claim 1 wherein step (a) includes a pre-concentration step to increase the concentration of the volatiles before presenting to the sensor device. 14. A method according to claim 1 wherein exposure of the sensor device to the sample leads to an output signal in the form of tailing peak, and in step (c) the parameters are selected from (i) peak height, (ii) maximum positive gradient, (iii) maximum negative gradient, (iv) time at which peak occurs after exposure of the sensor to the sample; (v) response decay constant; and (vi) logarithmic slope. 15. A method according to claim 14 in which the parameters are (i) and (ii). 16. A method according to claim 1 in which the magnitudes of one or more of said parameters are used to provide quantitative data about the amounts of volatile components. 17. Apparatus for use in carrying out the method of claim 1 including said single sensor device, a gaseous sample supply system coupled to the sensor device for providing samples to the sensor device, and a computer or microcontroller coupled to the sensor device for receiving and analysing its output and providing a display and/or an output signal indicative of the result. 18. Apparatus according to claim 17 wherein the sensor device is part of an endoscope or bronchoscope. |
<SOH> BACKGROUND ART <EOH>The smell associated with bacterial infection and the putrefaction associated with tissue destruction have long been recognised. It is now clear that many bacterial species produce specific odours. This is most notable in the anaerobic bacteria such as bacteroides and clostridia species. Often a pungent odour can only be detected if there is an overwhelming infection. Given a mild infection in the urine of a child with Eschericha coli imparts a distinct fishy odour, often detected by the mother who is familiar with the normal smell. Certain metabolic diseases may be first detected from the patient's odour. Prior to the advent of molecular and biochemical medicine, the sweet smell imparted to the breath of an unconscious child was the first clue of an acidotic diabetic coma. A musty odour in an older patient could indicate imminent hepatic failure, or a urinose smell, kidney failure. Halitosis or simple bad breath may have many causes, but is often related to excessive bacterial overgrowth in the stomach (associated with gastric cancer) or in the lungs (with bronchiectasis and secondary infection). The sense of smell has long been used as a means of disease diagnosis. Indeed, many diseases are known to emit characteristic odours that are used as markers of the diseased state (Barr et al., 2001). Detection of Microbial Odours The rapid detection of an infecting organism can be extraordinarily helpful for the correct treatment of patients. The result of bacterial infection is often to produce pus, which is a mixture of bacteria and dead white blood cells. Pus can easily be seen but the causal bacteria have often to await culture techniques to allow detection. Rapid detection allows correct antibiotic treatment to be given. The rapid detection of microbes is not only important in medicinal practice but also in the food and drink industry and in environmental monitoring. A number of “rapid” methods have been described based on different chemical, physical and biological techniques (Hobson et al., 1996). It is well known that different microbes display different metabolic pathways. These biochemical differences are inherent to the microbe and can be utilised as a means of detecting different microbial species. A common way of doing this is by the use of selective nutrient media that promote the growth of certain microbes by making available nutrients that can be metabolised for growth leading to the formation of visible colonies on a culture plate. Such microbiological plating techniques are widely used for microbial identification purposes. An extension of these ideas is the detection of metabolic volatile products that emanate from specific micro-organisms. A good example of this approach is embodied in research performed as far back as the 1970s where complex laboratory analytical techniques were used to identify specific end-products of metabolism as a means of identifying different microorganisms. Reports by Hayward et al. in 1977 and by Coloe in 1978 describe the detection of metabolic volatile end-products from E. coli and P. mirabilis using gas-liquid chromatography. In this work, the metabolic activity of bacteria on growth media led to the production of volatile chemicals that appeared in the head space of the growth vessel and were subsequently detected using a gas-liquid chromatography detector. Since different microbes display different metabolic pathways, it became feasible to distinguish between different species by recognising the formation of specific volatile markers using the gas-liquid chromatography detection method. The work of Hayward et al. in 1977 and Coloe in 1978 showed this approach to be highly effective in the identification of E.coli and P. mirabilis. These authors successfully applied the microbial odour analysis method to the rapid diagnosis of bacteria responsible for urinary tract infections using the chromatography detector. Further work in the 1980s and 1990s utilised a different detector for microbial volatile products using an array of chemical sensors. These array-based detectors for volatile chemicals employed a number of broad-specificity gas sensors. Such detector assemblies are commonly known as electronic noses. In this respect, WO 97/ 08337 and U.S. Pat. No. 5,807,701 describe methods for the identification of microbes using arrays of sensors that respond to the different gases or vapours that are produced by different microbes grown in nutrient media. Since different microbial species display different metabolic products, a broadly responsive array is thought to provide a good detector in order to capture sufficient information to make subsequent predictions on which species are present more accurate. The sensors in the array interact with the different products causing multiple sensor signals that are subsequently collectively analysed by pattern recognition techniques using software. By using an appropriate pattern recognition technique, it becomes possible to recognise sensor patterns produced by different microbes. Detectors of Odours from Metabolic Diseases A number of different techniques have been employed to examine the chemical make-up of odours from bodily fluids such as those imparted to breath and urine. These detection techniques are broadly similar to those already described for the detection of microbial odours, namely, complex instrumentation such as gas chromatographs and mass spectrometers and the electronic nose. Recently, the use of odours for metabolic disease detection was shown: The combination of twenty-two breath volatiles (predominantly alkanes, their derivatives and benzene compounds) could be used to discriminate between patients with and without lung cancer (Phillips et al., 1999) creating the possibility of a lung cancer ‘breathalyser’ for rapid diagnosis and screening (Gardner and Bartlett, 1994). |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a schematic view of a sensor assembly embodying the invention. FIG. 2 is an example of a sensor response curve. FIG. 3 is a graphic display showing bacterial discrimination from maximum positive slope and peak height (normalised and mean centred). detailed-description description="Detailed Description" end="lead"? |
Buckling arm robot |
The invention relates to a buckling arm robot comprising a base element (1), at least two articulation blocks (5, 11), at least three support tubes (9, 16, 16′), a working element (30), mechanical and electric drive elements, power supply elements (28) and external computer performance elements (32). The power electronics are completely integrated into the buckling arm robot. In order to control the position, a micro-computer is allocated to each motor-gearing unit in close proximity to the latter. Said arrangement provides an internal computer performance, which is locally distributed among the mechanical drive elements and the working element (30), thus forming a local intelligence. An external interface (26) provides access to the power supply elements (28) and the external computer performance elements (32). Sensors as working elements (30) permit a learning capacity by means of the external computer performance elements (32). The buckling arm robot is characterised by a low weight (less than 5.0 kg, preferably less than 3.0 kg) with an active radius of approximately 0.5 m, great flexibility in its modular construction and an advantageous ratio of load capacity to own weight. The invention also relates to the stationary use of buckling robots of this type, to their use as rail-mounted robots or as mobile robots. |
1. Bending-arm robot comprising a base element, at least two joint blocks, at least three support tubes, working means, mechanical and electrical driving means, and current supply means, wherein the mechanical drive means consist of at least four motor gear units which are situated in the base element, in the joint blocks, and in the support tubes; wherein the electrical driving means consist of at least four microcontrollers, which are situated in the base element and in the support tube, a microcontroller being allocated to, connected to, and arranged near to, each motor gear unit; wherein a digital bus system connects the electrical driving means and the working means with an external interface situated in the base element; wherein the interface is connected via a connecting cable to the current supply means and via a second connecting cable (31) to the external computer power means; wherein the arrangement of the microcontrollers confers an internal computer power which is present distributed locally with the mechanical drive means and the working means and thereby forms a local intelligence; wherein the mechanical driving means are provided for the movement of the joint blocks, the support tubes, and the working means; wherein for this purpose the local intelligence is available in the electrical driving means and an external intelligence is available in the external computer power means; and wherein the whole power electronics is integrated. 2. Bending-arm robot according to claim 1, wherein a first motor gear unit with the associated microcontroller is situated in the base element, and is provided for movement around a first axis with a rotation angle α of about 360°. 3. Bending-arm robot according to claim 1, wherein a second motor gear unit in the joint block lies axially in the joint axis, or respectively the second axis; wherein the associated microcontroller is situated in the support tube and is provided for movement around a second axis with a rotation angle α of about 150°. 4. Bending-arm robot according to claim 1, wherein a third motor gear unit lies axially in the joint axis, or respectively the third axis, in the second joint block; wherein the associated microcontroller is situated in the support tube and is provided for movement around a third axis with a rotation angle α of about 240°. 5. Bending-arm robot according to claim 1, wherein a fourth motor gear unit is situated in the support tube and the associated microcontroller is situated in the support tube and is provided for the movement around a fourth axis with a rotation angle α of about 240°. 6. Bending-arm robot according to claim 1, wherein a fifth motor gear unit is situated in the support tube and the associated microcontroller is situated in the support tube and is provided for the movement of the working means around a fifth axis. 7. Bending-arm robot according to claim 1, wherein the support tubes are easily detachable from the joint blocks or the working means, respectively, and are interchangeable, and adaptable specifically according to use. 8. Bending-arm robot according to claim 1, wherein the support tube is of telescopic construction. 9. Bending-arm robot according to claim 1, wherein the mechanical driving means have an incremental encoder for position determination and provided for position control, the signal evaluation taking place directly by means of the associated microcontroller of the electrical driving means, or respectively locally per axis. 10. Bending-arm robot according to claim 9, wherein the incremental encoder is integrated into the motor block of the corresponding motor gear unit. 11. Bending-arm robot according to claim 1, wherein the working means contain sensors. 12. Bending-arm robot according to claim 11, wherein as sensors there are provided IR sensors, local force sensors, conductivity sensors, extension sensors, ultrasound sensors, lasers and a miniature camera. 13. Bending-arm robot according to claim 11, wherein sensors of different modality are present which form a sensor redundancy which increases learning ability. 14. Bending-arm robot according to claim 1, wherein the working means are constituted as gripper arms with a rotatably mounted passive joint contained therein and always remaining in a vertical alignment, using gravity. 15. Bending-arm robot according to claim 1, wherein adaptive controls and predictive parameters are provided for the movements of the joint blocks, the support tubes and the working means, the means for external computer power being available for their operation or respectively for their calculation, and learning ability is conferred by means of artificial intelligence algorithms. 16. Bending-arm robot according to claim 1, wherein operation takes place free from protective screens. 17. Bending-arm robot according to claim 1, wherein it weighs less than 5.0 kg, preferably less than 3.0 kg. 18. Bending-arm robot according to claim 1, wherein the ratio of weight to useful load is up to a minimum of 5.0. 19. Bending-arm robot according to claim 1, wherein in the inoperative position it has maximum dimensions of 10.5 cm×33 cm×33 cm. 20. Bending-arm robot according to claim 1, wherein the support tube has a flange, on which the digital bus system is available to the working means at the interface. 21. Bending-arm robot according to claim 1, wherein the electrical driving means have in-circuit programmable flash memory which makes firmware updates possible without the necessity for mechanical intervention or an interchange of components. 22. Bending-arm robot according to claim 1, wherein the current supply means consist of a 12 V accumulator. 23. Bending-arm robot according to claim 1, wherein the maximum power consumption is 30 watts. 24. Bending-arm robot according to claim 1, wherein the base element, the joint blocks, and the working means have rounded edges. 25. Bending-arm robot according to claim 1, wherein a protective place per rotation axis is present by means of fastening screws at the transition from the motor shaft to the aluminum construction, and ensures protection against the action of excessive forces. 26. Bending-arm robot according to claim 1, wherein ball bearings or slide bearings are provided for mounting. 27. Bending-arm robot according to claim 1, wherein the cabling takes place internally. 28. Use of the bending-arm robot according to claim 1, fixedly mounted on a stationary base. 29. Use of the bending-arm robot according to claim 1, on a traveling base as a rail-guided robot. 30. Use of the bending-arm robot according to claim 1, on a traveling base as a mobile robot. 31. Bending-arm robot comprising a base element, at least two joint blocks, at least three support tubes, working means, mechanical and electrical driving means, and current supply means, wherein the mechanical drive means consist of at least four motor gear units which are situated in the base element, in the joint blocks, and in the support tubes; wherein the electrical driving means consist of at least four microcontrollers, which are situated in the base element and in the support tube, a microcontroller being allocated to, connected to, and arranged near to, each motor gear unit; wherein the arrangement of the microcontrollers confers an internal computer power which is present distributed locally with the mechanical drive means and the working means and thereby forms a local intelligence; wherein an external intelligence is available in the external computer power means; and wherein a protective place per rotation axis is present by means of fastening screws at the transition from the motor shaft of the electrical driving means to the aluminum construction, which ensures protection against the action of excessive forces. 32. Bending-arm robot according to claim 31, wherein the fastening screws yield at too great a pressure and are quickly replaced after action of an excessive force. 33. Bending-arm robot according to claim 31, wherein the maximum power consumption is 30 watts and wherein because of the limited occurring forces operation is possible in a very small space where humans have direct access. 34. Bending-arm robot according to claim 31, wherein the working means as sensors there are provided IR sensors, local force sensors, conductivity sensors, extension sensors, ultrasound sensors and/or lasers. 35. Bending-arm robot according to claim 34, wherein sensors of different modality are present which form a sensor redundancy which increases learning ability. 36. Bending-arm robot according to claim 31, wherein adaptive controls and predictive parameters are provided for the movements of the joint blocks, the support tubes and the working means, the means for external computer power being available for their operation or respectively for their calculation, and learning ability is conferred by means of artificial intelligence algorithms. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Mobile robots today have constantly increasing importance. However, most manipulators are lacking as regards their practical usefulness (e.g., [1] Moeller et al., 1998) or are usable only for specific applications ([2] Topping and Smith, 2000). The combination of industrial robot arms and mobile platforms is also scarcely possible, since the requirements for fastening, energy supply, computer power and space requirements are mutually incompatible. [3] Onori et al. (2000) describe a hyper-flexible automatic mounting system. The concept provides for the transition from manual to automatic mounting, so that working steps are gradually automated with small flexible units. The coexistence of manual and automatic operation is emphasized here. It is proposed that respective automation systems are built up from different standardized components. It has not been possible to achieve this principle up to now, however, for reasons of standardization procedures. [1] Moeller, R., Lambrinos, D., Pfeifer, R., Wehner, R. (1998): Insect strategies of visual homing in mobile robots. Proc. Computer Vision and Mobile Robotics Workshop, CVMR '98, 3745, FORTH, Heraklion, Greece, 1998. [2] Mike Topping, Jane Smith (2000): Hand 1—A Rehabilitation Robotic System for the Severely Disabled. Proceedings of the 31st International Symposium on Robotics, May 14-17, 2000, Montreal, Canada; pp. 254-257. [3] Onori M., Alsterman, H., Bergdahl, A., Johansson, R. (2000): Hyper Flexible Automatic Assembly, Needs and Possibilities with Standards Assembly Solutions. Proceedings of the 31st International Symposium on Robotics, May 14-17, 2000, Montreal, Canada; pp. 265-270. In U.S. Pat. No. 4,641,251, a mechanism is described for protection from unforeseen obstacles. An auxiliary control system is used for this purpose and registers arm sensors and movements which deviate from the programmed movements or from expected sensor signals. The system can be used against various kinds of damage. According to EP 0616874, a flexible robot arm is known, which is designed for a portable robot with movements up/down and also in two mutually perpendicular horizontal directions. This arm is designed for a mobile platform. This robot is designed for great loads of a specific region of industry. Its weight and the lack of multifarious use are disadvantages. According to U.S. Pat. No. 4,986,723, an anthropomorphic robot arm is known, with hand, wrist joint, and arm. The hand contains a baseplate, plural flexible fingers each with plural joints, and an opposed thumb which can rotate in one direction. Actuators within the arm drive each degree of freedom independently, so that the same movements are possible as in a human arm. Furthermore, in U.S. Pat. No. 4,737,697, a teaching method for industrial robots is described. A position encoder generates a signal which indicates the present position of the arm, against which a manually controlled positioning system stores the positions to be assumed. A servo-control system responds to the signals, so that the present position of the arm travels to the desired position during the playback. The arm can be moved manually to the desired position during the training. According to CN 1,225,523, a miniature robot for medical applications is known. This shows the great advances in miniaturization of robots, and how these can be constructed so that the potential for damage caused by robots remains minimal. Disadvantages of these systems are that: (a) the cooperation of humans and robots for performance of a task still functions very poorly, for reciprocal safety reasons, (b) mounting of bending-arm robots, which take over industrial handling tasks, is too difficult on medium size through small movable systems, (c) the power electronics is installed in a separate box, which itself limits mobile use due to its large dimensions and its weight, (d) the robots execute computing power at a central unit, and therefore no “local intelligence” is present in the region of the actuators and sensors, and unnecessarily large cabling is thus required and the possibilities of learning ability of the robots are limited, (e) no bending-arm robot is available which fulfills both industrial requirements and also can be used in a simple manner for tasks in the home region and also in the service sector, (f) the working means of the robots do not possess a sensory system which permits the execution of a task under different situations and conditions, and (g) the ratio of weight to maximum useful load is too high. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention has as its object to propose a bending-arm robot in which the power electronics is fully integrated, which has a low weight and an internal, locally distributed computer power, and which possesses learning ability with the use of external computer power, so that the above disadvantages are removed. According to the invention, this object is attained with a bending-arm robot according to the wording of claim 1 . |
Methods for high throughput genome analysis using restriction site tagged microarrays |
A method for high-throughput analysis of genomic material originating from complex biological systems, including complex microbial systems and a method of detecting changes in a genomic material using restriction site tagged (RST) microarrays and sequence passporting technique (in particular microarrays containing NotI-clones). Using the present invention method, methylation or silencing of specific alleles, homozygous and hemizygous deletions, epigenetic factors, genetic predisposition, etc, information which is particularly useful in diagnosis and treatment of cancer diseases, can be detected. The RST microarrays and passporting can also be used for qualitative and quantitative analysis of complex microbial systems. |
1. Method for preparing nucleic acid or and/or modified nucleic acid reference material bound to a solid phase, comprising steps of: digesting nucleic acid and/or modified nucleic acid reference material using biochemical and/or chemical approaches, to obtain sequence fragments surrounding a specific restriction enzyme recognition site, selecting said nucleic acid and/or modified nucleic acid sequence fragments flanking a specific restriction enzyme recognition site. 2. Method according to claim 1, wherein said reference material is digested by a first restriction enzyme and/or one or more second restriction enzymes. 3. Method according to claim 2, wherein the restriction enzymes are endonucleases. 4. Method according to claim 3, wherein the recognition sites of the first endonuclease is scarcely distributed along said genomic material and is located adjacent to gene sequences, and the recognition sites of said one or more second restriction endonucleases are more frequently occurring along said genomic material than the sites of the first endonuclease. 5. Method of claim 4, wherein the digestion by the first and second restriction endonucleases are performed simultaneously, and different linkers are ligated to the ends resulting from cutting by the first and second restriction endonucleases, respectively, which linkers are designed such that when primers are added in order to make PCR reactions, only the fragments containing ends resulting from cutting by the first restriction endonuclease will be amplified. 6. Method of claim 4, wherein the reference material is first digested by the one or more second restriction endonucleases, the ends of the thus obtained fragments are self-ligated into the form of circular nucleic acid and/or modified nucleic acid molecules, and any linear fragments remaining after self-ligation are inactivated before digestion with the first restriction endonuclease, whereby the linear fragments resulting from the digestion by the first endonuclease are subjected to PCR amplification. 7. Method of claim 2, wherein the first restriction endonuclease in NotI, or any other restriction endonuclease, the restriction sites of which occurs in proximity to CpG islands in the genomic material. 8. Method of claim 2, wherein the first restriction endonuclease is NotI, PmeI or Sbfl, or a combination of two or more of said endonucleases, and the second endonuclease is BamHI, BclI, BglII or Sau3A, or a combination of two or more of said endonucleases. 9. Method according to claim 1, wherein said nucleic acid and/or modified nucleic acid reference material is selected from RNA, DAN, peptides or modified oligonucleotides, or a combination of two or more of said materials. 10. Method according to claim 1, wherein the solid phase is a glass slide, coded beads, cellulose, such as nitrocellulose, or filters. 11. Method of claim 1, wherein the genomic material is derived from one or more humans, from different locations in the body/bodies and at the same or different points in time. 12. Method of claim 1, wherein the genomic material is derived from bacteria from the gut, skin or other parts of the human body. 13. Method of claim 1, wherein the genomic material is derived from any organism, bacteria, animal, or plant, or product produced there from, or from any substance wherein genomic material can be contained, especially air and water. 14. Use of representation of the genome, or of a part thereof, of an organism, comprising multiple copies of the nucleic acid and/or modified nucleic acid fragments, or a selection thereof, obtained by means of the method of claim 1 in discriminating between different genomes, detecting methylations, deletions, mutations and other changes within genomic material obtained from the same individual at different points of time, or in the genomic material obtained from one individual as compared to a standard representation obtained from at least one other individual, or a combination thereof. 15. Use of the representation according to claim 14, wherein the representation in liquid form is hybridized to the nucleic acid and/or modified nucleic acid fragments present in the form of said solid phases. 16. Use of the representation of the genome, or of a part thereof, of an organism, comprising multiple copies of the nucleic acid and/or modified nucleic acid fragments, or a selection thereof, obtained by means of the method of claim 1 for: studying methylation and copy number changes in eukaryotic genomes for diagnosis, prognosis, identification of cancer causing genes, etc, genotyping different microorganisms (viruses, prokaryotic, eukaryotic), studying biocomplexity and diversity of complex biological systems, i.e. human gut, bacterial flora in water, food, air resources, identifying pathogenic organisms in different sources including complex biological mixtures, producing passports (images of microarrays hybridizations, database containing tag sequences) for different purposes: to describe organisms at different conditions, i.e. different ages, disease/healthy, infected/uninfected etc, identifying new organisms, e.g. bacterial species, producing microarrays (DNA-and oligo-based) to study all above described features, verification and maintenance of large biological collections/banks, i.e. verifying cell lines and individual organisms for higher organisms and confirming the purity of the particular strain for microbial species, producing kits for labeling and hybridization with microarrays, producing kits for making sequence tagging (passporting), and producing oligo microarrays to analyze sequence tags. 17. Use of the representation according to claim 16, wherein the representation in liquid form is hybridized to the nucleic acid and/or modified nucleic acid fragments present in the form of said solid phases. 18. NotI genomic subtraction method for cloning deleted sequences (CODE-genomic subtraction method) based on the use of fragments obtained by the method for preparing nucleic acid or and/or modified nucleic acid reference material bound to a solid phase, comprising the steps of digesting nucleic acid and/or modified nucleic acid reference material using biochemical and/or chemical approaches, to obtain sequence fragments surrounding a specific restriction enzyme recognition site, selecting said nucleic acid and/or modified nucleic acid sequence fragments flanking a specific restriction enzyme recognition site. 19-20. (canceled) |
<SOH> BACKGROUND OF THE INVENTION <EOH>Genomic subtractive methods in principle are very useful for identification of disease genes including tumour suppressor genes. However, among many suggested techniques only a modified variant of genomic subtraction called Representational Difference Analysis (RDA, Lisitsyn et al., 1993) and RFLP subtraction (Restriction Fragment Length Polymorphism)(Rosenberg et al., 1994) have been reproducibly succesful in cloning deleted sequences. Three main drawbacks limited wide use of these related methods: both are very complicated and laborious, they are very sensitive to minor impurities and experiments result in cloning only a few deleted sequences. It is important to note that these methods only work well with enzymes not being associated with CpG islands. Methylation-sensitive-representational analysis (MS-RDA, Ushijima et al., 1997) has more specific aims, i.e. they work with CpG Islands, but still is not avoided limitations of the original RDA. Moreover, differentially cloned products usually do not have any connections with genes. Deletions of non-functional regions occur frequently in the human genome and cloning of such segments will not yield valuable information (Lisitsyn et al., 1995). RDA is also unable to detect differences due to point mutations, small deletions or insertions, unless they affect a particular restriction enzyme recognition site. Another source of artefacts is the PCR amplification after the first hybridization step and before the nuclease treatment. The presence of excess driver DNA can result in a reduced efficiency of the amplification tester:tester duplexes due to the opportunity for the residual driver:driver and driver:tester duplexes to act as competitors. As RDA is based mainly on specific PCR amplification of desired products and use many cycles (95-110), it suffers from a “plateau effect” that is characterised by a decline in the exponential rate of accumulation of amplification products (Innins and Gelfand, 1990). However, the major problem results from the inefficiency of the multiple restriction digestion and ligation reactions that are used in this method and leads to the generation of false positives. The presence of genetic alterations in tumours is now widely accepted, and explains the irreversible nature of tumours. However, observations on tissue differentiation indicated that it shares something in common with carcinogenesis, i.e. “epigenetic” changes. Now, DNA methylation in CpG sites is known to be precisely regulated in tissue differentiation, and is supposed to be playing a key role in the control of gene expression in mammalian cells. The enzyme involved in this process is DNA methyltransferase, which catalyzes the transfer of a methyl group from S-adenosyl-methionine to cytosine residues to form 5-methylcytosine, a modified base that is found mostly at CpG sites in the genome. The presence of methylated CpG islands in the promoter region of genes can suppress their expression. This process may be due to the presence of 5-methylcytosine that apparently interferes with the binding of transcription factors or other DNA-binding proteins to block transcription. DNA methylation is connected to histone deacetylation and chromatin structure, and regulatory enzymes of DNA methylation are being cloned. In different types of tumours, aberrant or accidental methylation of CpG islands in the promoter region has been observed for many cancer-related genes resulting in the silencing of their expression. The genes involved include tumour suppressor genes, genes that suppress metastasis and angiogenesis, and genes that repair DNA, suggesting that epigenetics plays an important role in tumourigenesis. The potent and specific inhibitor of DNA methylation, 5-aza-2-deoxycytidine (5-AZA-CdR) has been demonstrated to reactivate the expression of most of these malignant suppressor genes in human tumour cell lines. These genes may be interesting targets for chemotherapy with inhibitors of DNA methylation in patients with cancer, and may help to clarify the importance of this epigenetic mechanism in tumourigenesis. Spontaneous regression of malignant tumours used to enchant researchers, but it has now been observed that genes inactivated by hypermethylation are frequently involved in tumours that relatively often undergo spontaneous regression. Carcinogenic mechanisms of some carcinogens seem to involve modifications of an epigenetic switch, and some dietary factors also have the possibility to modify the switches. Review articles in the literature make it clear that methylation is a basic, vital feature/mechanism in mammalian cells. It is involved in hereditary and somatic cancers, hereditary and somatic diseases, apoptosis, replication, recombination, temperature control, immune response, mutation rate (i.e. in p53). Through methylation food can induce cancer, etc., it is believed that it can be used for diagnostic, prognostic, prediction and even for direct treatment of cancer. Inactivation of DNA methyltransferase is lethal for mice. Based on the growing understanding of the roles of DNA methylation, several new methodologies have been developed to make a genome-wide search for changes in DNA methylation. There are four main genome-wide screening methods (see Sugimura T, Ushijima T, 2000) for testing methylation in human genome: restriction landmark genomic scanning (RLGS, Costello et al., 2000), methylation-sensitive-representational difference analysis (MS-RDA), methylation-specific AP-PCR (MS-AP-PCR) and methyl-CpG binding domain column/segregation of partly melted molecules (MBD/SPM). Although each of them has their own advantages, none of them is suited for large-scale screening since all four are rather inefficient and complicated; they can be used only for testing a few samples. For example, after analysis of 1000 clones isolated using MBD/SPM, nine DNA fragments were identified as CpG islands and only one was specifically methylated in tumour DNA. Recently developed microarrays of immobilized DNA open new possibilities in molecular biology. These DNA arrays, containing either cDNA or genomic DNA, are fabricated by high speed robotics on glass substrates. Probes that are labeled by different colors are hybridized. In one such hybridization thousands of genes or genomic DNA fragments can be analyzed allowing massive parallel gene expression and gene discovery studies. In pilot experiments microarrays with immobilized P1 and BAC clones DNA demonstrated that they could be used for high resolution analysis of DNA copy number variation using CGH (comparative genome hybridization). It has been suggested that this approach can work if inserts of human DNA in the cloning vectors are larger than 50 kb. In the future, when microarrays with P1 and BAC clones covering the whole human genome will be created, this approach will most likely replace coventional CGH. Clearly, construction of such microarrays with mapped P1 and BAC clones is very expensive, laborious and time consuming. Construction of such microarrays cannot be achieved in a single research laboratory. If small-insert NotI liking clones could full the same function this will open the way to construct such microarrays for CGH analysis for a single research group and for many organisms. PACs and BACs covering the whole human genome are not available yet. Pollack et al., 1999 suggested to use cDNA microarrays for genomic DNA copy number changes but small size of cDNA clones and high ratio of background hybridization compared to real signal makes this suggestion problematic. In the fall 2000 Affymetrix launched the selling of GeneChipHuSNP Mapping Assay. These microarrays contain 1.494 SNP loci. In the promotion papers it was shown that this microarrays can be used for the detection of loss of heterozygosity (LOH). However 13% of SNPs failed in the majority of samples whereas only 354 SNPs were informative in one particular experiment. Lucito et al. (2000) used for the detecting copy number fluctuations in tumour cells modification of RDA technology. In this method BglII representations were used in conjunction with DNA microarrays. As there are many small BglII clones in the human genome (150.000) it will be not easy and cheap to make comprehensive microarrays with unique clones covering the whole human genome. Presently, there are some methods available to analyze complex microbial mixtures, e.g. by enzyme analysis (Katouli et al., 1994) which requires growth of colonies outside the body, or analysis of the composition fatty acids in stools which gives crude indications of the composition of the normal flora (refs.), however all them have obvious limitations. The application of culture-independent techniques based on molecular biology methods that can overcome some shortcomings of conventional cultivation methods. In recent years the approaches based on PCR amplification of 16S rRNA genes have been most popular. One modification of the approach utilized fingerprinting of all the species in the gut using, for instance, denaturing gradient gel electrophoresis (DGGE) with PCR amplified fragments of 16S rRNA genes. In another application, PCR amplified fragments of 16S rRNA genes were directly cloned and sequenced. These studies yielded important information however intrinsic disadvantage of the approach limits its application. The problem is that 16S rRNA genes are highly conserved and therefore the same sequenced fragment can belong to different species. It is also important to keep in mind that in fingerprinting experiments similar fragments can represent different species, and different fragments can represent the same species. |
<SOH> SUMMARY OF THE INVENTION <EOH>In view of the drawbacks associated with the prior art methods for analysis of genomic material originating from complex biological systems, there is a need for uncomplicated, quick and reliable genome analysis methods. Therefore, the object of the present invention is to provide novel and unique techniques for analysis of genomic material originating from complex biological systems, including complex microbial systems. The main objects of the present invention are the following: One object of the present invention is to prepare and to use NotI-clone (in general PCR fragments, oligonucleotides, etc.) microarrays for studying methylation and/or copy number changes in eukaryotic genomes for diagnosis, prognosis, identification of cancer causing genes. NotI microarrays are the only existing microarrays giving the opportunity to detect copy number changes and methylation simultaneously. This includes comparison of normal and malignant cells at genomic and/or RNA level; comparison of primary tumours and metastases; analysis of families suffering from hereditary diseases including cancers; and diagnostics and disease prediction. Capability to establish differences between normal and tumour cells is instrumental for cloning cancer causing genes and for early diagnosis and prevention of cancer. It is also very important for differentiation, development and evolution studies. Another object of the present invention is to provide techniques allowing qualititative and quantitative analysis of complex microbial systems, such as the normal flora of the gut. A further object of the present invention is to prepare NotI sequencing passports (“NotI passport”) (collection of NotI tags: short sequences surrounding genomic NotI sites) and to use them to study the same problems as were mentioned above for NotI microarrays. Wide screening of genomic material using RST encounter many problems, e.g. the size of the human genome/microbial mture and the number of repeat sequences. We have solved these problems by developing a new method for labeling genomic DNA, where only sequences surrounding NotI (or any other restriction) sites are labeled (tagged), herein called NotI Representation (NR). In the present invention, Restriction Site Tags (RSTs) are generated from thousands of microorganisms or human genomes and used for the generation of NotI RST microarrays passports which describe uniquely not only individual human cell/organism or bacterial strains but most or all the members of a microbial flora of e.g. in the gut. With the NotI or RST genome scanning method according to the present invention, large scale scanning of microbial genomes on a quantitative and qualitative basis is possible. From the results of our experiments, we have shown that it is possible to create a large database containing NotI microarrays passports, i.e. NotI microarray images. Many samples of colon flora have been compared to determine their exact composition. The present invention procedure is universal, i.e. we can use any other enzyme for creating “RST microarray passports”. Moreover, any biochemical or chemical approach cutting DNA (RNA) in a specific position scarcely distributed along DNA (RNA) can be used. For example, it can be enzyme like cre-recombinase or chemically modified oligonucleotide forming triplex DNA and initiating DNA break. The polymorphism of NotI representations can be increased by using several enzymes in addition to BamHI, e.g. BclI, BglII, HindIII etc. In pilot experiments we have produced NotI microarrays from gram-positive and gram-negative bacteria and have shown that even very similar E. coli strains can be easily discriminated using this technique. Using the above mentioned technique we can identify important pathogenic bacteria in the human organism. These ‘NotI microarrays passports’ can be produced for individuals, normal/tumour pairs, different cell NotI Representation (NR). A pilot experiment using NR probes demonstrated the power of the method, and we successfully detected Chr.3 NotI clones deleted in ACC-LC5 and MCH939.2 cell lines. Such NotI RST microarrays can be prepared for any human or any groups of humans, who for example suffer from the same specific disease, in order to detect a certain disease which cannot be detected by other means. NotI RST microarrays can also be prepared for any mammal (like cattles or dogs) or microbial organism. NotI arrays will speed up cancer research very significantly and can replace CGH, LOH and many cytogenetic studies. The NotI scanning approach will find mainly deleted, amplified, or methylated genes but it will also identify polymorphic and mutated NotI sites. Comparing these NotI passports can give a clue to understanding many diseases and other fundamental biological processes. Using the present invention method of producing RST microarrays, restriction enzyme tagged (RST) microarrays for any enzyme can be created. The microarrays according to the present invention represent a novel type of microarrays, which is completely different from the existing ones (oligonucleotides, cDNA, genomic BAC/PAC clones). To be able to establish differences between individual compositions of the normal gut flora will be instrumental for future analysis of how the normal flora composition is influenced by diet, special foods, geographical location, colon, ovarian, etc. cancers and other diseases. It has particularly wide applications for cancer research. The present invention method will probably have strong impact both on basic science and on human and animal health, agriculture, medicine, pharmacology, etc. We propose to use our NotI clones as a complement to microarrays based on P1 and BAC clones covering the whole human genome. Microarrays based on small-insert NotI linking clones have been developed, and can have a similar function. Approximately 10.000-20.000 NotI clones, covering the whole human genome and containing 10%-20% of all genes (40%-50% of them are not present in ESTs microarrays) are already available. In order to achieve what is described above, the present invention comprises the following embodiments: In one embodiment of the present invention provides a method for preparing nucleic acid or and/or modified nucleic acid reference material bound to a solid phase, comprising the steps of digesting nucleic acid and/or modified nucleic acid reference material using biochemical and/or chemical approaches, to obtain sequence fragments surrounding a specific recognition site, selecting said nucleic acid and/or modified nucleic acid sequence fragments associated with a specific recognition site. Said reference material is digested by a first restriction enzyme and/or one or more second restriction enzymes, e.g. endonucleases, such as cre-recombinase, In one embodiment of the present invention the recognition sites of the first endonuclease is scarcely distributed along said genomic material and is located adjacent to gene sequences, and the recognition sites of said one or more second restriction endonucleases are more frequently occurring along said genomic material than the sites of the first endonuclease. In another embodiment of the present invention the digestion by the first and second restriction endonucleases are performed simultaneously, and different linkers are ligated to the ends resulting from cutting by the first and second restriction endonucleases, respectively, which linkers are designed such that when primers are added in order to make PCR reactions, only the fragments containing ends resulting from cutting by the first restriction endonuclease will be amplified. In still another embodiment of the present invention the reference material is first digested by the one or more second restriction endonucleases, the ends of the thus obtained fragments are self-ligated into the form of circular nucleic acid and/or modified nucleic acid molecules, and any linear fragments remaining after self-ligation are inactivated before digestion with the first restriction endonuclease, whereby the linear fragments resulting from the digestion by the first endonuclease are subjected to PCR amplification. In these embodiments the first restriction endonuclease is NotI, or any other restriction endonuclease, the restriction sites of which occurs in proximity to CpG islands in the genomic material. The first restriction endonuclease can also be NotI, PmeI or SbfI, or a combination of two or more of said endonucleases, and the second endonuclease can be BamHI, BclI, BglII or Sau3A, or a combination of two or more of said endonucleases. Said nucleic acid and/or modified nucleic acid reference material can be selected from RNA, DNA, peptides or modified oligonucleotides, or a combination of two or more of said materials. In the present invention nucleic acid and/or modified nucleic acid is bound to a solid glass support in the form of a microarray. However, the present invention is not limited to using glass microarrays. Solid phases such as filters, e.g. nylon filters, coded beads, cellulose, such as nitrocellulose, or other solid supports can also be used to bind nucleic acid and/or modified nucleic acid. In general DNA, oligonucleotides, etc. bound to a solid phase can be used. The genomic material that can be used according to the present invention can be derived from one or more humans, from different locations in the body/bodies and at the same or different points in time. Said genomic material can be derived from bacteria from the gut, skin or other parts of the human body. However, it can also be derived from any organism, bacteria, animal, or plant, or product produced therefrom, or from any substance wherein genomic material can be contained, especially air and water. The present invention also pertains to the fragments that can be obtained using the present invention, and the nucleic acid or and/or modified nucleic acid microarrays containing these fragments. The present invention further pertains to representations of the genome, or of a part thereof, of an organism, comprising multiple copies of the nucleic acid and/or modified nucleic acid fragments, or a selection thereof, obtained by means of the present invention method. These representations, in liquid form, are hybridized to the nucleic acid and/or modified nucleic acid fragments present in the form of said solid phases. Said representations can be used for discriminating between different genomes, detecting methylations, deletions, mutations and other changes within genomic material obtained from the same individual at different points of time, or in the genomic material obtained from one individual as compared to a standard representation obtained from at least one other individual, or a combination thereof. In addition to the above-mentioned applications, these representations can be used for: studying methylation and copy number changes in eukaryotic genomes for diagnosis, prognosis, identification of cancer causing genes, etc, genotyping different microorganisms (viruses, prokaryotic, eukaryotic), studying biocomplexity and diversity of complex biological systems, i.e. human gut, bacterial flora in water, food, air resources, identifying pathogenic organisms in different sources including complex biological mixtures, producing passports (images of microarrays hybridizations, databases containing tag sequences) for different purposes: to describe organisms at different conditions, i.e. different ages, disease/healthy, infected/uninfected etc, identifying new organisms, e.g. bacterial species, producing microarrays (DNA- and oligo-based) to study all above described features, verification and maintenance of large biological collection/banks, i.e. verifying cell lines and individual organisms for higher organisms and confirming the purity of the particular strain for microbial species, producing kits for labeling and hybridization with microarrays, producing kits for making sequence tagging (passporting), and producing oligo microarrays to analyze sequence tags, Finally, the present invention also pertains to a NotI CODE genomic subtraction method based on the use of the above described fragments. |
Fitting for connecting two components |
A fitment comprised of two plate-shaped fitment halves (1a, 1b) for the joining of two structural parts (2a, 2b), which are screwed together with the opposite and equally engaging fitment halves (1a, 1b). By a longitudinal movement of the structural parts (2a, 2b) relative to one another, a retaining flap (7) held with a fastening screw (9) in a first holding recess (8) in fitment half (1b) folds around in the transverse axis and encloses with a second holding recess (10) a head (13) of a fastening screw (14) rigidly joining the other fitment half (1a). This reliably prevents a loosening of the joining in all directions. |
1. A fitment comprised of two fitment halves for the form-fitting joining of two structural parts, wherein one of the fitment halves is attached to one of the structural parts and has elements that can be engaged with one another and that effect the joining of structural parts, is hereby characterized in that fitment halves are configured in plate shape, have one end segment with an attachment hole, and this end segment is bent back around an angle of 180° and is longitudinally slotted, have another cropped end segment with a longitudinal slot, wherein a recess is provided at each slot end for the uptake of a screw head, at least one other fastening hole is provided between end segments, a plate-shaped retaining flap is arranged in the inside space created by the bend of end segment of fitment half, and this flap has the following features: a first holding recess, in order to hold retaining flap in bend space by means of a fastening screw, a second holding recess and a swivel-point support arranged between the first and the second holding recess, whereby the retaining flap is dimensioned such that upon introducing the cropped end segment of the other fitment half into the bend space of fitment half, the retaining flap is tilted in the direction of the arrow and thus the second holding recess encloses the head of a fastening screw, which fastens the other fitment half, and this screw is arranged in fastening hole. 2. The fitment according to claim 1, further characterized in that parallelly aligned chamfers, which facilitate the coupling together when the fitment halves are oppositely and equally engaged with one another, are formed at the end segments of the fitment half, whereby the chamfers point to the fastening side of the fitment half. 3. The fitment according to claim 1 or 2, further characterized in that the retaining flap is a permanent magnet. |
Use of hypoxia inducible factor 2alpha for curing neonatal respiratory distress syndrome and as a target for the treatment of pulmonary hypertension |
The current invention relates to the field of hypoxia-induced disorders and more specifically to the use of hypoxia inducible factor 2aα as a target in a method for the screening for molecules that can be used for the treatment of pulmonary hypertension. The invention further relates to the use of HIF-2α and/or of the HIF-2aα inducible protein VEGF for the treatment of neonatal respiratory distress syndrome. |
1. A method of using hypoxia inducible factor 2α (HIF-2α) or fragments thereof as a target to screen for molecules that are able to inhibit the development of pulmonary hypertension wherein said method comprises the following steps: incubating a mixture comprising HIF-2α or a fragment thereof and at least one molecule, allowing binding between HIF-2α or a fragment thereof and said molecule, isolating said molecule binding to HIF-2α, or a fragment thereof and determining the ability of said molecule to inhibit the development of pulmonary hypertension. 2. A method of using HIF-2α or fragments thereof to screen for molecules that are able to inhibit the development of pulmonary hypertension wherein said method comprises the following steps: incubating a mixture comprising HIF-2α or a fragment thereof, a reporter construct wherein the reporter gene is driven by HIF-2α, and at least one molecule, determining if the latter incubation results in at least 50% reduction in expression of said reporter gene, and determining the ability of said molecule to inhibit the development of pulmonary hypertension. 3. A method for the production of a pharmaceutical composition comprising the usage of HIF-2α or a fragment thereof according to claim 1 and further comprising mixing said molecule identified, or a derivative or homologue thereof, with a pharmaceutically acceptable carrier. 4. A method of using HIF-2α or a fragment or homologue thereof for the manufacture of a medicament to treat neonatal respiratory distress syndrome. 5. A method of using VEGF or a fragment or homologue thereof for the manufacture of a medicament to treat neonatal respiratory distress syndrome. 6. A method for the production of a pharmaceutical composition comprising the usage of HIF-2α or a fragment thereof according to claim 2 and further comprising mixing said molecule identified, or a derivative or homologue thereof, with a pharmaceutically acceptable carrier. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Preterm delivery is the chief problem in obstetrics today, affecting 10% of all births 1 . It accounts for more than 70% of perinatal mortality and nearly half of long-term neurological morbidity, especially in infants who are born at less than 32 weeks of gestation and weigh less than 1,000 g. With ˜60% of these newborns developing respiratory distress syndrome (RDS) and a 50% lethality, RDS is the leading cause of neonatal mortality 2 . RDS results from insufficient production of surfactant by immature type 2 pneumocytes in preterm infants, but can also result from dysfunction or deficiency of surfactant in term infants due to inherited mutations, meconium aspiration, hemorrhage, infections and others 3 . Surfactant is a mixture of phospholipids and surfactant-associated proteins (SP-A to SP-D), which lowers surface tension at the air-water interface and thereby prevents alveolar collapse and respiratory failure. Surfactant phospholipids are synthetized from substrates, provided by glycogen stores in fetal immature pneumocytes 4 . Neonatal intensive care has improved the survival of infants with RDS, but often at the expense of the development of bronchopulmonary dysplasia or chronic lung disease of prematurity 5 . Treatment with oxygen may irreversibly damage lung parenchyma and angiogenesis, while prenatal steroid treatment causes neurological, metabolic, cardiovascular and hormonal side-effects, and impairs growth 6 . Surfactant treatment is effective, but expensive and only symptomatic 7 . Interactions between branching airways and blood vessels are critical for normal lung development 8 , A major factor in lung vascular development is vascular endothelial growth factor (VEGF), which binds its receptors Flk-1 (VEGF-R2) and Flt-1 (VEGF-R1) 9 . Three VEGF-isoforms exist: a diffusable VEGF 120 , a matrix-bound VEGF 188 and VEGF 164 , which can bind matrix and is still diffusable. VEGF is deposited at the leading edge of branching airways, where it stimulates vascularization 10 . Indirect evidence suggests, however, that VEGF also affects epithelial growth and differentiation. Type 2 pneumocytes and bronchiolar epithelial cell produce VEGF and possess VEGF receptors 11,12 VEGF levels are also considerably higher in the bronchoalveolar fluid than in the blood 12 , suggesting that epithelial cells affect their own function by releasing VEGF into the airway lumen. Remarkably, the lung is one of the few organs where VEGF levels remain elevated in the adult, even though no active angiogenesis occurs. Previous studies provided circumstantial evidence for a role of VEGF in lung development, but did not provide functional in vivo proof for a role of VEGF in lung maturation and surfactant production. For instance, VEGF levels in tracheal aspirate were lower in infants with lung immaturity developing bronchopulmonary dysplasia than in those surviving without pulmonary complications in some 13 -15 but not in other studies 16 . Exogenous VEGF stimulates growth of epithelial cells in early embryonic lung explants in vitro 17 , but the relevance of endogenous VEGF for lung maturation just prior to birth in vivo and the possible therapeutic potential of VEGF in preventing RDS in preterm infants remain unknown. In the present invention we show that loss of HIF-2α causes fatal RDS in newborn due to insufficient surfactant production. We show that VEGF plays an important role in lung maturation since VEGF levels are reduced in HIF-2α deficient mice, neonates expressing only the VEGF 120 isoform or with impaired HIF-2α-dependent VEGF expression die of RDS, and intra-amniotic administration of anti-Flk-1 antibodies aggravated lung prematurity. Importantly, intra-uterine delivery of VEGF before birth or intra-tracheal injection of VEGF after birth stimulates conversion of glycogen to surfactant, improved lung function and prevented RDS in premature. In summary, one aspect of the invention shows the use of VEGF for the manufacture of a medicament to treat RDS in premature infants. A second aspect of the invention deals with the manufacture of a medicament to treat and/or to prevent pulmonary hypertension. Hypoxia causes proliferation of pulmonary vascular cells, in contrast with the usual growth-suppressive effect of hypoxia on most other cell types. Chronic hypoxic conditions are known to induce pulmonary vascular remodeling and subsequent pulmonary hypertension and right ventricular hypertrophy, thereby constituting a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). Although several molecules such as endothelin-1 and platelet derived growth factor (PDGF) are believed to play an important role during pulmonary hypertension, the precise molecular mechanisms of this process are still elusive. It has been shown that the transcription factor HIF-1α is involved in the physiological response to chronic hypoxia. Heterozygous HIF-1α +/− mice showed delayed polycythemia and right ventricular hypertrophy and impaired pulmonary hypertension and vascular remodeling after exposure to chronic hypoxia, indicating a significant role for HIF-1α in the development of pulmonary hypertension. HIF-1α was originally cloned as a basic helix-loop-helix transcription factor, mediating the cellular adaptation to hypoxia. During hypoxia HIF-1α upregulates the expression of a number of genes involved in erythropoiesis, glycolysis and angiogenesis by formation of a heterodimer with HIF-1β (also termed aryl hydrocarbon receptor nuclear translocator; ARNT), which binds to a hypoxia-response element (HRE) in the promoter of these target genes. In addition, HIF-1α has also been implicated in the induction of apoptosis in hypoxic and hypoglycaemic conditions. Recently, a novel hypoxia-inducible factor, HIF-2α (also known as EPAS-1, HLF, HRF or MOP2) was identified, which is also able to bind to hypoxia-response elements after heterodimerization with HIF-1β. Although HIF-2α is a homologue of HIF-1α, the role of HIF-2α in glycolytic, angiogenic, apoptotic or possible disease processes is unknown and unpredictable. In the present invention, we have examined the endogenous role of HIF-2α by targeted gene-inactivation in murine embryonic stem (ES) cells. It has been found that HIF-2α is a new therapeutic target for the treatment of pulmonary hypertension. |
Device for applying a product |
The present invention relates to a device for applying a substance, in particular a cosmetic. The device comprising a support, a compressible applicator member mounted securely to a face of the support, and having a peripheral edge with at least a portion thereof situated at a distance from the face of the support, the applicator member being fastened to the support by a fastening zone that extends at a distance from a peripheral edge of the face of the support. |
1. A device for applying a substance, in particular a cosmetic, the device comprising: a support having a face and a fastening zone; and a compressible applicator member mounted in a fixed manner on said face of said support and having a peripheral edge, at least a portion of said peripheral edge being situated at distance from said face, said applicator member being fastened to said support via said fastening zone that extends at a distance from a peripheral edge of said face. 2. A device for applying a substance, in particular a cosmetic, the device comprising: a support having a face and a fastening zone; and a compressible applicator member mounted in a fixed manner on said face of said support and having a peripheral edge, at least a portion of which is situated at a distance from said face, a cross-section of said face being of area greater than or equal to an area defined inside said peripheral edge. 3. A device for applying a substance, in particular a cosmetic, the device comprising: a support presenting a first face having a profile; and a compressible applicator member having a peripheral edge and a second face fastened to said first face, said second face having a profile different from said profile of said first face so that a portion of said peripheral edge of said second face is at a distance from said first face. 4. A device for applying a substance, in particular a cosmetic, the device comprising: a support; and a compressible applicator member having a shape that is generally flat transversely to an axis (X), said applicator member comprising at least a first portion fastened to said support and at least a second portion spaced apart from said support, said second portion co-operating therewith when said applicator member is not compressed to define at least an acute angle in a plane containing said axis (X) and forming an outwardly-open void as partly defined by said support and said applicator member enabling said applicator member to bend towards said support during application. 5. The device according to claim 4, wherein said second portion is suitable for coming to bear at least in part against said support, during application. 6. The device according to claim 4, wherein said applicator member is generally disk-shaped. 7. The device according to any one of claims 4 to 5, wherein said second portion presents a surface facing said support which is outwardly convex. 8. The device according to any one of claims 4 to 5, wherein said void is annular in shape as defined by said applicator member and said support. 9. The device according to claim 4, wherein said first portion is situated substantially in the center of a face of said applicator member located facing said support. 10. The device according to claim 4, wherein said applicator member is fastened in a non-removable manner to said support. 11. The device according to claim 4, wherein said applicator member is fastened to said support in a removable manner. 12. The device according to claim 11, further comprising hooks disposed on said applicator member and loops disposed on said support, or vice versa, wherein said applicator member is fastened to said support by mechanical fastening of said hooks and loops. 13. The device according to claim 4, wherein said applicator member presents an application face that is generally convex. 14. The device according to claim 4, wherein said applicator member presents an application face that is generally concave. 15. The device according to claim 4, wherein said applicator member presents an application face that is substantially plane. 16. The device according to claim 4, wherein said applicator member presents a flocked face that is used for application. 17. The device according to claim 4, wherein said applicator member comprises at least two layers of foam that are assembled together. 18. The device according to claim 17, wherein said applicator member includes at least one interval cavity. 19. The device according to claim 18, wherein said two layers of foam are assembled together so as to form said internal cavity. 20. The device according to claims 17, 18 or 19, wherein said two layers of foam are assembled together by heat-sealing. 21. The device according to claim 17, wherein at least one of said two layers of foam is flocked on the outside. 22. The device according to claim 4, wherein said support comprises a rigid portion having said applicator member fastened thereto. 23. The device according to claim 22, wherein said rigid portion comprises a sintered piece. 24. The device according to claim 4, wherein said support comprises a flexible portion on which said applicator member is fastened. 25. The device according to claim 24, wherein said flexible portion comprises a compressible element. 26. The device according to claim 25, wherein said compressible element comprises at least one layer of foam. 27. The device according to claims 25 or 26, wherein said compressible element is hollowed out internally. 28. The device according to claim 24, wherein said flexible portion includes an elastomer wall. 29. The device according to claim 4, wherein said support presents a substantially plane face having said applicator member fastened thereto. 30. The device according to claim 4, wherein said support presents a generally outwardly convex face having said applicator member fastened thereto. 31. The device according to claim 4, wherein said support comprises a hollow part to which said applicator member is fastened. 32. The device according to claim 4, wherein said applicator member presents a maximum thickness measured along said axis which is no greater than one-third of the greatest dimension of said applicator member measured perpendicularly to said axis. 33. The device according to claim 4, wherein said acute angle is less than or equal to 60°. 34. The device according to claim 4, wherein a maximum distance measured perpendicularly to said axis over which said second portion is cantilevered-out is greater than or equal to one-seventh of the greatest dimension of said applicator member, measured perpendicularly to said axis. 35. The device according to claim 4, wherein said support is shaped to serve as a closure member for closing a receptacle containing the substance. 36. The device according to claim 4, wherein said support includes at least one substance feed orifice. 37. A packaging and applicator device for a substance, in particular a receptacle, the device comprising a receptacle containing said substance and an applicator device as defined by claims 1 to 4. 38. The device according to claim 37, wherein said applicator member is compressed when said receptacle is closed. 39. A device according to claim 37, wherein said applicator device is configured to close said receptacle in substantially a leaktight manner. 40. The device according to claim 37, further comprising a sieve wherein said applicator member comes into contact with said sieve when said receptacle is closed. 41. The device according to claim 37, wherein said applicator device is secured to said receptacle during application. 42. An applicator member comprising at least two layers of foam that are assembled together and flocked on the outside. 43. An applicator member according to claim 42, wherein said two layers of foam are assembled together at their periphery. 44. An applicator member comprising at least two layers of foam assembled together at their periphery and defining between them an air-filled cavity. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The present invention relates to devices for applying a substance, in particular a cosmetic, and more particularly but not exclusively it relates to devices for applying a substance over a large area of the body or the face. Numerous applicator devices comprising a support and an applicator member fixed to the support are known from FR 2 798 646, U.S. Pat. No. 1,172,293, U.S. Pat. No. 5,492,426, and U.S. Pat. No. 5,636,931. In particular, applicator devices are known that comprise an applicator member fixed to a support that also serves as a handle member and as a closure member for a receptacle. In some of those devices, the applicator member is fixed via a plane face to a wall of the support that is likewise plane. In others, the applicator member comprises a layer of foam covering a block of elastomer material. There exists a need in particular to improve application comfort. In a first aspect, the present invention provides a device for applying a substance, in particular a cosmetic, the device comprising: a support; a compressible applicator member mounted in a fixed manner on a face of the support and having a peripheral edge at least a portion of which is situated at a distance from the face, the applicator member being fastened to the support via a fastening zone that extends at a distance from the peripheral edge of the face. In a second aspect, the present invention provides a device for applying a substance, in particular a cosmetic, the device comprising: a support; and a compressible applicator member mounted in fixed manner on a face of the support and having a peripheral edge, at least a portion of which is situated at a distance from the face. A cross-section of the face having an area greater than or equal to the area defined inside the peripheral edge. In a third aspect, the present invention provides a device for applying a substance, in particular a cosmetic, the device comprising: a support presenting a first face; and a compressible applicator member having a second face fastened to the first face, the second face having a profile different from the profile of the first face so that a portion of a peripheral edge of the second face is at a distance from the first face. In a fourth aspect, the present invention provides a device for applying a substance, in particular a cosmetic, the device comprising: a support; and a compressible applicator member having a shape that is generally flat transversely to an axis the applicator member comprising: at least a first portion fastened to the support; and at least a second portion spaced apart from the support, co-operating therewith when the applicator member is not compressed to define at least an acute angle in a plane containing the axis and forming an outwardly-open empty space enabling it to bend towards the support during application. According to a characteristic of the present invention, the angle may be acute and the second portion creates a void defined by the support and the applicator member. The void opens out to the outside and enables the second portion to bend towards the support during application. The possibility of the second portion of the applicator member that is spaced apart from the support bending towards the support during application enables the applicator member to match its shape gently to any change in surface relief during application. This increases the comfort of application. The way in which the product is spread can also be different from that which is obtained with a prior art applicator device that does not have any flexible peripheral lip. The second portion may be suitable for bearing at least in part against the support during application. By way of example, the applicator member may be generally disk-shaped, being circularly symmetrical or otherwise. Facing the support, the second portion may present a surface that is outwardly convex. The applicator member and the support may define an annular void adjacent to the point where they contact one another. The first portion may be situated substantially in the center of a face of the applicator member disposed facing the support. The applicator member may be fixed in a non-removable manner to the support. In a variant, the applicator member may alternatively be fixed in a removable manner to the support. For example, the applicator member may be fixed to the support by mechanical hooking of the Velcro® type such as by hooks and loops. The applicator member may present an application face that is generally convex, generally concave, or indeed substantially plane, for example. The applicator member may have no housing for receiving a supply of substance, and in particular when the applicator member comprises a cellular material, it may have no housing of size greater than that of the cells. The second portion may be more flexible than the support. The applicator member may present a flocked face for application purposes, thereby making it easier to load it with substance and making application softer. The applicator member may comprise at least two layers of foam assembled together. The applicator member may include at least one inside cavity filled with air, giving flexibility to the applicator member. The two above-mentioned layers of foam may be assembled together in such a manner as to form the cavity between them. The two layers of foam may be assembled together by heat-sealing, in particular. At least one of the two layers of foam may be flocked on the outside. Making the applicator member by assembling together layers of foam may serve to give the applicator member a periphery with a rounded shape. It is possible to use layers of foam that are initially plane. The foams used for making the applicator member may be flocked while they are flat, prior to being cut out and assembled together to form the applicator member, thus making it easier to obtain high quality flocking. The support may include a rigid portion on which the applicator member is fixed. This rigid portion may comprise a sintered piece, for example. The support may also include a flexible portion on which the applicator member is fixed. By way of example, the flexible portion may comprise a compressible element which may comprise at least one layer of foam and/or may be internally hollowed out, for example. The flexible portion may also comprise an elastomer wall. The support may present a face on which the applicator member is secured, which face may have various shapes. For example, the support may present a face that is substantially plane, to which the applicator member is secured. The support may also present a face that is generally outwardly convex, to which the applicator member is secured. The support may include a solid or a hollow portion to which the applicator member is secured. The applicator member may present a maximum thickness measured along the axis that is no greater than one-third the greatest dimension of the applicator member measured perpendicularly to the axis. The greatest dimension corresponds, for example, to its greatest diameter if the applicator member is circularly symmetrical. The above-defined acute angle may be less than or equal to 60°, for example. By way of example, the maximum distance over which the second portion can be cantilevered-out and as measured perpendicular to the axis may be greater than or equal to one-seventh or even one-fourth of the greatest dimension of the applicator member as measured perpendicularly to the axis. The support may be configured to serve as a closure member for a receptacle containing the substance, e.g. a substantially leaktight closure member. The support may include at least one substance feed orifice. The present invention may also provide a device for packaging and applying a substance, in particular a cosmetic. The device comprises a receptacle containing the substance together with an applicator device as defined above. The applicator member may optionally be compressed when the receptacle is closed. The applicator device may be configured to close the receptacle in a substantially leaktight manner. The applicator member may come into contact with a sieve when the receptacle is closed. The applicator device may optionally be secured to the receptacle while application is taking place. In another of its aspects, the present invention also provides an applicator member having at least two assembled-together layers of foam, one of the layers optionally being flocked. Both layers may be flocked on the outside. The two layers may be assembled together at their periphery by heat-sealing, in particular. In another of its aspects, the present invention provides an applicator member comprising at least two layers of foam assembled together at their periphery and defining between them a cavity filled with air. In another of its aspects, the present invention provides a device for applying a substance, in particular a cosmetic, the device comprising: a support; a compressible applicator member fastened to the support without being able to retract into the inside thereof, having a general shape that is flattened transversely to an axis. The applicator member comprises: at least a first portion fastened to the support; and at least a second portion outside the first portion and spaced apart from the support. The maximum distance measured perpendicularly to the axis over which the second portion is cantilevered-out may be greater than or equal to one-seventh or even one-fourth of the greatest dimension of the applicator member measured perpendicularly to the axis. In another of its aspects, the present invention may also provide a device for applying a substance, in particular a cosmetic, the device comprising: a support; and a compressible applicator member having an outside surface that is flocked at least in part. The compressible applicator member comprising: at least a first portion fastened to the support; and at least an outer second portion spaced apart from the support and co-operating therewith when the applicator member is not compressed to define an empty space enabling it to bend towards the support during application. In another of its aspects, the present invention may provide a device for applying a substance, in particular a cosmetic, the device comprising: a support; and a compressible applicator member, comprising: at least a first portion fastened to the support; at least an outer second portion spaced apart from the support; and an internal cavity filled with air. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>The present invention can be better understood on reading the following detailed description of non-limiting embodiments of the invention, and on examining the accompanying drawings, in which: FIG. 1 is a diagrammatic axial section view of an embodiment of the device of the present invention; FIG. 2 shows the applicator device of FIG. 1 in isolation; FIG. 3 shows the applicator member deforming while it is in use; FIGS. 4 to 12 show various configurations, amongst others, for the applicator member; FIG. 13 shows the applicator member being fastened in a removable manner; FIGS. 14 to 20 show various configurations, amongst others, for the support; FIGS. 21 and 22 are diagrammatic views of applicator devices comprising superposed flexible disks; FIG. 23 is a fragmentary view of a support comprising superposed compressible elements presenting differing degrees of compressibility; and FIGS. 24 and 25 are fragmentary diagrams of two other embodiments of packaging and applicator devices. detailed-description description="Detailed Description" end="lead"? |
Method for Solid-Phase-Micro Extraction and Apparatus Therefor |
The present invention is directed to a system for pre-treatment of a sample to be introduced in a chromatograph, and a method for performing solid-phase extraction of a component present in a sample. The system uses a syringe having a needle being provided with a porous body having a monolithic structure along at least an appropriate length of the needle and across an overall diameter of the needle. The method includes the steps of inserting the needle into the sample, passing the sample through the needle to retain an analyte within the porous body, and desorbtion of the retained analyte from the porous body. |
1. A method for performing solid-phase-micro extraction of a component present in a sample, which uses a syringe having a cylinder and a plunger slidable within the cylinder, a tip of the syringe being provided with a needle and the needle being provided with a porous body having a monolithic structure along at least a portion of the length of the needle and across an overall diameter of the needle, comprising the steps of inserting the needle into the sample, passing the sample through the needle to retain an analyte within the porous body, and desorbing the retained analyte from the porous body. 2. An apparatus for performing solid-phase-micro extraction of a component present in a sample, comprising a syringe having a cylinder and a plunger slidable within the cylinder, a tip of the syringe being provided with a needle and the needle being provided with a porous body having a monolithic structure along at least a portion of the length of the needle and across an overall diameter of the needle, such that the sample is retained within the porous body when the sample passes through the needle and subsequently desorbed from the porous body. 3. A method for performing solid-phase-micro extraction of a component present in a sample, comprising the steps of providing a syringe having a cylinder and a plunger slidable within the cylinder, a tip of the syringe being provided with a needle and the needle being provided with a porous body structure along at least a portion of the length of the needle and across an overall diameter of the needle, wherein at least a portion of the needle within which the porous body is formed is attachable and detachable from the syringe or the needle, and wherein an analyte is retained within the porous body by passing a sample through the porous body when the sample passes through the needle. 4. An apparatus for performing solid-phase-micro extraction of a component present in a sample, comprising a syringe having a cylinder and a plunger slidable within the cylinder, a tip of the syringe being provided with a needle an the needle being provided with a porous body along at least a portion of the length of the needle and across an overall diameter of the needle, and that the entire needle or at least a portion of the needle within which the porous body is formed is selectively attachable and detachable with respect to the syringe or the needle. 5. A needle for selective attachment and detachment with a syringe or for use with a syringe, comprising a needle body and a porous body having a monolithic structure across at least an overall diameter of an inner diameter of the needle and extending along at least a portion of the length of the needle. 6. The needle according to claim 5, wherein the needle is a sample tip. 7. The needle according to claim 5, wherein an outside of the needle is provided with an outer cylinder. 8. The method for performing solid-phase-micro extraction according to claim 1, wherein the porous body is a single pore. 9. The apparatus for performing solid-phase-micro extraction according to claim 2, wherein the porous body is a single pore. 10. The method for performing solid-phase-micro extraction according to claim 1, wherein the porous body is a double pore. 11. The apparatus for performing solid-phase-micro extraction according to claim 2, wherein the porous body is a double pore. |
<SOH> BACKGROUND ART <EOH>In a chromatographic analysis, it has been said that the time and effort required for the so-called pre-treatment, including sampling, extraction of an analyte, and sample preparation such as concentration represents 80% of the analytical work. Solid-Phase-Micro extraction (SPME) developed by Pawliszyn in 1990 is a method for pre-treating a sample, where such works and introduction into the chromatograph can be simply performed. In the SPME method, a fiber whose surface is coated with a liquid phase is exposed to a headspace or a solution of the sample in order to perform extraction, and an analyte extracted into the fiber liquid phase is thermally desorbed at a injection port during GC and is introduced to the GC (Japanese Patent Laid-Open No. 5-506715). In addition, an In-tube SPME method in which a capillary column of GC is used for an adsorption mechanism (Hiroyuki Katayama, Shizuo Narimatsu, Heather L Lord, J. Pawliszyn Chromatography 20 (1999) 237-249) has been used recently. In this method, a sample is made to flow into the capillary column and a liquid phase in the column is allowed to retain the analyte, then the solvent is made to flow therethrough for desorbing the analyte by the use of the solvent. On the other hand, another method has been suggested in which a syringe is used and an analyte is retained by a hollow needle having a stationary phase being fixed on an inner surface of the hollow needle, then the analyte is desorbed by making a solvent flow through the needle or by heating the needle (Japanese Patent Laid-Open No. 8-94597). Conventionally, when the analyte is concentrated, a column whose cylindrical body is packed with a bead-like inorganic filler has been generally used. In the former technique, a sample retention capacity is generally increased by making a thickness of the fiber liquid layer larger, in order to increase a sample capacity. However, there is a problem that the time required for equilibrating the analyte with the liquid phase becomes longer as the film thickness is increased. As for extraction of an agricultural chemical dissolved in water which is performed by actually using a liquid phase having a thickness of 100 μm, it has been frequently reported that the time required for reaching an equilibrium was 15 to 60 minutes or more (J. Beltram, F. J. L pez. F. Hern ndez Journal of Chrmatography A. 885 (2000) 389-404). Although the equilibration time has been reduced by stirring the sample and by shaking the syringe or heating the sample for example in order to reduce the equilibration time, substantial reduction in the equilibration time has not been achieved (Makoto Okawa, Takashi Kasamatsu, Yoshiya Akiba, the 8 th Symposium on Environmental Chemistry, Kyushu, 1999). In addition, this method cannot be applied to an analysis of a thermally decomposable component because the sample is thermally desorbed when the sample is introduced into the analytical system. When the thermal desorption in the SPME is performed at an injection port of an existing gas chromatograph, a peak width is finally broadened because a low boiling component largely diffuses at a time of its injection. In the In-tube SPME method using a capillary column as well as in the In-tube SPME method using a syringe, a stationary phase is provided on an inner surface of the hollow needle and a center thereof is hollow. The sample freely passes through the hollow portion, thus, opportunities that the analyte diffuses into the stationary phase are reduced, and the time required for reaching an equilibrium becomes longer. In addition, it becomes necessary to increase an inner diameter of the needle and to increase the film thickness, in order to increase a sample capacity. However, as the inner diameter increases, a contact efficiency is reduced due to an extended diffusion time. Further, in a method which uses a column being packed with a filler, there are some problems as follows: (1) a flow rate depends on the packing state, so that analytical values will vary; and (2) resistance to a stream of the fluid becomes larger and the flow rate per unit time is decreased, so that the analytical time becomes longer. In this method, thermal desorption is also carried out at an existing GC injection port, so that broadening of a peak width cannot be avoided. Therefore, an object of the present invention is: to increase a sample capacity relative to that obtained by the conventional capillary column; to reduce a distribution resistance relative to that obtained by a column packed with particulate substances; and to reduce a time required for reaching a distribution equilibrium of an analyte compared with that obtained by the conventional SPME or In-tube method, by the use of a porous body having an integral structure of open cell structures (a so-called monolithic structure) when a pre-treatment for introducing a sample into a chromatograph is performed. The present invention is widely applicable to pre-treatments of a gas chromatography, a high-performance liquid chromatography, and other analytical methods. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a side view illustrating a syringe used for the present invention, which is partially sectioned in a vertical direction; FIG. 2 illustrates the practice of a method according to the present invention; FIG. 3 illustrates the practice of other method according to the present invention; FIG. 4 illustrates the practice of other syringe used for the present invention; FIG. 5 illustrates the practice of other syringe used for the present invention; FIG. 6 illustrates the practice of other method according to the present invention; FIG. 7 is a chromatogram obtained by an experimental example carried out according to the present invention; FIG. 8 is a chromatogram obtained by the above described experimental example which has been carried out by means of a hollow column; FIG. 9 is an explanation drawing of other example according to the present invention; FIG. 10 illustrates the use of other example according to the present invention; FIG. 11 is an explanation drawing of other example according to the present invention; and FIG. 12 illustrates the use of the above described other example. detailed-description description="Detailed Description" end="lead"? |
Optical encoding/decoding device |
An encoding/decoding device for OCDMA communications with an optical network is provided. The device uses a single reflecting element to perform both the encoding of outgoing signal and the decoding of incoming signal. A directional optical assembly allows to differentiate the origin of the signals to forward the outgoing signals after encoding to the network and the incoming signals after decoding to a receiver. |
1. An optical encoding/decoding device for a network terminal exchanging encoded outgoing and incoming optical signals with an optical network, said network terminal including a transmitter for transmitting uncoded outgoing signals and a receiver for receiving decoded incoming signals, the device comprising: a reflective element for respectively reflecting the uncoded outgoing signals into the encoded outgoing signals, and reflecting the encoded incoming signals into the decoded incoming signals; and a directional optical assembly optically coupled to the transmitter, the receiver, the network and the reflective element, said optical assembly: receiving the uncoded outgoing signals from the transmitter, sending said uncoded outgoing signals through the reflective element to obtain the encoded outgoing signals, and directing said encoded outgoing signals to the network; and receiving the encoded incoming signals from the network, sending said encoded incoming signals through the reflective element to obtain the decoded incoming signals, and directing said decoded incoming signals to the receiver. 2. The optical encoding/decoding device according to claim 1, wherein the reflective element is an Optical Code Division Multiple Access (OCDMA) encoder/decoder. 3. The optical encoding/decoding device according to claim 1, wherein the reflective element has a single extremity optically coupled to the directional optical assembly for receiving therefrom the uncoded outgoing signals and encoded incoming signals and sending back thereto the encoded outgoing signals and decoded incoming signals. 4. The optical encoding/decoding device according to claim 3, wherein said directional optical assembly includes: a first port connected to the transmitter for receiving therefrom the uncoded outgoing signals and being optically coupled to a first path; a second port connected to the extremity of the reflective element; a third port connected to the network for sending thereto the encoded outgoing signals and receiving therefrom the encoded incoming signals, said third port being optically coupled to a second path optically coupled to the second port and crossing the first path; and a fourth port connected to the receiver for sending thereto the decoded incoming signals. 5. The optical encoding/decoding device according to claim 4, wherein said directional optical assembly comprises a first polarisation beam splitter disposed in the first path, said first polarisation beam splitter maintaining a propagation of horizontally polarised light along said first path and coupling vertically polarised light out of the first path, vertically polarised light travelling along the first path towards the first port being redirected towards the fourth port. 6. The optical encoding/decoding device according to claim 5, further comprising polarising means for horizontally polarising the encoded incoming signals optically coupled to the second path. 7. The optical encoding/decoding device according to claim 6, wherein the directional optical assembly comprises an active polarisation controller optically coupled to the third port for aligning polarisation components of the encoded incoming signals received at the third port into horizontally polarised light, said active polarisation controller defining the polarising means. 8. The optical encoding/decoding device according the claim 7, wherein said directional optical assembly comprises a second polarisation beam splitter disposed at a crossing point of the first and the second path, said second polarisation beam splitter optically coupling vertically polarised light between the first path and a portion of the second path optically coupled to the second port and maintaining a propagation of horizontally polarised light along the first and the second paths. 9. The optical encoding/decoding assembly according to claim 8, wherein the directional optical assembly further comprises a first polarisation changing element disposed in the first path between the first and second polarisation beam splitters for rotating by 90 degrees the polarisation of light travelling away from the first port without affecting light travelling towards said first port; 10. The optical encoding/decoding device according to claim 9, a second polarisation changing element disposed in the second path between the second beamsplitter and the second port, for rotating by 90 degrees the polarisation of light passing twice therethrough while propagating to and back from the reflective element. 11. The optical encoding/decoding device according to claim 10, wherein the first polarisation changing element comprises: a quarter-wave plate rotating by +45 degrees the polarisation of light travelling away from the first port and by −45 degrees the polarisation of light travelling towards the first port; and a Faraday rotator rotating by +45 degrees the polarisation of light travelling away from and towards the first port. 12. The optical encoding/decoding device according to claim 10, wherein the second polarisation changing element comprises: a quarter-wave plate rotating by +45 degrees the polarisation of light travelling away from the second port and by −45 degrees the polarisation of light travelling towards the second port; and a Faraday rotator rotating by +45 degrees the polarisation of light travelling away from and towards the second port. 13. The optical encoding/decoding element according to claim 10, wherein the second polarisation changing element comprises: a Faraday rotator rotating by +45 degrees the polarisation of light travelling away from and towards the second port. 14. The optical encoding/decoding device according to claim 1, wherein the reflective element comprises: a first extremity optically coupled to the directional optical assembly for receiving therefrom the uncoded outgoing signals and transmitting thereto the encoded outgoing signals; and a second extremity opposed to the first extremity and optically coupled to the directional optical assembly for receiving therefrom the encoded incoming signals and transmitting thereto the decoded incoming signals. 15. The optical encoding/decoding device according to claim 14, wherein the directional optical assembly comprises: a first port connected to the transmitter for receiving therefrom the uncoded outgoing signals, said first port being optically coupled to the first extremity of the reflective element; a second port optically coupled to the first extremity of the reflective element for receiving therefrom the encoded outgoing signals and connected to the network for sending thereto said encoded outgoing signals; a third port connected to the network for receiving therefrom the encoded incoming signals and optically coupled to the second extremity of the reflective element; a fourth port optically coupled to the second extremity of the reflective element for receiving therefrom the decoded incoming signals and connected to the receiver for sending thereto said decoded incoming signals; a fifth port connected to the first extremity of the reflective element; and a sixth port connected to the second extremity of the reflective element. 16. The optical encoding/decoding device according to claim 15, further comprising: polarising means for horizontally polarising the encoded incoming signals received at the third port. 17. The optical encoding/decoding device according to claim 16, wherein the directional optical assembly comprises an active polarisation controller disposed downstream the third port for aligning polarisation components of the encoded incoming signals received at said third port into horizontally polarised light, said third port polarisation controller defining the polarising means. 18. The optical encoding/decoding device according the claim 16, wherein said directional optical assembly comprises: a first polarisation changing element disposed upstream the first extremity of the reflective element for rotating by 90 degrees the polarisation of light travelling away from the first extremity of the reflective element without affecting light travelling towards said first extremity of the reflective element; and a first polarisation beam splitter disposed between the first port and the first polarisation changing element for optically coupling vertically polarised light between the first port and the first extremity of the reflective element and optically coupling horizontally polarised light between said first extremity of the reflective element and the second port; said directional optical assembly further comprising: a second polarisation changing element disposed upstream the second extremity of the reflective element for rotating by 90 degrees the polarisation of light travelling away from the second extremity of the reflective element without affecting light travelling towards said second extremity of the reflective element; and a second polarisation beam splitter disposed between the third port and the second polarisation changing element for optically coupling horizontally polarised light between the third port and the second extremity of the reflective element and optically coupling vertically polarised light between said second extremity of the reflective element and the fourth port. 19. The optical encoding/decoding device according to claim 18, wherein the directional optical assembly further comprises: a first isolator disposed between the first port and the first polarisation beam splitter for blocking light travelling towards said first port; and a second isolator disposed between the third port and the second polarisation beam splitter for blocking light travelling towards said third port. 20. The optical encoding/decoding device according to claim 18, wherein the first polarisation changing element comprises: a quarter-wave plate rotating by +45 degrees the polarisation of light travelling away from the first extremity of the reflecting element and by −45 degrees the polarisation of light travelling towards said first extremity of the reflective element; and a Faraday rotator rotating by +45 degrees the polarisation of light travelling away from and towards the first extremity of the reflective element. 21. The optical encoding/decoding device according to claim 18, wherein the second polarisation changing element comprises: a quarter-wave plate rotating by +45 degrees the polarisation of light travelling away from the second extremity of the reflective element and by −45 degrees the polarisation of light travelling towards the second extremity of the reflective element; and a Faraday rotator rotating by +45 degrees the polarisation of light travelling away from and towards the second extremity of the reflective element. 22. The optical encoding/decoding device according the claim 16, wherein said directional optical assembly comprises: a first polarisation changing element disposed upstream the first extremity of the reflective element for rotating by 45 degrees the polarisation of light travelling therethrough; and a first polarisation beam splitter disposed between the first port and the first polarisation changing element for optically coupling vertically polarised light between the first port and the first extremity of the reflective element and optically coupling horizontally polarised light between said first extremity of the reflective element and the second port; said directional optical assembly further comprising: a second polarisation changing element disposed upstream the second extremity of the reflective element for rotating by 45 degrees the polarisation of light travelling therethrough; and a second polarisation beam splitter disposed between the third port and the second polarisation changing element for optically coupling horizontally polarised light between the third port and the second extremity of the reflective element and optically coupling vertically polarised light between said second extremity of the reflective element and the fourth port. 23. The optical encoding/decoding device according to claim 22, wherein the directional optical assembly further comprises: a first isolator disposed between the first port and the first polarisation beam splitter for blocking light travelling towards said first port; and a second isolator disposed between the third port and the second polarisation beam splitter for blocking light travelling towards said third port. 24. The optical encoding/decoding device according to claim 22, wherein the first polarisation changing element comprises a Faraday rotator. 25. The optical encoding/decoding device according to claim 22, wherein the second polarisation changing element comprises a Faraday rotator. 26. An optical encoding/decoding system for exchanging encoded outgoing and incoming optical signals with an optical network, said system comprising: a transmitter for transmitting uncoded outgoing signals; a receiver for receiving decoded incoming signals; a reflective element for respectively reflecting the uncoded outgoing signals into the encoded outgoing signals, and reflecting the encoded incoming signals into the decoded incoming signals; and a directional optical assembly optically coupled to the transmitter, the receiver, the network and the reflective element, said optical assembly: receiving the uncoded outgoing signals from the transmitter, sending said uncoded outgoing signals through the reflective element to obtain the encoded outgoing signals, and directing said encoded outgoing signals to the network; and receiving the encoded incoming signals from the network, sending said encoded incoming signals through the reflective element to obtain the decoded incoming signals, and directing said decoded incoming signals to the receiver. |
<SOH> BACKGROUND OF THE INVENTION <EOH>OCDMA (Optical Code Division Multiple Access) is a multiplexing technique whereby an optical signal is encoded by using several optical wavelengths, which are preferably spread over time. Such a technique was introduced by Fathallah et al. in U.S. pending patent application Ser. No. 09/192,180 entitled “Fast Frequency Hopping Spread Spectrum for Code Division Multiple Access Communications Networks”. A first reflective element is generally used for the encoder, and a is second reflective element having the same reflection pattern as the encoder but time inverted, is used as the decoder. The preferred reflective element for the encoder and the decoder are fibre Bragg gratings (FBG) since they are readily fibre compatible. Current networks require the provision of two identical reflective elements at each location where encoding and decoding operations are performed. Both operations are traditionally done separately. FIG. 1 (PRIOR ART) shows the architecture of such a network 10 , where the central office 12 and every user 14 are provided with both an encoder 16 and a decoder 18 , which happen to be identical except for the time-reversal property when time spreading is used. The encoding and decoding of information is a symmetric process as shown in FIG. 2 (PRIOR ART). The same reflective element can be used from the first port to work as an encoder in the Central Office (or at a user station) and from the second port as a decoder at a user station (or at the Central Office). FIG. 3A (PRIOR ART) illustrates the data flow in a traditional bi-directional encoding/decoding device. In this system, a message sent from the user (via a transmitter) to the Central Office is directed towards the encoder by a three-port circulator C 1 . The principle of operation of an optical circulator is well known to those versed in the art. The encoder reflects the signal modified in accordance with its particular code, and sends it back towards the circulator C 1 . The signal is then redirected to the bi-directional link between the user and the network to be forwarded to the central office. Similarly, an encoded incoming message from the Central Office will go to circulator C 2 which sends it to the decoder. Reflection by the decoder will decode the signal and send it back to circulator C 2 , which redirects it to the receiver. FIG. 3B (PRIOR ART) illustrates the data flow in a traditional unidirectional network. The principle of operation is similar to that of the device of FIG. 3A , with the exception that two different ports are connected to the network for respectively receiving therefrom and transmitting thereto optical signals. It would however be advantageous to provide a device where both reflecting operations, the encoding and the decoding, could be done by the same element, thereby eliminating the need for extra reflective elements at each location. Of course, the user's reflective element should still be a mirror image of the Central Office's reflective element for the system to be operational. |
<SOH> OBJECTS AND SUMMARY OF THE INVENTION <EOH>It is therefore an object of the present invention to provide an optical encoding/decoding device using a single reflective element for both operations. It is a preferential object of the invention to provide such a device adapted for bi-directional networks. It is another preferential object of the invention to provide such a device adapted for unidirectional networks. Accordingly, the present invention provides an optical encoding/decoding device for a network terminal exchanging encoded outgoing and incoming optical signals with an optical network. The network terminal includes a transmitter for transmitting uncoded outgoing signals and a receiver for receiving decoded incoming signals. The device includes a reflective element for respectively reflecting the uncoded outgoing signals into the encoded outgoing signals, and reflecting the encoded incoming signals into the decoded incoming signals. The device also includes a directional optical assembly optically coupled to the transmitter, the receiver, the optical network and the reflective element. The optical assembly receives the uncoded outgoing signals from the transmitter, sends these uncoded outgoing signals through the reflective element to obtain the encoded outgoing signals, and directs these encoded outgoing signals to the network. The optical assembly also receives the encoded incoming signals from the network, sends these encoded incoming signals through the reflective element to obtain the decoded incoming signals, and directs these decoded incoming signals to the receiver. The present invention also provides an optical encoding/decoding system for a network terminal exchanging encoded outgoing and incoming optical signals with an optical network. The system includes a transmitter for transmitting uncoded outgoing signals, a receiver for receiving decoded incoming signals, and a reflective element for respectively reflecting the uncoded outgoing signals into the encoded outgoing signals, and reflecting the encoded incoming signals into the decoded incoming signals. The system also includes a directional optical assembly optically coupled to the transmitter, the receiver and the reflective element. The optical assembly receives the uncoded outgoing signals from the transmitter, sends these uncoded outgoing signals through the reflective element to obtain the encoded outgoing signals, and directs these encoded outgoing signals to the network. The optical assembly also receives the encoded incoming signals from the network, sends these encoded incoming signals through the reflective element to obtain the decoded incoming signals, and directs the decoded incoming signals to the receiver. In accordance with a particularly advantageous embodiment of the invention, the encoding/decoding device and system above use light polarisation as a means to differentiate between incoming and outgoing signals. Advantageously, the present invention may be used in the context of OCDMA optical communications. Other features and advantages of the invention will be better understood upon reading of preferred embodiments thereof with reference to the appended drawings. |
Inhibition of jun kinase |
Disclosed herein are compositions and methods used to modulate a NH2-terminal Jun Kinase activity. These compositions and methods can be employed to regulate metabolic disorders associated with, for example, insulin such as diabetes. The reduction in NH2-terminal Jun Kinase activity can lead to the reduction in weight and improve insulin sensitivity. |
1. A method of treating a metabolic disorder associated with insulin resistance, comprising administering to a mammal an inhibitor of a NH2-terminal Jun Kinase (JNK). 2. The method of claim 1, wherein said inhibitor binds to an ATP binding site in JNK. 3. The method of claim 1, wherein said inhibitor binds to a catalytic domain of JNK. 4. The method of claim 1, wherein said JNK is JNK1. 5. The method of claim 1, wherein said JNK is JNK2. 6. The method of claim 1, wherein said JNK is JNK1 and JNK2. 7. The method of claim 1, wherein said inhibitor is SP600125. 8. A method of improving insulin sensitivity, comprising administering to a mammal an inhibitor of a NH2-terminal Jun Kinase (JNK). 9. A method of treating or preventing the development of obesity in an individual, comprising administering to said individual an inhibitor of a NH2-terminal Jun Kinase (JNK). 10. A method of diagnosing insulin resistance or a risk of developing insulin resistance, comprising measuring the level of NH2-terminal Jun Kinase (JNK) activity in a tissue of a mammal, wherein an increase in activity compared to a normal control indicates that said mammal is suffering from or at risk of developing insulin resistance. 11. A method of diagnosing insulin resistance or a risk of developing insulin resistance, comprising measuring the level of NH2-terminal Jun Kinase (JNK) expression in a tissue of a mammal, wherein an increase in the level of expression compared to a normal control indicates that said mammal is suffering from or at risk of developing insulin resistance. 12. The method of claim 10 or 11, wherein said JNK is JNK1. 13. A method of inhibiting fat accumulation in liver tissue, comprising contacting said tissue with an inhibitor of a JNK. 14. The method of claim 13, wherein said inhibitor binds to an ATP binding site in JNK. 15. The method of claim 13, wherein said inhibitor binds to a catalytic domain of JNK. 16. The method of claim 13, wherein said JNK is JNK1. 17. The method of claim 13, wherein said JNK is JNK2. 18. The method of claim 13, wherein said JNK is JNK1 and JNK2. 19. The method of claim 13, wherein said inhibitor is SP600125. 20. The method of claim 13, wherein said inhibitor preferentially reduces enzymatic activity of JNK1 compared to JNK2. 21. A method of improving insulin sensitivity, comprising administering a therapeutically effective amount to a mammal an inhibitor of a NH2-terminal Jun Kinase (JNK). 22. A method of treating the development of obesity in an individual, comprising administering a therapeutically effective amount to said individual an inhibitor of a NH2-terminal Jun Kinase (JNK). 23. A method of preventing the development of obesity in an individual, comprising administering a therapeutically effective amount to said individual an inhibitor of a NH2-terminal Jun Kinase (JNK). |
<SOH> BACKGROUND OF THE INVENTION <EOH>An estimated one-half of adults in the country are either overweight or obese. Obesity can least to a greater risk for developing a host of diseases, including diabetes, heart disease, stroke and certain cancers. Patients with non-insulin dependent diabetes mellitus (NIDDM) may develop insulin resistance and impaired glucose tolerance. |
<SOH> SUMMARY <EOH>The invention is based on the discovery that reduced expression of a NH2-terminal Jun Kinase (JNK), e.g., JNK1, leads to reduced weight and improved insulin sensitivity. Accordingly, the invention features a method of treating a metabolic disorder associated with insulin resistance by administering to a mammal an inhibitor of JNK. The mammal, e.g., a human patient, is identified as being obese or at risk of becoming obese. By “obese” is meant having an excess amount of adipose tissue. Standard clinical tests are used to determine whether an individual is obese, e.g., by calculating relative weight or body mass index (BMI) for an individual and comparing the values to a predetermined standard of ideal or desirable relative weight or BMI. For example, assessment of skin fold thickness over various areas of the body is taken into consideration together with height, weight, and age to determine the amount of adipose tissue content in an individual. Excess of adipose tissue content is determined by comparing the value against average (or standard) values for an individual of comparable age. For example, a 20% increase in mean relative weight or a BMI above the 85 th percentile for young adults constitutes a health risk and may indicate therapeutic intervention, e.g., treatment with a JNK inhibitor. The inhibitors are also administered to individuals who are not obese, but wish to reduce their weight. The mammal is identified as suffering from diabetes, is at risk of developing diabetes, suffering from insulin resistance, or at risk of developing insulin resistance. The term “diabetes,” includes both insulin-dependent diabetes mellitus (i.e., IDDM, also known as type I diabetes) and non-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type II diabetes). Preferably, the mammal is suffering from or at risk of developing Type II diabetes. JNK inhibitors are compounds, which reduce the enzymatic activity of a JNK, e.g., JNK1 or JNK2, or expression of a JNK isotype. For example, compounds, which inhibit JNK enzymatic activity, bind to an ATP binding site in JNK or bind to a catalytic domain of JNK. The compound preferentially inhibits JNK1 compared to JNK2 or other JNK isotypes. Alternatively, the compound inhibits JNK2 or both JNK1 and JNK2. For example, the compound is SP600125. Compounds, e.g., polypeptides, organic compounds, or inorganic compounds, are isolated or purified. An “isolated” or “purified” composition is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which it is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. A polypeptide that is substantially free of cellular material includes preparations of the polypeptide in which the polypeptide is separated from cellular components of the cells from which it is isolated, e.g., the polypeptide is recombinantly produced. Preferably, a preparation of a therapeutic compound, e.g., a JNK inhibitor, is at least 75%, more preferably 80%, more preferably 85%, more preferably 90%, more preferably 95%, more preferably 98%, and most preferably 99 or 100% of the dry weight of the preparation. The invention also includes a method of improving insulin sensitivity or alleviating a symptom of insulin resistance, reducing the severity of insulin resistance, diabetics, or an associated metabolic disorder, by administering to a mammal an inhibitor of JNK expression or activity. Methods of treating or preventing the development of obesity are also within the invention. Metabolic conditions associated with insulin resistance include high blood glucose levels, markedly elevated serum insulin concentrations, and insensitivity to intravenously administered insulin. Insulin resistance is defined as the requirement of 200 or more units of insulin per day to control hyperglycemia and prevent ketosis. Compounds are administered at a dose that is therapeutically effective. The term “therapeutically effective amount” as used herein means that the amount of a compound(s) or pharmaceutical composition elicits a beneficial biological or medicinal response in a tissue, system, animal or human. For example, a therapeutically effective amount of a JNK inhibitory compound is a dose which leads to a clinically detectable improvement in insulin sensitivity, weight loss, or a reduction in hepatic fat content. A method of identifying an individual that is at risk of developing insulin resistance is carried out by measuring the level of JNK activity in a tissue of a mammal. Measuring the level of JNK activity in a tissue of a mammal is also useful to diagnose insulin resistance, diabetes, or a predisposition to develop the disorders. An increase in activity compared to a normal control indicates that the mammal is suffering from or is predisposed to developing insulin resistance. Insulin resistance or a predisposition thereto is also diagnosed by measuring the level of JNK expression in a tissue of a mammal. JNK expression is measured by detecting a gene product, e.g., using an antibody or other specific ligand, or by detecting gene transcription, e.g., using a standard Northern blot assay or reverse transcriptase polymerase chain reaction (RT-PCR). An increase in the level of expression compared to a normal control indicates that the mammal is suffering from or is predisposed to developing insulin resistance, or at risk of developing the disorder. The invention also includes a method of inhibiting fat accumulation in liver tissue by contacting the tissue with an inhibitor of a JNK. For example, the JNK inhibitor reduces JNK enzymatic activity as described above, e.g., SP600125. The inhibitor preferentially reduces enzymatic activity of JNK1 compared to JNK2. For example, the inhibitor reduces JNK1 activity by at least 10%, more preferably 20%, 50%, 100%, and 200% compared to the level of reduction of JNK2 activity. The method is useful to prevent the development or slow the progression of fatty liver disease or hepatosteosis. The method is carried out by identifying an individual who is at risk of developing fatty liver disease, e.g., by identifying one who consumes excessive amounts or alcohol, one who is at least 10% above ideal body weight, one who is obese, or one who has a family history of liver disease, and administering to the individual an inhibitor of JNK1 activity. Liver tissue is contacted directly in situ, e.g., by direct injection into the liver, or systemically, e.g., by oral or intravenous administration. Contacting liver tissue with a compound which preferentially inhibits JNK1 activity leads to reduced accumulation of fat in hepatic cells. Other features, objects, and advantages of the invention will be apparent from the description and drawings. |
Photocatalytic coating material having photocatalytic activity and adsorption property and method for preparing the same |
Disclosed is a photocatalytic coating sol composition and the method for preparing the same. The photocatalityc coating sol composition comprising 0.1% to 20% by weight of a photo-catalyst, 0.1% to 10% by weight of an inorganic adsorbent, 1% to 20% by weight of an inorganic binder, 55% to 95% by weight of an organic solvent and if necessary 0.1% by weight to 10% by weight of a metal compound. Specifically, the present invention can remove harmful substances by coating photocatalytic coating sol composition prepared from photocatalyst, inorganic adsorbent, inorganic binder, metal compound and organic solvent on metal filter such as aluminum etc., and plastic filter such as polyethylene and polypropylene etc. used in environmental contaminants treatment system or air conditioning plant such as air-conditioner and air-cleaner, according to any one of and ordinary coating techniques such as spray method or dipping method etc. at room temperature. |
1. A photocatalytic coating sol composition comprising 0.1% to 20% by weight of a photocatalyst, 0.1% to 10% by weight of an inorganic adsorbent, 1% to 20% by weight of an inorganic binder, and 55% to 95% by weight of an organic solvent. 2. The photocatalytic coating sol composition according to claim 1, further comprising 0.1% to 10% by weight of a metal compound. 3. The photocatalytic coating sol composition according to claim 2, wherein the metal compound is selected from the group consisting of copper compound, silver compound, bengala, vermilion, cadmium red, yellow earth, cadmium yellow, emerald rock, chromium oxide green, Prussian blue, cobalt blue, manganese and carbon black. 4. The photocatalytic coating sol composition according to claim 1, wherein the photocatalyst is selected from the group consisting of TiO2, ZnO2, ZnO, CaTiO, WO3, SnO2, MoO3, Fe2O3, InP, GaAs, BaTiO3, KNbO3, Fe2O3, and Ta2O5. 5. The photocatalytic coating sol composition according to claim 4, wherein the average diameter of the photocatalyst particles is 5 to 50 nm. 6. The photocatalytic coating sol composition according to claim 1, wherein the inorganic adsorbent is silicates compound of magnesium or calcium, talc, diatomite, or zeolite coated with silver and/or copper ion. 7. The photocatalytic coating sol composition according to claim 1, wherein the inorganic binder is an isopropoxide compound or a silane compound. 8. The photocatalytic coating sol composition as according to claim 1, wherein the organic solvent is an alcohol having lower alkyl group. 9. A method for the preparation of a photocatalytic coating sol composition, comprising the steps of: stirring at 1000 to 1500 rpm at room temperature for 10 to 30 min after mixing 1% to 20% by weight of an inorganic binder, 55% to 95% by weight of an organic solvent and 0.1% to 0.5% by weight of a strong acid or a strong base if necessary; and treating for 10 to 15 min in an ultrasonic device after adding 0.1% to 20% by weight of a photocatalyst powder and 0.1% to 10% by weight of an inorganic adsorbent to the mixture, and adding 0.1% to 10% by weight of metal a compound to the mixture, if necessary. 10. A substrate prepared by coating the photocatalytic coating sol composition according to claim 1 using a printing method, a spraying method or a dipping method, and followed by drying. 11. The substrate according to claim 10, wherein the substrate is aluminum filter, a polyethylene filter or a polypropylene filter. 12. A substrate prepared by coating the photocatalytic coating sol composition according to claim 2 using a printing method, a spraying method or a dipping method, and followed by drying. 13. A substrate prepared by coating the photocatalytic coating sol composition according to claim 3 using a printing method, a spraying method or a dipping method, and followed by drying. 14. A substrate prepared by coating the photocatalytic coating sol composition according to claim 4 using a printing method, a spraying method or a dipping method, and followed by drying. 15. A substrate prepared by coating the photocatalytic coating sol composition according to claim 5 using a printing method, a spraying method or a dipping method, and followed by drying. 16. A substrate prepared by coating the photocatalytic coating sol composition according to claim 6 using a printing method, a spraying method or a dipping method, and followed by drying. 17. A substrate prepared by coating the photocatalytic coating sol composition according to claim 7 using a printing method, a spraying method or a dipping method, and followed by drying. 18. A substrate prepared by coating the photocatalytic coating sol composition according to claim 8 using a printing method, a spraying method or a dipping method, and followed by drying. |
<SOH> BACKGROUND ART <EOH>Previously, the conventional method for treating environmental contaminants could be classified into two methods. One is a physico-chemical method which includes adsorption, cooling condensation, solvent scrubber, catalytic oxidation method. And another is a biological treatment method. However, the adsorption method and the cooling condensation method are ineffective for fundamentally treating the contaminants, and thus there is a limitation on using these methods. The solvent scrubber method is a type of a chemical deodorization method in which the contaminants are neutralized due to chemicals, whereby removal rate of the contaminants is high for limited areas. However, the above methods have several disadvantages, because an additional device is required to spray the chemicals in order to take place the reaction of the chemicals effectively with the contaminants in areas having vast production source of contaminants, and a large amount of chemicals must be used for neutralizing the contaminants in an area having a large amount of contaminants in high concentration. Meanwhile, both in direct combustion method and the catalytic oxidation method, substances causing pollutions are removed through an oxidation process, which show a high removal rate, yet produce secondary contaminants such as NO x and SO x , and require high cost. A method for biological treating the contaminants using microorganisms has been widely used in recent years owing to low initial investment costs as well as operating costs, has been studied actively in industrially advanced countries such as Europe and North America, and thus has reached to a commercialization step. According to this method, various microorganisms capable of removing the contaminants are immobilized in a carrier, which is advantageous in removing the contaminants in a high rate. And also, it allows using small-sized equipments. However, the method has technical problems, for example, contaminants used as nutrients for growth of the microorganisms must be continuously administered into a reactor where a substantial contaminants removal is performed, the carrier must be washed periodically, the microorganisms must be well controlled, and process of this method must be operated continuously. Recently, in order to solve the above problems, there is an increasing interest in removing contaminants and odor materials using photocatalyst as a high-grade oxidation technique. Specifically, Korean Patent Application No. 1999-0052838 discloses a filter using photocatalyst coated with titanium dioxide (TiO 2 ), zinc oxide (ZnO) and silver (Ag) etc. on filter such as non-woven fabric, activated carbon and Zeolite etc. Korean Patent Application No. 2000-0034908 discloses a method for treating volatile organic compounds by using photocatalyst, and Korean Utility Model Application No. 2000-0029990 discloses a device for treating water by using titanium oxides. The photocatalytic oxidation refers to the decomposing reaction of gaseous or liquid phase organic materials which are adsorbed on the surface of the photocatalyst owing to the strong oxidation of hydroxyl radicals (—OH) generated by a hole, wherein the hole is generated together with an electron when a light energy, more than the bandgap energy, is irradiated on the photocatalyst. That is, the photocatalyst shows catalytic activity by absorbing light energy, and the generated oxidation strength is used to decompose environmental contaminants by oxidation. Representative materials inducing photocatalytic reaction may be, for example, TiO 2 , ZnO 2 , ZnO, SrTiO 3 , CdS, GaP, InP, GaAs, BaTiO 3 , KbO 3 , Fe 2 O 3 , Ta 2 O 5 , WO 3 , SnO 2 , Bi 2 O 3 , NiO, Cu 2 O, SiO, SiO 2 , MoS 2 , InPb, RuO 2 , CeO 2 etc., and could be used by adding metals such like Pt, Rh, Ag, Cu, Sn, Ni, Fe etc. and metal oxide thereof to the above photocatalyst. Among them, titanium dioxide (TiO 2 ) is mostly used because it is harmless to human body, exhibits excellent photocatalytic activity, good photo-corrosion resistance and requires low cost. The titanium dioxide absorbs and reacts at a wavelength less than 388 nm and generates the electron (conduction band) and the hole (valence band). Hereby, glow lamp and mercuric lamp besides solar energy lamp could be used for UV ray as a light source. The electron and the hole generated by the above reaction recombine with each other within 10 −12 sec to 10 −9 sec. However, if the contaminants are adsorbed on the surface prior to recombination of the electron and the hole, the contaminants are decomposed by the electron and the hole. The reaction mechanism of this photocatalyst can be represented as the following reaction formulas 1 to 5. in-line-formulae description="In-line Formulae" end="lead"? TiO 2 +hv →e − +h + [Reaction formula 1] in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? e − +O 2 →O 2 − radical [Reaction formula 2] in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? h + +—OH →—OH radical [Reaction formula 3] in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? O 2 − radical+A (organics, microorganisms, contaminants)→ A′ [Reaction formula 4] in-line-formulae description="In-line Formulae" end="tail"? in-line-formulae description="In-line Formulae" end="lead"? —OH radical+B (organics, microorganisms, contaminants)→ B′ [Reaction formula 5] in-line-formulae description="In-line Formulae" end="tail"? There have been extensive researches performed in order to develop a method for preparing coating sol composition containing photocatalyst (e.g. titanium dioxide) to provide a photocatalytic active material, which are capable of removing the contaminants by adsorption and decomposition. Specifically, the technique for antifogging is disclosed in PCT Publication No. WO96/029375, wherein the technique prevents substrate from forming haze and water-drop thereon by coating a photocatalyst layer on transparent substrates such as mirror, lens and plate. Also, the technique has been practically used in anti-fouling field, such as a filter for an air cleaner, the filter deodorizing odor components (e.g. cigarette smoke) by using titanium dioxide as photocatalyst, antibiotic filter having antibacterial function in water or atmosphere, glass and tile. And, a filter being coated with a photocatalyst can be applied to photocatalytic system to decompose the volatile organic compounds. However, since the photocatalytic reaction is a surface reaction, there is a need for developing a technique capable of adsorbing a large amount of organic contaminants or odor materials. A method for coating photocatalyst via a liquid phase, which is most commonly used, uses titanium alkoxide as a starting material to prepare a sol composition, which coats a carrier (Japanese patent publication No. 5-253544). However, the method requires complex process steps such as generating photocatalytic particles on the carrier after coating, crystallization of anatase type having high photocatalytic activity, and sintering at the temperature range of 400 to 600° C. to give adherence to a carrier, resulting in high manufacturing cost. Also, the application of this method is restricted to coat on polymer materials such as plastics having poor heat resistance. Further, even though a photocatalytic coating on tiles and ceramics having excellent heat-resistance is carried out and then treated at high temperature, there are still problems such as large power consumption. Meanwhile, photocatalytic coating method via a gaseous phase not using photocatalytic coating sol composition includes spattering method or chemical vapor depositing method disclosed in Japanese Patent publication No. 60-44053. However, there are also problems such as high initial investment cost due to the manufacturing of equipments, high consumption of electric power and manufacturing time due to the increase of coating film thickness. Also, if titanium dioxide is formed as a thin-film on a support according to the sol-gel method, it requires much time for decomposing contaminants because of limited contact area of contaminants on the thin-film containing photocatalyst. For effective removing of environmental contaminants using photocatalyst, there is a need for enlarging surface area of photocatalyst or increasing the intensity of light source. Specifically, filter for air handling unit such as air purifier, air-conditioner etc. which is used for removing odor material and the like, requires about 10 −3 sec of treatment time, and thus it requires development to the sol for coating having high adsorption power and high photocatalytic activity. Conventionally, in order to uniformly disperse different kinds of particles between different kinds of particles in solution state, different kinds of sol composition were physically mixed with each other (U.S. Pat. No. 5,591,380), or two kinds of alkoxides as starting materials were dissolved simultaneously into the solvent to prepare sol composition (U.S. Pat. No. 4,176,089). However, in case of mixing two kinds of sol composition, the stability of sol composition decreases and turns into gel in short time. During the coating process, the coating film becomes thick and is delaminated from the carrier after the heating treatment. And, the methods have the disadvantage in that the condition of the manufacture process must be controlled accurately when sol particles are dispersed by dissolving start materials simultaneously. The present inventors have made a research to develop a photocatalytic coating composition having high adsorption and high photocatalytic activity, and as a result, the present invention has been completed on the basis of the discovery described below. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Further objects and advantages of the invention can be more fully understood from the following detailed description taken in conjunction with the accompanying drawing in which: FIG. 1 shows a graph of photocatalytic activity of metal mesh coated with a photocatalytic coating sol composition prepared without adding inorganic adsorption and metal compound; FIG. 2 shows a graph of photocatalytic activity of metal mesh coated with a photocatalytic coating sol composition according to Example 6 of the present invention; FIG. 3 shows a graph of photocatalytic activity of metal mesh coated with a photocatalytic coating sol composition according to Example 7 of the present invention; FIG. 4 shows a graph of antibiotic experiment results of metal mesh coated with a photocatalytic coating sol composition prepared according to the present invention and photocatalytic coating sol composition prepared without adding inorganic adsorbent and metal ions, respectively; FIG. 5 shows a graph of de-colorization experiment result of polyethylene filter coated with a photocatalytic coating sol composition prepared according to the present invention; FIG. 6 shows a graph of activity experiment result of polyethylene filter coated with a photocatalytic coating sol composition prepared according to the present invention; FIG. 7 shows the graph of saturated activity experiment result of polyethylene filter coated with a photocatalytic coating sol composition prepared according to the present invention; FIG. 8 shows an electron microscope photograph taken from the surface of polyethylene filter coated with a photocatalytic coating sol composition prepared according to the present invention; and FIG. 9 shows an electron microscope photograph taken from section of polyethylene filter coated with a photocatalytic coating sol composition prepared according to the present invention. detailed-description description="Detailed Description" end="lead"? |
P450 proteins |
This invention relates to proteins, termed BAA92678.1 and BAA31683.1, herein identified as P450 enzymes and to the use of these proteins and nucleic acid sequences from the encoding genes in the diagnosis, prevention and treatment of disease. |
1. A polypeptide, which polypeptide: i) comprises or consists of the amino acid sequence as recited in SEQ ID NO:2, or SEQ ID NO:4; ii) is a fragment thereof having P450 activity or having an antigenic determinant in common with the polypeptide of (i); or iii) is a functional equivalent of (i) or (ii). 2-50. (canceled) 51. A polypeptide which is a fragment according to claim 1(ii), which includes the P450 region of the P450G1 polypeptide, said P450 region being defined as including between residues 559 and 1031 inclusive, of the amino acid sequence recited in SEQ ID NO:2, wherein said fragment possesses the catalytic residues CYS973 or equivalent residues, and possesses P450 activity. 52. A polypeptide which is a functional equivalent according to claim 1(iii), is homologous to the amino acid sequence as recited in SEQ ID NO:2, possesses the catalytic residues CYS973 or equivalent residues, and has P450 activity. 53. A polypeptide according to claim 52, wherein said functional equivalent is homologous to the P450 region of the P450G1 polypeptide. 54. A polypeptide which is a fragment according to claim 1(ii), which includes the P450 region of the P450G2 polypeptide, said P450 region being defined as including between residue 205 and residue 506 of the amino acid sequence recited in SEQ ID NO:4, wherein said fragment possesses the catalytic residues CYS480 or equivalent residues, and possesses P450 activity. 55. A polypeptide which is a functional equivalent according to claim 1(iii), is homologous to the amino acid sequence as recited in SEQ ID NO:4, possesses the catalytic residues CYS480 or equivalent residues, and has P450 activity. 56. A polypeptide according to claim 55, wherein said functional equivalent is homologous to the P450 region of the P450G2 polypeptide. 57. A fragment or functional equivalent according to claim 1, which has greater than 80% sequence identity with an amino acid sequence as recited in any one of SEQ ID NO:2 and SEQ ID NO:4, or with a fragment thereof that possesses P450 activity, preferably greater than 85%, 90%, 95%, 98% or 99% sequence identity, as determined using BLAST version 2.1.3 using the default parameters specified by the NCBI (the National Center for Biotechnology Information; http://www.ncbi.nlm.nih.gov/) [Blosum 62 matrix; gap open penalty=11 and gap extension penalty=1]. 58. A functional equivalent according to claim 1, which exhibits significant structural homology with a polypeptide having the amino acid sequence given in any one of SEQ ID NO:2 and SEQ ID NO:4, or with a fragment thereof that possesses P450 activity. 59. A fragment as recited in claim 1, having an antigenic determinant in common with the polypeptide which consists of 7 or more (for example, 8, 10, 12, 14, 16, 18, 20 or more) amino acid residues from the sequence of SEQ ID NO:2 or SEQ ID NO:4. 60. A purified nucleic acid molecule which encodes a polypeptide according to claim 1. 61. A purified nucleic acid molecule according to claim 60, which has the nucleic acid sequence as recited in SEQ ID NO:1 or SEQ ID NO:3, or is a redundant equivalent or fragment thereof. 62. A fragment of a purified nucleic acid molecule according to claim 60, which comprises between nucleotides 1675 and 3093 of SEQ ID NO:1, or is a redundant equivalent thereof. 63. A fragment of a purified nucleic acid molecule according to claim 60, which comprises between nucleotides 617 and 1519 of SEQ ID NO:3, or is a redundant equivalent thereof. 64. A purified nucleic acid molecule which hybridizes under high stringency conditions with a nucleic acid molecule according to claim 60. 65. A vector comprising a nucleic acid molecule as recited in claim 60. 66. A host cell transformed with a vector according to claim 65. 67. A ligand which binds specifically to, and which preferably inhibits the P450 activity of a polypeptide according to claim 1. 68. A ligand according to claim 67, which is an antibody. 69. A compound that either increases or decreases the level of expression or activity of a polypeptide according to claim 1. 70. A compound according to claim 69 that binds to a polypeptide without inducing any of the biological effects of the polypeptide. 71. A compound according to claim 69, which is a natural or modified substrate, ligand, enzyme, receptor or structural or functional mimetic. 72. A polypeptide according to any one of claim 1, for use in therapy or diagnosis of disease. 73. A nucleic acid molecule according to claim 60, for use in therapy or diagnosis of disease. 74. A vector according to claim 65, for use in therapy or diagnosis of disease. 75. A ligand according to claim 67, for use in therapy or diagnosis of disease. 76. A compound according to claim 69, for use in therapy or diagnosis of disease. 77. A method of diagnosing a disease in a patient, comprising assessing the level of expression of a natural gene encoding a polypeptide according to claim 1, or assessing the activity of the polypeptide, in tissue from said patient and comparing said level of expression or activity to a control level, wherein a level that is different to said control level is indicative of disease. 78. A method according to claim 77 that is carried out in vitro. 79. A method according to claim 77, which comprises the steps of: (a) contacting a ligand with a biological sample under conditions suitable for the formation of a ligand-polypeptide complex; and (b) detecting said complex. 80. A method according to claim 77, comprising the steps of: a) contacting a sample of tissue from the patient with a nucleic acid probe under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule encoding the polypeptide and the probe; b) contacting a control sample with said probe under the same conditions used in step a); and c) detecting the presence of hybrid complexes in said samples; wherein detection of levels of the hybrid complex in the patient sample that differ from levels of the hybrid complex in the control sample is indicative of disease. 81. A method according to claim 77, comprising: a) contacting a sample of nucleic acid from tissue of the patient with a nucleic acid primer under stringent conditions that allow the formation of a hybrid complex between a nucleic acid molecule encoding the polypeptide and the primer; b) contacting a control sample with said primer under the same conditions used in step a); and c) amplifying the sampled nucleic acid; and d) detecting the level of amplified nucleic acid from both patient and control samples; wherein detection of levels of the amplified nucleic acid in the patient sample that differ significantly from levels of the amplified nucleic acid in the control sample is indicative of disease. 82. A method according to claim 77, comprising: a) obtaining a tissue sample from a patient being tested for disease; b) isolating a nucleic acid molecule encoding the polypeptide from said tissue sample; and c) diagnosing the patient for disease by detecting the presence of a mutation which is associated with disease in the nucleic acid molecule as an indication of the disease. 83. The method of claim 82, further comprising amplifying the nucleic acid molecule to form an amplified product and detecting the presence or absence of a mutation in the amplified product. 84. The method of either claim 82, wherein the presence or absence of the mutation in the patient is detected by contacting said nucleic acid molecule with a nucleic acid probe that hybridises to said nucleic acid molecule under stringent conditions to form a hybrid double-stranded molecule, the hybrid double-stranded molecule having an unhybridised portion of the nucleic acid probe strand at any portion corresponding to a mutation associated with disease; and detecting the presence or absence of an unhybridised portion of the probe strand as an indication of the presence or absence of a disease-associated mutation. 85. A method according to claim 77, wherein said disease is a cell proliferative disorder, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorder, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorder, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorder including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorder; metabolic disorder including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection or other pathological condition. 86. Use of a polypeptide according to claim 1 as a P450 enzyme. 87. Use of a nucleic acid molecule according to claim 60 to express a protein that possesses P450 activity. 88. A method for modulating the metabolism of a drug compound in a patient utilising a polypeptide according to claim 1. 89. A pharmaceutical composition comprising a polypeptide according to claim 1. 90. A pharmaceutical composition comprising a nucleic acid molecule according to claim 60. 91. A pharmaceutical composition comprising a vector according to claim 65. 92. A pharmaceutical composition comprising a ligand according to claim 67. 93. A pharmaceutical composition comprising a compound according to claim 69. 94. A vaccine composition comprising a polypeptide according to claim 1. 95. A vaccine composition comprising a nucleic acid molecule according to claim 60. 96. A polypeptide according to claim 1 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 97. A nucleic acid molecule according to claim 60 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 98. A vector according to claim 65 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 99. A ligand according to claim 67 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 100. A compound according to claim 69 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 101. A pharmaceutical composition according to claim 1 for use in the manufacture of a medicament for the treatment of cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. 102. A method of treating a disease in a patient, comprising administering to the patient a polypeptide according to claim 1. 103. A method of treating a disease in a patient, comprising administering to the patient a nucleic acid molecule according to claim 60. 104. A method of treating a disease in a patient, comprising administering to the patient a vector according to claim 65. 105. A method of treating a disease in a patient, comprising administering to the patient a ligand according to claim 67. 106. A method of treating a disease in a patient, comprising administering to the patient a compound according to claim 69. 107. A method of treating a disease in a patient, comprising administering to the patient a pharmaceutical composition according to claim 1. 108. A method according to claim 102, wherein, for diseases in which the expression of the natural gene or the activity of the polypeptide is lower in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an agonist. 109. A method according to claim 102, wherein, for diseases in which the expression of the natural gene or activity of the polypeptide is higher in a diseased patient when compared to the level of expression or activity in a healthy patient, the polypeptide, nucleic acid molecule, vector, ligand, compound or composition administered to the patient is an antagonist. 110. A method of monitoring the therapeutic treatment of disease in a patient, comprising monitoring over a period of time the level of expression or activity of a polypeptide according to claim 1, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease. 111. A method of monitoring the therapeutic treatment of disease in a patient, comprising monitoring over a period of time the level of expression of a nucleic acid molecule according to claim 60 in tissue from said patient, wherein altering said level of expression or activity over the period of time towards a control level is indicative of regression of said disease. 112. A method for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a polypeptide according to claim 1, with one or more compounds suspected of possessing binding affinity for said polypeptide or nucleic acid molecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide. 113. A method for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a nucleic acid molecule according to claim 60, with one or more compounds suspected of possessing binding affinity for said polypeptide or nucleic acid molecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide. 114. A method for the identification of a compound that is effective in the treatment and/or diagnosis of disease, comprising contacting a host cell according to claim 66, with one or more compounds suspected of possessing binding affinity for said polypeptide or nucleic acid molecule, and selecting a compound that binds specifically to said nucleic acid molecule or polypeptide. 115. A kit useful for diagnosing disease comprising a first container containing a nucleic acid probe that hybridises under stringent conditions with a nucleic acid molecule according to claim 60; a second container containing primers useful for amplifying said nucleic acid molecule; and instructions for using the probe and primers for facilitating the diagnosis of disease. 116. The kit of claim 115, further comprising a third container holding an agent for digesting unhybridised RNA. 117. A kit comprising an array of nucleic acid molecules, at least one of which is a nucleic acid molecule according to claim 60. 118. A kit comprising one or more antibodies that bind to a polypeptide as recited in claim 1 and a reagent useful for the detection of a binding reaction between said antibody and said polypeptide. 119. A transgenic or knockout non-human animal that has been transformed to express higher, lower or absent levels of a polypeptide according to claim 1. 120. A method for screening for a compound effective to treat disease, by contacting a non-human transgenic animal according to claim 119 with a candidate compound and determining the effect of the compound on the disease of the animal. 121. Use of a polypeptide according to claim 1, to modulate the rate at which a medicament is metabolised by the body. 122. Use of a nucleic acid molecule according to claim 60, to modulate the rate at which a medicament is metabolised by the body. 123. Use of a vector according to claim 65, to modulate the rate at which a medicament is metabolised by the body. 124. Use of a ligand according to claim 67, to modulate the rate at which a medicament is metabolised by the body. 125. Use of a compound according to claim 69, to modulate the rate at which a medicament is metabolised by the body. |
<SOH> BACKGROUND <EOH>The process of drug discovery is presently undergoing a fundamental revolution as the era of functional genomics comes of age. The term “functional genomics” applies to an approach utilising bioinformatics tools to ascribe function to protein sequences of interest. Such tools are becoming increasingly necessary as the speed of generation of sequence data is rapidly outpacing the ability of research laboratories to assign functions to these protein sequences. As bioinformatics tools increase in potency and in accuracy, these tools are rapidly replacing the conventional techniques of biochemical characterisation. Indeed, the advanced bioinformatics tools used in identifying the present invention are now capable of outputting results in which a high degree of confidence can be placed. Various institutions and commercial organisations are examining sequence data as they become available and significant discoveries are being made on an on-going basis. However, there remains a continuing need to identify and characterise further genes and the polypeptides that they encode, as targets for research and for drug discovery. Recently, a remarkable tool for the evaluation of sequences of unknown function has been developed by the Applicant for the present invention. This tool is a database system, termed the Biopendium search database, that is the subject of co-pending International Patent Application No. PCT/GB01/01105. This database system consists of an integrated data resource created using proprietary technology and containing information generated from an all-by-all comparison of all available protein or nucleic acid sequences. The aim behind the integration of these sequence data from separate data resources is to combine as much data as possible, relating both to the sequences themselves and to information relevant to each sequence, into one integrated resource. All the available data relating to each sequence, including data on the three-dimensional structure of the encoded protein, if this is available, are integrated together to make best use of the information that is known about each sequence and thus to allow the most educated predictions to be made from comparisons of these sequences. The annotation that is generated in the database and which accompanies each sequence entry imparts a biologically relevant context to the sequence information. This data resource has made possible the accurate prediction of protein function from sequence alone. Using conventional technology, this is only possible for proteins that exhibit a high degree of sequence identity (above about 20%-30% identity) to other proteins in the same functional family. Accurate predictions are not possible for proteins that exhibit a very low degree of sequence homology to other related proteins of known function. In the present case, a protein whose sequence is recorded in a publicly available database as KIAA1440 (NCBI Genebank nucleotide accession number AB037861 and a Genebank protein accession number BAA92678.1), is implicated as a novel member of the P450 family. A second protein whose sequence is recorded in a publicly available database as KIAA0708 (NCBI Genebank nucleotide accession number AB014608 and a Genebank protein accession number BAA31683.1), is also implicated as a novel member of the P450 family. Introduction to P450s P450s are a large superfamily of enzymes all of which use a heme bound iron atom to catalyse the insertion of an oxygen atom into a substrate. The overall reaction of a P450 converts an organic substrate, molecular oxygen and NADPH to a hydroxylated organic substrate, water and NADP+. The oxidation of NADPH is generally carried out by a separate enzyme or enzymes: P450 reductase or ferredoxin and ferredoxin reductase, which subsequently transfer the electrons to the P450. Examples have been found where P450 and P450 reductase have been fused however. Subsequent rearrangements and reactions of the hydroxylated product lead to P450s catalysing a over 40 known reactions. P450s catalyse the oxygenation of a large range of substrates: over 1000 are known to date and there may be 10 6 in total. This broad range of biochemical functions gives P450s a similarly broad range biological functions: detoxification of harmful chemicals, activation (by modification) of beneficial drug precursors and hormones, activation of harmful chemicals (such as carcinogens), breakdown and synthesis of steroids, vitamins, fatty acids, pigments, pheromones, insecticides amongst other classes of biological molecule. P450s are found in nearly all known organisms including plants, animals, fungi and bacteria. In mammals P450s are found in most tissues though their concentration is highest in the liver where the detoxification of many chemicals takes place. P450 genes are also implicated in growth and differentiation of cells due to their tissue and developmental specific expression patterns. The P450's role in the metabolism (both activation and deactivation) of drugs and carcinogens has made them the subject of much medical interest. The susceptibility of a drug to inactivation by P450s may make it biologically inactive. Also many drugs are administered in an inactive form and only become active when they have passed through the liver and been altered by P450s once and even twice. P450s have been the subject of extensive site-directed mutagenesis experiments which have aimed to determine residues essential for substrate binding specificity. Most P450 structures are of soluble bacterial enzymes though there have been efforts to homology model mammalian enzymes in order to aid understanding of variations in substrate binding specificities and to aid rational drug design efforts. Fungal and bacterial P450s are also of medical interest because of their potential as antibiotic targets. P450s catalyse the formation of many crucial biological compounds required by pathogens and inhibitors of P450 activity are usually strong antibiotics. Inhibitors of P450s could stop inactivation of drugs and activation of carcinogens. Or example, the drug exemestane has been approved for use as an inhibitor of aromatase P450 in breast cancer. Azole antifungals such as Nizoral and Diflucan inhibit the P450 lanosterol demethylase, which catalyses the synthesis of ergosterol, a major component of fungal plasma membranes. Recent studies have also crystallised a Mycobacterium tuberculosis P450 in complex with two different azole inhibitors, 4-phenylimidazole (4-PI) and FLU, helping understanding of binding of these important antifungals. There is thus a great need for the identification of novel P450s, as these proteins are implicated in the diseases identified above, as well as in other disease states, such as cell proliferative disorders, including neoplasm, melanoma, lung, colorectal, breast, pancreas, head and neck and other solid tumours; autoimmune/inflammatory disorders, including allergy, inflammatory bowel disease, arthritis, psoriasis and respiratory tract inflammation, asthma, and organ transplant rejection; cardiovascular disorders, including hypertension, oedema, angina, atherosclerosis, thrombosis, sepsis, shock, reperfusion injury, and ischemia; neurological disorders including, central nervous system disease, Alzheimer's disease, brain injury, amyotrophic lateral sclerosis, and pain; developmental disorders; metabolic disorders including diabetes mellitus, osteoporosis, and obesity; AIDS, renal disease, infections including viral infection, bacterial infection, fungal infection and parasitic infection and other pathological conditions. The identification of novel P450s in bacterial, fungal and human systems is therefore extremely relevant for the treatment and diagnosis of disease, particularly those set out above. |
<SOH> BRIEF DESCRIPTION OF THE FIGURES <EOH>FIG. 1 : This is the front end of the Biopendium Target Mining Interface. A search of the database is initiated using the PDB code “1DT6”. FIG. 2A : A selection is shown of the Inpharmatica Genome Threader results for the search using 1DT6. The arrow indicates Homo Sapiens P450, a typical P450. FIG. 2B : A selection is shown of the Inpharmatica Genome Threader results for the search using 1DT6. The arrow indicates BAA92678.1 (P450G1). FIG. 2C : Full list of forward PSI-BLAST results for the search using 1DT6. BAA92678.1 (P450G1) is not identified. FIG. 3 : The Redundant Sequence Display results page for BAA92678.1 (P450G1). FIG. 4 : PFAM search results for BAA92678.1 (P450G1). FIG. 5 : SWISS-PROT protein report for BAA92678.1 (P450G1). FIG. 6A : This is the front end of the Biopendium database. A search of the database is initiated using BAA92678.1 (P450G1), as the query sequence. FIG. 6B : A selection of the Inpharmatica Genome Threader results of search using BAA92678.1 (P450G1), as the query sequence. The arrow points to 1DT6. FIG. 6C : A selection of the reverse-maximised PSI-BLAST results obtained using BAA92678.1 (P450G1), as the query sequence. FIG. 7 : AlEye sequence alignment of BAA92678.1 (P450G1) and 1DT6. FIG. 8A : LigEye for 1DT6 that illustrates the sites of interaction of the small molecule inhibitor of Mus Musculus P450, 1DT6 FIG. 8B : iRasMol view of 1DT6, Mus Musculus P450. The coloured balls represent the amino acids in Mus Musculus P450 that are involved in the active site and PROSITE motif and that are conserved in BAA92678.1 (P450G1). FIG. 9 : Report from the NCBI UniGene database for BAA92678.1 (P450G1). FIG. 10 : Report from the SAGE database for BAA92678.1 (P450G1). FIG. 11 : Report from the HUGE database for BAA92678.1 (P450G1). FIG. 12 : This is the front end of the Biopendium Target Mining Interface. A search of the database is initiated using the PDB code “1DZ6:A”. FIG. 13A : A selection is shown of the Inpharmatica Genome Threader results for the search using 1DZ6:A. The arrow indicates Homo Sapiens P450, a typical P450. FIG. 13B : A selection is shown of the Inpharmatica Genome Threader results for the search using 1DZ6:A. The arrow indicates BAA31683.1 (P450G2). FIG. 13C : Full list of forward PSI-BLAST results for the search using 1DZ6:A. BAA31683.1 (P450G2) is not identified. FIG. 14 : The Redundant Sequence Display results page for BAA31683.1 (P450G2). FIG. 15 : PFAM search results for BAA31683.1 (P450G2). FIG. 16 : SWISS-PROT protein report for BAA31683.1 (P450G2). FIG. 17A : This is the front end of the Biopendium database. A search of the database is initiated using BAA31683.1 (P450G2), as the query sequence. FIG. 17B : A selection of the Inpharmatica Genome Threader results of search using BAA31683.1 (P450G2), as the query sequence. The arrow points to 1DZ6:A. FIG. 17C : A selection of the reverse-maximised PSI-BLAST results obtained using BAA31683.1 (P450G2), as the query sequence. FIG. 18 : AlEye sequence alignment of BAA31683.1 (P450G2) and 1DZ6:A. FIG. 19A : LigEye for 1DZ6:A that illustrates the sites of interaction of the small molecule inhibitor of Mus Musculus P450, 1DZ6:A FIG. 19B : iRasMol view of 1DZ6:A, Mus Musculus P450. The coloured balls represent the amino acids in Mus Musculus P450 that are involved in the active site and PROSITE motif and that are conserved in BAA31683.1 (P450G2). FIG. 20 : Report from the NCBI UniGene database for BAA31683.1 (P450G2). FIG. 21 : Report from the SAGE database for BAA31683.1 (P450G2). FIG. 22 : Report from the HUGE database for BAA31683.1 (P450G2). FIG. 23 : Genes and diseases mapped to the same chromosomal location as BAA31683.1 (P450G2). FIG. 24 : Taqman RT-PCR quantitation data shows normalised expression of P450G1 (BAA92768.1) in 18 normal human tissues. FIG. 25 : Taqman RT-PCR quantitation data shows normalised expression of P450G2 (BAA31683.1) in 18 normal human tissues. detailed-description description="Detailed Description" end="lead"? |
Sohc type engine |
An SOHC-type engine in which first and second insertion/removal guide sections for guiding the insertion and removal of first and second spark plugs, respectively, are provided on a cylinder head including an intake valve and the first spark plug disposed therein and arranged along an axis of a camshaft, and an exhaust valve and the second spark plug disposed therein and arranged along the axis of the camshaft. |
1. An SOHC-type engine comprising first and second insertion/removal guide sections (68, 69) for guiding the insertion and removal of first and second spark plugs (66, 67), respectively, provided on a cylinder head (22) including an intake valve (47) and a first spark plug (67) disposed therein and arranged along an axis of a camshaft (34), and an exhaust valve (48) and a second spark plug (67) disposed therein and arranged along the axis of said camshaft (34), wherein a single rocker shaft (55) is disposed above said camshaft (34); and an intake-side rocker arm (59) pivotally following an intake-side cam (57) provided on said camshaft (34) to drive the intake valve (47) and an exhaust-side rocker arm (60) pivotally following an exhaust-side cam (58) provided on said camshaft (34) to drive the exhaust valve (48) carried commonly on said rocker shaft (55), wherein said first insertion/removal guide section (68) and the intake valve (47) are disposed so as to be superposed one on another at least partially in a view of projection onto a plane perpendicular to the axis of said camshaft (34), and said second insertion/removal guide section (69) and the exhaust valve (48) are disposed so as to be superposed one on another at least partially in a view of projection onto said plane. 2. An SOHC-type engine according to claim 1, wherein the shortest distance in said projection view between at least one of said first and second insertion/removal guide sections (68, 69) and said camshaft (34) is set smaller than the shortest distance in said projection view between at least one of valve stems (47a, 48a) of said intake and exhaust valves (47, 48) and said camshaft (34). 3. An SOHC-type engine according to claim 1, wherein the shortest distance in said projection view between said first insertion/removal guide section (68) and said camshaft (34) is set smaller than the shortest distance in said projection view between a valve stem (47a) of the intake valve (47) and said camshaft (34), and the shortest distance in said projection view between said second insertion/removal guide section (69) and said camshaft (34) is set smaller than the shortest distance in said projection view between a valve stem (48a) of the exhaust valve (48) and said camshaft (34). 4. An SOHC-type engine according to any of claims 1 to 3, wherein at least one of upper ends of said first and second insertion/removal guide sections (68, 69) is formed in a curved manner to protrude into a valve-operating chamber (26) defined between said cylinder head (22) and a head cover (23) coupled to said cylinder head (22). 5. An SOHC-type engine according to any of claims 1 to 3, wherein at least an upper portion of said first insertion/removal guide section (68) is formed to have an arcuate cross-sectional shape opened in a direction opposite from said camshaft (34). 6. An SOHC-type engine according to any of claims 1 to 3, wherein at least one of said first and second insertion/removal guide sections (68, 69) is disposed at least partially between each of head bolts (70) for fastening said cylinder head (22) to a cylinder block (21) at locations spaced apart from one another along the axis of said camshaft (34) and at least one of said intake and exhaust valves (47, 48). 7. An SOHC-type engine according to any of claims 1 to 3, wherein at least one of said first and second insertion/removal guide sections (68, 69) is disposed at least partially between a shaft bearing portion (32) provided on said cylinder head (22) to carry said camshaft (34) thereon for rotation and at least one of said intake and exhaust valves (47, 48). 8. An SOHC-type engine according to any of claims 1 to 3, wherein said first and second insertion/removal guide sections (68, 69) are formed to protrude toward said valve-operating chamber (26) at locations corresponding to contact potions of said intake-side and exhaust-side cams (57, 58) immersed partially in an oil bath (71) defined on said cylinder head (22) with said intake-side and exhaust-side rocker arms (59, 60). 9. An SOHC-type engine according to claim 1, wherein at least an upper end of said second insertion/removal guide section (69) is formed into a cylindrical shape, and bolts (82) for fastening a head cover (23) to said cylinder head (22) are disposed between said second insertion/removal guide sections (69) individually corresponding to a plurality of combustion chambers (29A, 29B, 29C and 29D). 10. An SOHC-type engine according to claim 1, wherein a first plug holder (73) connected to the first spark plug (66) inserted into said first insertion/removal guide section (68) protrude from said cylinder head (22); an ignition coil (76) connected to an upper end of said first plug holder (73) are fastened to a head cover (23) coupled to said cylinder head (22) by a single coil bolt (77); and a detent portion (78) are integrally provided on said head cover (23) to come into contact with the upper end of said first plug holder (73) in order to receive a load around the axis of said coil bolt (77) acting on a protrusion of said first plug holder (73) from said cylinder head (22) during tightening of said coil bolt (77). 11. An SOHC-type engine according to claim 10, wherein bolts (82) for fastening said head cover (23) to said cylinder head (22) are disposed between said detent portions (78) corresponding individually to a plurality of combustion chambers (29A to 29D). 12. An SOHC-type engine according to claim 10 or 11,—wherein each of said detent portions (78) is formed into a ring shape. 13. An SOHC-type engine according to any of claims 10 or 11, wherein a fastening boss (93) for fastening said ignition coil (76) is provided on said head cover (23) inside said detent portion (78). 14. An SOHC-type engine according to any of claims 10 or 11, wherein a resilient member (92) is mounted between said detent portion (78) and said first plug holder (73). 15. An SOHC-type engine according to claim 1, wherein upper end faces of said first and second insertion/removal guide sections (68, 69) are formed in the same plane, and a head cover (23) is coupled to said upper end faces of the first and second insertion/removal guide sections (68, 69). 16. An SOHC-type engine according to claim 1, wherein an upper portion of said first insertion/removal guide section (68), into which said first plug holder (73) connected to said first spark plug (66) is inserted, is formed to have an arcuate cross-sectional shape opened forwards in a direction (31) of forward movement of the vehicle. 17. An SOHC-type engine according to claim 1, wherein an upper portion of each of said first insertion/removal guide section (68) is formed to have an arcuate cross-sectional shape opened in direction opposite from said camshaft (34), and a boss (103) for mounting a fuel injection valve (102) is provided on said cylinder head (22) at a location adjoining a lower portion of said first insertion/removal guide section (68) in a direction along the axis of said camshaft (34). 18. An SOHC-type engine according to claim 1, wherein a boss (103) for mounting a fuel injection valve (102) is provided on the cylinder head (22) so as to be integrally connected to said first insertion/removal guide sections (68). 19. An SOHC-type engine according to claim 1, wherein said second insertion/removal guide section (69), an intake-side rocker arm (59), said intake valve (47) and a boss (103) provided on said cylinder head (22) to mount a fuel injection valve (102) are disposed substantially side by side on the same plane perpendicular to the axis of said camshaft (34). 20. An SOHC-type engine according to claim 1, wherein a protrusion (22a) is integrally provided on said cylinder head (22) to project outwards and sideways from a cylinder block (21); a spark plug chamber (109A, 109B, 109C, 109D) faced by a portion of said first spark plug (66) is defined in the cylinder head (22) in such a manner that a portion of said spark plug chamber is disposed on said protrusion (22a); and a drainage bore (11A, HOB, HOC, HOD) is provided in said protrusion (22a), so that one end thereof opens into a lower portion of said spark plug chamber (109A to 109D) and the other end thereof opens into an outer surface of a lower portion of said protrusion (22a). |
<SOH> BACKGROUND ART <EOH>Conventionally, such engine is already known from Japanese Patent Publication No. 60-10165 and the like, for example. In the conventional SOHC-type engine, a pair of rocker shafts are disposed on opposite sides of and above the camshaft, and an intake-side rocker arm moved following an intake-side cam on the camshaft to drive the intake valves is swingably carried on one of the rocker shafts, and an exhaust-side rocker arm moved following an exhaust-side cam on the camshaft to drive the exhaust valves is swingably carried on the other rocker shaft. Therefore, the width of the cylinder head in a direction perpendicular to the camshaft is obliged to become relatively large. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIGS. 1 to 13 show an embodiment of the present invention. FIG. 1 is a vertical sectional view of an upper portion of an engine, taken along a line 1 - 1 in FIG. 3 ; FIG. 2 is a vertical sectional view of the upper portion of the engine, taken along a line 2 - 2 in FIG. 3 ; FIG. 3 is across-sectional view of a cylinder head, taken along a line 3 - 3 in FIG. 2 ; FIG. 4 is a plan view taken along a line 4 - 4 in FIG. 1 for showing the arrangement in a valve-operating chamber; FIG. 5 is a side view of the cylinder head, taken in the direction of an arrow 5 in FIG. 4 ; FIG. 6 is a bottom view of the cylinder head, taken in the direction of an arrow 6 in FIG. 5 ; FIG. 7 is a sectional view of the cylinder head, taken along a line 7 - 7 in FIG. 3 ; FIG. 8 is a plan view taken in the direction of an arrow 8 in FIG. 1 ; FIG. 9 is a plan view of the entire arrangement of a head cover; FIG. 10 is a view for explaining the flowing of an EGR gas among an intake-side fastening face of the cylinder head, a gasket and a plate; FIG. 11 is a sectional view taken along a line 11 - 11 in FIG. 5 ; FIG. 12 is a view of a cooling water system showing the flowing of cooling water when the engine is cold; and FIG. 13 is a view of the cooling water system showing the flowing of cooling water when the engine is hot. detailed-description description="Detailed Description" end="lead"? |
Antibodies abolish prion propagation and remote clearance of infectivity |
Methods are disclosed whereby formulations of molecules are administered rendering cells resistant to infection with infectious proteins such as prions. The formulation preferably comprises a plurality of Fab fragments which (1) recognize and selectively bind to a range of epitopes on the protein of interest, (e.g. epitopes on PrPC) and (2) bind to epitopes which interrupt the chain of events resulting in a change of the protein's conformation to an infectious disease conformation of the protein. The molecules and formulation are also useful in clearing infectious proteins from cells. |
1. A method of preventing infection with PrPSc protein, comprising the steps of: contacting cells with a formulation of molecules which bind to a plurality of epitopes on PrPC protein; and allowing the molecules to remain in contact with the cells for a period of time and under conditions such that binding occurs between the molecules and a plurality of epitopes on PrPC whereby the molecules hinder a change in conformation from PrPC protein to PrPSc protein. 2. The method of claim 1, wherein the molecules are antibodies which bind to PrPC. 3. The method of claim 1, wherein the molecules comprise Fab fragments selected from the group consisting of D13, D18, R1 and R2. 4. A method of clearing a disease conformation of a protein from a cell, comprising the steps of: contacting a cell with a formulation of molecules, wherein the cell is infected with a protein which assumes a first non-disease conformation and wherein both conformations are present in the cell, allowing the molecules to remain in contact with the cell for a period of time and under conditions such that binding occurs between the molecules and a plurality of epitopes on the first conformation of the protein whereby conversion to the second conformation of the protein is prevented for a period of time sufficiently long to allow the cell to clear protein in the second conformation from the cell. 5. The method of claim 4, wherein the protein is a PrP protein, the first conformation is PrPC and the second conformation is PrPSc. 6. The method of claim 5, wherein the molecules are antibodies which bind PrPC. 7. The method of claim 5, wherein the molecules comprise Fab fragments selected from the group consisting of D13, D18, R1 and R2. 8. A method of assaying for molecules which hinder binding to PrPC, comprising the steps of: providing PrPC molecules; providing a test compound; providing an antibody which binds PrPC; allowing the test compound to interact with the PrPC molecules and antibody for a period of time and under conditions such that binding of the antibody to PrPC molecules would be expected; determining a level of binding of the PrPC to the antibody; and calculating the effect of the test compound to effect binding between the antibody and PrPC molecules. 9. The method of claim 8, wherein the antibody is selected from the group consisting of D18 and D13. 10. The method of claim 8, wherein the antibody is bound to a support surface and the PrPC and test compound are provided in a solution or a suspension. 11. The method of claim 8, wherein the PrPC is bound to a support and the antibody and the test compound are provided in a solution or a suspension. 12. A method of treatment, comprising: administering to a subject a therapeutically effective amount of an antibody which binds to PrPC wherein the antibody is present in a pharmaceutically acceptable carrier. 13. The method of claim 12, wherein the antibody is selected from the group consisting of D13 and D18. 14. A method of treatment, comprising: administering to a subject an antigen which results in the generation of antibodies by the subject wherein the antibodies bind PrPC. 15. A composition for preventing infection with PrPSc protein, comprising: a formulation comprising a pharmaceutically acceptable carrier and molecules which bind to a plurality of epitopes on PrPC protein which molecules remain bound to the epitopes for a period of time and under conditions such that binding occurs between the molecules and a plurality of epitopes on PrPC whereby the molecules hinder a change in conformation from PrPC protein to PrPSc protein. 16. The composition of claim 15, wherein the molecules are antibodies which bind epitopes on PrPC. 17. The composition of claim 15, wherein the molecules comprise Fab fragments selected from the group consisting of D13, D18, R1 and R2. 18. A composition for clearing a disease conformation of a protein from a cell, comprising: a formulation comprising a pharmaceutically acceptable carrier and molecules which bind a plurality of epitopes on a first conformation of a protein whereby conversion to a second conformation of the protein is prevented for a period of time sufficiently long to allow a cell to clear protein in the second conformation from the cell. 19. The composition of claim 18, wherein the protein is a PrP protein, the first conformation is PrPC and the second conformation is PrPSc. 20. The composition of claim 19, wherein the molecules are antibodies which bind PrPC. 21. The composition of claim 19, wherein the molecules comprise Fab fragments selected from the group consisting of D13, D18, R1 and R2. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the favored model of prion replication, direct interaction between a pathogenic prion protein (PrP Sc ) template and an endogenous cellular PrP (PrP C ) protein is proposed to drive the formation of nascent infectious prions. (Telling, G. C. et al. Evidence for the conformation of the pathologic isoform of the prion protein enciohering and propagating prion diversity. Science 274, 2079-2082 (1996); Prusiner, S. B. Prions. Proc. Natl Acad. Sci USA 95, 13363-13383 (1998).) Reagents specifically binding either PrP conformer have the potential to interrupt prion production by inhibiting this interaction. Concern over the continuing emergence of variant Creutzfeldt-Jacob disease, which is closely associated with exposure to bovine spongiform encephalopathy prions, has escalated the need for effective prion therapeutics. (Brown, P., Will, R. G., Bradley, R., Asher, D. M., and Detwiler, L. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: Background, evolution, and current concerns. Emerging Infectious Diseases 7, 6-16 (2001); Bruce, M. E. et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389, 498-501 (1997)) Prion propagation is thought to proceed via a mechanism involving specific interaction between PrP C and PrP Sc , possibly in the presence of an additional cellular factor. (Prusiner, S. B. Prions. Proc. Natl Acad. Sci USA 95, 13363-13383 (1998); Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136-144 (1982); Kaneko, K. et al. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc. Natl. Acad. Sci. USA 94, 10069-10074 (1998); Zulianello, L. et al. Dominant-negative inhibition of prion formation diminished by deletion mutagenesis of the prion protein. J.Virol. 74, 4351-4360 (2000)) The present invention is based in part on determining that antibodies recognizing PrP C prevent the requisite molecular interactions and impede PrP Sc formation. The reported efficiency with which a specific antibody reverses Alzheimer's pathology in vivo is supportive of this viewpoint. (Schenk, D. et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400, 173-177 (1999); Bard, F. et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916-919 (2000)). |
<SOH> SUMMARY OF THE INVENTION <EOH>Molecules and in particular antibodies are disclosed which are characterized by their ability to (a) prevent the formation of infectious proteins (e.g. prions); and/or (b) clear infectious proteins such as prions from infected cells. The molecules such as antibodies and therapeutically active fragments thereof are preferably included in a pharmaceutical formulation which is administered via a method of the invention to treat and/or prevent disease such as prion related diseases which are associated with a particular conformation (e.g. PrP Sc ) of a protein (e.g. a PrP protein). Methodology is disclosed whereby infection with PrP Sc protein is prevented and/or an established PrP Sc infection is treated and PrP Sc in cleared. The method comprising bringing certain molecules into contact with cells and allowing those molecules to remain in contact with the cells for a time and under conditions such that the molecules bind to epitopes on PrP C and thereby hinder a change in conformation from PrP C protein to PrP Sc protein. The molecules are preferably in a pharmaceutical formulation and more preferably comprise Fab fragments selected from the group consisting of D 13 , D 18 , R 1 and R 2 . The present invention focuses on a panel of recombinant antibody Fab fragments, which recognize different epitope regions on PrP, and inhibit prion propagation in PrP Sc -infected cultured mouse neuroblastoma cells (ScN2a). Antibodies disclosed here bind cell surface PrP C and thereby inhibit PrP Sc formation in a dose dependent manner. In cells treated with the most potent antibody, Fab D 18 , prion replication is completely abolished and pre-existing PrP Sc is rapidly cleared, demonstrating the ability of this antibody to cure an established PrP Sc infection. The potent activity of Fab D 18 is associated with (1) its ability to more completely recognize the total population of PrP C molecules on the cell surface relative to other antibodies and (2) with the location of the epitope on a PrP C protein that the Fab D 18 binds to. The results provided demonstrate the ability of antibodies to prevent and treat prion diseases and identify a region of PrP C for drug targeting. The invention further includes an assay device and method of carrying out an assay. The method comprises using high-throughput screening methodology to identify which molecules are capable of hindering binding between an antibody such as D 18 and PrP C . The identified molecules could then be tested using methodology described further here to determine their ability to prevent conversion of PrP C protein to PrP Sc protein in the presence of a natural milieu where such a conversion would normally be expected to take place. An aspect of the invention is molecules including antibodies and fragments thereof which effect the formation and/or clearance of infectious proteins from cells. There are two further aspects to the invention which are therapeutic in nature. First, antibodies are administered to treat a preexisting prion disease and/or to prevent an animal from developing a prion disease. Second, antigens are administered which generate an immune response (i.e. produce antibodies) and the antibodies generated treat a preexisting prion disease and/or prevent an animal from developing a prion disease. These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the molecules, antibodies and methodologies as more fully described below. |
Method and device for calculating a forward price for using links in a network |
The invention relates to a method for calculating in a network that comprises links a joint distribution of forward prices for using the links in the network. The method comprises the following steps: a) a provision step for providing an observed forward price of a forward contract for each of the links, b) a determination step for deriving from the observed forward prices a proposed joint distribution of forward prices by applying a forward pricing process to each of the links, thereby generating a geographical arbitrage in the network; c) an arbitrage reduction step for reducing the geographical arbitrage in the proposed joint distribution of forward prices by a geographical arbitrage reduction value; d) a verification step for verifying if the proposed joint distribution of forward prices together with the observed forward prices has a defined property in response to the determination step and the arbitrage reduction step; if the verification step results in the defined property being not present e) a generation step for generating a property reduction value; repeating the determination step, the arbitrage reduction step and the verification step, applying the property reduction value to the forward pricing process of each of the links. |
1. Method for calculating in a network that comprises links, a joint distribution of forward prices for using the links in the network, said method comprising: a provision step for providing an observed forward price of a forward contract for each of said links; a determination step for deriving from the observed forward prices a proposed joint distribution of forward prices by applying a forward pricing process to each of said links, thereby generating a geographical arbitrage in the network; an arbitrage reduction step for reducing the geographical arbitrage in the proposed joint distribution of forward prices by a geographical arbitrage reduction value; a verification step for verifying if the proposed joint distribution of forward prices together with the observed forward prices has a defined property in response to the determination step and the arbitrage reduction step; if the verification step results in the defined property being not present a generation step for generating a property reduction value; repeating the determination step, the arbitrage reduction step and the verification step, applying the property reduction value to the forward pricing process of each of said links. 2. Method according to claim 1, wherein the verification step comprises a detection step for detecting a difference from the defined property of the proposed joint distribution of forward prices together with the observed forward prices; a decision step for deciding whether or not the detected difference satisfies a defined criterion. 3. Method according to claim 2, wherein the defined criterion comprises a predefined threshold. 4. Method according to claim 2 or comprising for satisfying the defined criterion: a difference reduction step for reducing the detected difference by adding to the forward pricing process of each of said links the property reduction value. 5. Method according to claim 1 further comprising deriving from the joint distribution of forward prices a forward price for a specific link. 6. Method according to claim 1, wherein the forward pricing process comprises one or more functions of: Heath-Jarrow-Morton,Ciewlow-Strickland,Manoliu-Tompaidis, Brace-Gatareck-Musiela, Jamshidian. 7. Method according to claim 1, wherein the defined property is a Martingale. 8. Method according to claim 1 further comprising a statistics step for deriving statistical estimates of properties of the property reduction value. 9. Method according to claim 8 further comprising repeating the statistics step sequentially over time to obtain simulations of forward prices. 10. Method according to claim 1 further comprising applying the method to a subset of the network. 11. (Cancelled) 12. (Cancelled) 13. (Cancelled) 14. A computer readable medium containing a computer executable code that when read by a computer causes the computer to perform a method for calculating a joint distribution of forward prices for using links in a network, said method comprising: a provision step for providing an observed forward price of a forward contract for each of said links; a determination step for deriving from the observed forward prices a proposed joint distribution of forward prices by applying a forward pricing process to each of said links, thereby generating a geographical arbitrage in the network; an arbitrage reduction step for reducing the geographical arbitrage in the proposed joint distribution of forward prices by a geographical arbitrage reduction value; a verification step for verifying if the proposed joint distribution of forward prices together with the observed forward prices has a defined property in response to the determination step and the arbitrage reduction step; if the verification step results in the defined property being not present a generation step for generating a property reduction value; repeating the determination step, the arbitrage reduction step and the verification step, applying the property reduction value to the forward pricing process of each of said links. 15. The computer readable medium according to claim 14, wherein the verification step comprises a detection step for detecting a difference from the defined property of the proposed joint distribution of forward prices together with the observed forward prices; a decision step for deciding whether or not the detected difference satisfies a defined criterion. 16. The computer readable medium according to claim 15, wherein the defined criterion comprises a predefined threshold. 17. The computer readable medium according to claim 15 comprising for satisfying the defined criterion: a difference reduction step for reducing the detected difference by adding to the forward pricing process of each of said links the property reduction value. 18. The computer readable medium according to claim 14 further comprising deriving from the joint distribution of forward prices a forward price for a specific link. 19. The computer readable medium according to claim 14, wherein the forward pricing process comprises one or more functions of: Heath-Jarrow-Morton,Clewlow-Strickland,Manoliu-Tompaidis, Brace-Gatareck-Musiela, Jamshidian. 20. The computer readable medium according to claim 14, wherein the defined property is a Martingale. 21. The computer readable medium according to claim 14 further comprising a statistics step for deriving statistical estimates of properties of the property reduction value. 22. The computer readable medium according to claim 21 further comprising repeating the statistics step sequentially over time to obtain simulations of forward prices. 23. The computer readable medium according to claim 14 further comprising applying the method to a subset of the network. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Derivatives, especially derivatives of forward contracts, are important for risk management and hedging. However there is currently no method available to price contingent claims where the underlying asset is a claim on some part of a network and taking into account properties of forward prices on networks, specifically geographical-(no)-arbitrage and the requirement that tradeable commodities (e.g. Forwards) should be Martingales (under an appropriate measure). Forward derivatives will be of larger importance for bandwidth than for many conventional commodities because bandwidth cannot be stored for later use whilst forward-based contracts are storable over their lifetime (creation to maturity). A forward contract is a contract entered into at a given time for certain delivery at a later point in time, the contract maturity T. The price of a forward contract is often denoted by F(0,T) when it is entered into and denoted by F(t,T) at later times where t>=0 and t<=T. A forward curve at any time t is a set of prices of forward contracts of different maturities. For example a forward curve at time t for maturities between t and T* (where T*>=t) comprises all the forward prices F(t,T) with such that T>=t and T<=T*. Bandwidth is becoming commoditized and markets are starting to appear. Potential behaviors of these markets are not understood because these markets are still in the early stages of development. The instruments traded on bandwidth markets, mostly over-the-counter (OTC), are typically forward contracts covering long (months to years) periods. This is partly due to inefficient negotiation and contract settlement mechanisms. New switching technologies, public pooling, and interconnection points are expected to hasten automation towards more liquid bandwidth markets and shorter contract periods as well as the development of a spot market. Additionally, fiber swaps are not uncommon. Forward derivatives, especially forward call options, are expected to appear given their appropriateness for risk management. Call options on forwards provide the right, but not the obligation, to use capacity in the future starting at some fixed date for a given duration upon payment of some price agreed when the contract is established. These options may be of a European (decide on use only at maturity), American (decide on use at any time up to maturity), or other type (design to meet customer requirements). Swaptions between different network providers are developing together with more specialised instruments with unique applicability to a networked commodity. Point-to-point bandwidth capacity cannot be stored for later use and so forward contracts are the primary market instruments, as in other commodity markets including electricity. Today, there is no suitable forward curve model that takes into account the special characteristics of bandwidth as a tradable commodity. Standard models cannot be blindly applied because they generate geographical arbitrage opportunities since they do not take into account alternative paths between points with equivalent quality of service (QoS). Hence a model of the forward curve to price a particular set of forward-derivative contracts will be highly useful both for comparing different forward contracts and for valuing derivatives. A forward contract is defined as a contract in which capacity is bought today to be used starting at a fixed date in the future and for a fixed duration. As indicated, conventional forward curve models developed are insufficient because they do not include the network structure of the bandwidth market. That is, alternative routes with equivalent quality of service (QoS) are perfect substitutes. This has been shown to greatly affect spot price development. There is a need for a multi-factor forward curve model that takes into consideration geographical arbitrage terms and desired properties such as the Martingale structure. The model should allow the calculation of a distribution of forward prices for using links in a network. This patent application is related to another patent application, entitled “METHOD AND DEVICE FOR CALCULATING A PRICE FOR USING A SPECIFIC LINK IN A NETWORK” filed on 18 Apr. 2001, presently assigned to the assignee of the instant application and the disclosure of which is incorporated herein by reference. |
<SOH> SUMMARY AND ADVANTAGES OF THE INVENTION <EOH>According to one aspect of the present invention there is provided a method for calculating in a network that comprises links a joint distribution of forward prices for using the links in the network. The method comprises the following steps: a) a provision step for providing an observed forward price of a forward contract for each of the links, b) a determination step for deriving from the observed forward prices a proposed joint distribution of forward prices by applying a forward pricing process to each of the links, thereby generating a geographical arbitrage in the network; c) an arbitrage reduction step for reducing the geographical arbitrage in the proposed joint distribution of forward prices by a geographical arbitrage reduction value; d) a verification step for verifying if the proposed joint distribution of forward prices together with the observed forward prices has a defined property in response to the determination step and the arbitrage reduction step; if the verification step results in the defined property being not present e) a generation step for generating a property reduction value; repeating the determination step, the arbitrage reduction step and the verification step, applying the property reduction value to the forward pricing process of each of the links. An advantage of the method is that it enables derivative contracts to be consistently priced to market expectations, as these can be expressed through forward curve statics and dynamics. A single forward price for a specific link within the network can easily be derived from the joint distribution of forward prices. The verification step can comprise a detection of a difference from the defined property of the proposed joint distribution of forward prices together with the observed forward prices and a decision step for deciding whether or not the detected difference satisfies a defined criterion. The defined criterion can comprise a predefined threshold. This allows to fine tune the result of the joint distribution of forward prices. For satisfying the defined criterion the method can comprise a difference reduction step for minimizing the detected difference by applying to the forward pricing process of each of the links a property reduction value. In an preferred embodiment, the steps of the method are repeated from the determination step to the decision step. This can be done until a satisfying result in view of the defined criterion, i.e. the predefined threshold, is reached. When the defined property is a Martingale, and the forward prices are appropriately discounted, for example by using an appropriate yield curve, then the advantage occurs that the result matches market behavior as expected for tradable instruments. Forward curves result from repeating the given method for forward prices of a range of forward price maturities. The method for calculating a joint distribution of forward prices, also referred to as forward curves, for using links in the network has the following properties: The specific nature of bandwidth is considered, i.e. it is a network-based commodity. Observed forward prices can be used as an input. Geographical arbitrage can occur due to the fact of multiple possible paths with equivalent quality of service (QoS). Arbitrage across time for the forward prices themselves is also considered by insisting that the discounted forward prices are Martingales under an appropriate discounting and measure. In general, the method takes as basis or input a graph of traded forward contracts reflecting indivisible point-to-point bandwidth capacity on the underlying network. The forward prices are initially modeled as independent for each link of the graph by using a forward pricing process, such as the so-called process of Heath-Jarrow-Morton, Clewlow-Strickland [CS00], Manoliu-Tompaidis [MT99]. Brace-Gatareck-Musiela, or Jamshidian, Further, there are compensators added, as a geographical-no-arbitrage is imposed on forward prices at each time step and a time-no-arbitrage is imposed by adding a term whose value is such that the discounted forward price under risk neutral measure is, for example, a Martingale. The steps are repeated until a desired result is reached. The advantage of this method of forward curve creation is that it enables pricing of derivative contracts taking into account the topology of the underlying networks. Moreover, the method can be used for calculating functions of forward prices, i.e. derivative prices. Also possible is to use the method for calculating hedging strategies. In accordance with a second aspect of the present invention there is provided a network-pricing device comprising: a computer program product according to the method, a processor for executing the method, the processor having access to network information comprising for the network the observed forward price for each of the links. Embodiments of this aspect of the invention therefore employ similar principles to embodiments of the first aspect of the invention. |
Hop extracts and use thereof in the production of a medicament having estrogenic properties |
A hop extract obtained from the female hop cones of certain varieties of hops, primarily includes the following prenylflavanoid constituents: xanthohumol, isoxanthohumol and 8-prenylnaringenine, in defined weight proportions. The extract is used in the production of a medicament having estrogenic properties, used to treat physiological disorders related to perimonopause or menopause such as hot flashes. The medicament can also be used in dietary compositions of food supplements and cosmetic compositions. |
1. A hop extract obtained from female Humulus lupulus hop cones derived from at least one of the following hop varieties: brewer's gold, cascade, cluster, colombus, galena, northern brewer, nugget, zeus, magnuim, perle or taurus, and containing, among the prenylflavonoids, mainly the following three constituents: xanthohumol, isoxanthohumol and 8-prenylnaringenin. 2. The hop extract as claimed in claim 1, characterized in that it contains at least one other prenylflavonoid from: desmethylxanthohumol, tetrahydroxygeranylchalcone, 5-prenylxanthohumol, dehydrocycloxanthohumol, dehydrocycloxanthohumol hydrate, 6-prenylnaringenin, 8-geranylnaringenin, 6-geranylnaringenin and 3′-geranylchalconaringenin. 3. The hop extract as claimed in claim 1, characterized in that it contains at least 3% by weight of prenylflavonoids. 4. The extract as claimed in claim 1, characterized in that it contains said three constituents in the following weight proportions: from 1 to 30 g of xanthohumol, from 0.01 to 50 g of isoxanthohumol and from 0.5×10−3 to 10 g of 8-prenylnaringenin, in 100 g of dry extract. 5. The extract as claimed in claim 1, characterized in that it contains said three constituents in the following weight proportions: from 3 to 15 g of xanthohumol, from 3 to 30 g of isoxanthohumol and from 0.01 to 5 g of 8-prenylnaringenin, in 100 g of dry extract. 6. The use of the extract as claimed in claim 1, for producing a medicament having estrogenic properties. 7. The use of the extract as claimed in claim 1, for producing a medicament intended for the treatment of physiological disorders related to perimenopause and menopause. 8. The use as claimed in claim 7, for producing a medicament intended for the treatment of hot flushes. 9. A method for producing a medicament having estrogenic properties comprising the steps of mixing xanthohumol, isoxanthohumol and 8-prenylnaringenin in the following relative weight proportions in 100 g of dry extract: from 1 to 30 g of xanthohumol, from 0.01 to 50 g of isoxanthohumol and from 0.5×10−3 to 10 g of 8-prenylnaringenin. 10. A method for producing a medicament for the treatment of physiological disorders related to perimenopause and menopause comprising the steps of mixing xanthohumol, isoxanthohumol and 8-prenylnaringenin in the following relative weight proportions in 100 g of dry extract: from 3 to 15 g of xanthohumol, from 3 to 30 g of isoxanthohumol and from 0.01 to 5 g of 8-prenylnaringenin. 11. The method as claimed in claim 9, for producing a medicament for the treatment of hot flashes. 12. A dietetic composition containing a mixture of xanthohumol, isoxanthohumol and 8-prenylnaringenin in the following relative weight proportions in 100 g of dry extract: from 1 to 30 g of xanthohumol, from 0.01 to 50 g of isoxanthohumol and from 0.5 to 10 g of 8-prenylnaringenin. 13. A food supplement containing a mixture of xanthohumol, isoxanthohumol and 8-prenylnaringenin in the following relative weight proportions in 100 g of dry extract: from 1 to 30 g of xanthohumol, from 0.01 to 50 g of isoxanthohumol and from 0.5 to 10 g of 8-prenylnaringenin. 14. A cosmetic composition containing a mixture of xanthohumol, isoxanthohumol and 8-prenylnaringenin in the following relative weight proportions in 100 g of dry extract: from 1 to 30 g of xanthohumol, from 0.01 to 50 g of isoxanthohumol and from 0.5 to 10 g of 8-prenylnaringenin. |
Compositions, formulations and kit with anti-sense oligonucleotide and anti-inflammatory steroid and/or obiquinone for treatment of respiratory and lung disesase |
A pharmaceutical composition and formulations comprise preventative, prophylactic or therapeutic amounts of an oligo(s) anti-sense to a specific gene(s) or its corresponding mRNA(s), and a glucocorticoid and/or non-glucocorticoid steroid or a ubiquinone or their salts. The agents, composition and formulations are used for treatment of ailments associated with impaired respiration, bronchoconstriction, lung allergy(ies) or inflammation, and abnormal levels of adenosine, adenosine receptors, sensitivity to adenosine, lung surfactant and ubiquinone, such as pulmonary fibrosis, vasoconstriction, inflammation, allergies, allergic rhinitis, asthma, impeded respiration, lung pain, cystic fibrosis, bronchoconstriction, COPD, RDS, ARDS, cancer, and others. The present treatment is effectively administered by itself for conditions without known therapies, as a substitute for therapies exhibiting undesirable side effects, or in combination with other treatments, e.g. before, during and after other respiratory system therapies, radiation, chemotherapy, antibody therapy and surgery, among others. Each of the agents of this invention may be administered directly into the respiratory system so that they gain direct access to the lungs, or by other effective routes of administration. A kit comprises a delivery device, the agents and instructions for its use. |
1. A pharmaceutical composition, comprising a pharmaceutically or veterinarily acceptable carrier or diluent, and prophylactic or therapeutic amounts of a first and second active agents; the first active agent comprising an oligonucleotide(s) (oligo(s)) that is anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ and 3′ intron-exon junctions, or regions within 2 to 10 nucleotides of the junctions of one or more gene(s) encoding or to regulatory sequence(s) associated with one or more target polypeptide(s) associated with lung and/or nasal airway dysfunction, or anti-sense to the corresponding mRNA; or combinations or mires of the oligo(s); and the second active agent comprising an anti-inflammatory steroid (AIS) of chemical formula wherein R1, R2, R3, R4, R6, R7, R8, R9, R10, R12, R13, R14 and R19 are independently H, OR, halogen, (C1-C10) alkyl, (C1-C10) alkene, (C1-C10) alkyne, (C1-C10) alkoxy, or two or more of R1, R2, R3, R4, R6, R7, R8, R9, R10, R12, R13, R14 and R19 can be linked by combination of the atoms of C, O, N, S, P and Si to form a 3 to 15 member ring(s), in the α- and/or β-configuration; R5, R6, R10, and R11, are independently OH, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20, —OPOR20R21, (C1-C10) alkyl, (C1-C10) alkene, (C1-C10) allyne or OR23, wherein, R23 is hydrogen or SO2OM, wherein M is selected from H, Na, sulfatide; or phosphatide wherein R24 and R25, which may be the same or different, are straight or branched (C1-C20) alkyl, (C1-C20) alkene, (C1-C20) alkyne, sugar, polyethyleneglycol (PEG) or glucuronide R5 and R6 taken together are ═O; R10 and R11 taken together are ═O; R15 is (1) H, halogen, (C1-C10) alkyl, (C1-C10) alkene, (C1-C10) alkyne, or (C1-C10) alkoxy when R16 is —C(O)OR22, (2) H, halogen, OH, (C1-C10) alkyl, (C1-C10) alkene or (C1-C10) alkyne, when R16 is halogen, OH, (C1-C10) alkyl, (C1-C10) alkene or (C1-C10) alkyne, (3) H, halogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, formyl, (C1-C10) alkanoyl or epoxy when R16 is OH, (4) OR, SR, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20 or —OPOR20R21 when R16 is H, or R15 and R16 taken together are ═O; R17 and R18 are independently (1) H, —OH, halogen, (C1-C10) alkyl, (C1-C10) alkene, (C1-C10) alkyne or —(C1-C10) alkoxy when R6 is H OR, halogen, (C1-C10) alkyl or —C(O)OR22, (2) H, (C1-C10alkyl)n amino, (C1-C10 alkene)n amino, (C1-C10alkyne)n amino, ((C1-C10) alkyl)n amino-(C1-C10) alkyl, ((C1-C10) alkene)n amino-(C1-C10) alkyl, ((C1-C10) alkyne)n amino-(C1-C10) alkyl, ((C1-C10) alkyl)n amino-(C1-C10) alkene, ((C1-C10) alkene)n amino-(C1-C10) alkene, ((C1-C10) alkyne)n amino-(C1-C10) alkene, ((C1-C10) alkyl)n amino-(C1-C10) alkyne, ((C1-C10) alkene)namino-(C1-C10) alkyne, ((C1-C10) alkyne)n amino-(C1-C10) alkyne, (C1-C10) alkoxy, hydroxy-(C1-C10) alkyl, hydroxy-(C1-C10) alkene, hydroxy-(C1-C10) alkyne, (C1-C10) alkoxy-(C1-C10) alkyl, (C1-C10) alkoxy-(C1-C10) alkene, (C1-C10) alkoxy-(C1-C10) alkyne, (halogen)m (C1-C10) alkyl, (halogen)m (C1-C10) alkene, (halogen)m (C1-C10) alkyne, (C1-C10) alkanoyl formyl, (C1-C10) carbalkoxy or (C1-C10) alkanoyloxy when R15 and R16 taken together are ═O, (3) R17 and R18 taken together are ═O; (4) R17 and R18 taken together with the carbon to which they are attached form a 3-6 member ring containing 0 or 1 oxygen atom; or (5) R15 and R17 taken together with the carbons to which they are attached form an epoxide ring; R20 and R21 are independently OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether; R22 is H, (halogen)m (C1-C10) alkyl, (halogen)m(C1-C10) alkene, (halogen)m (C1-C10) alkyne, (C1-C10) alkyl, (C1-C10) alkene or (C1-C10) alkyne; n is 0, 1 or 2; and m is 1, 2 or 3; or pharmaceutically or veterinarily acceptable salts thereof; and/or a ubiquinone of the chemical formula wherein n=1 to 12, or pharmaceutically or veterinarily acceptable salts thereof; the first and second agents being present in amounts effective for reducing or depleting levels of, or reducing sensitivity to, adenosine, reducing levels of adenosine receptors, producing bronchodilation, increasing levels of ubiquinone or lung surfactant in a subject's tissue (s), or treating bronchoconstriction, lung inflammation or lung allergies or a respiratory or lung disease or condition. 2. The composition of claim 1, wherein the oligo contains up to about 15% A. 3. The composition of claim 1, wherein the oligo(s) of the first active agent is (are) anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, and regions within 2 to 10 nucleotides of the junctions of at least one oncogene(s) or a gene(s) encoding, or regulating expression of, a target polypeptide(s) associated with lung and/or nasal airway dysfunction or cancer, is (are) anti-sense to the corresponding mRNA(s). Multiple target anti-sense oligo(s) (MTAs) or combinations thereof; the polypeptides comprising peptide factors and transmitters, antibodies, cytokines or chemokines, enzymes, binding proteins, adhesion molecules, their receptors, or malignancy associated proteins. 4. The composition of claim 3, wherein the oligo(s) is (are) anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, or regions within 2 to 10 nucleotides of the junctions of at least one oncogene(s) or a gene(s) encoding, or regulating expression of, a target polypeptide(s) associated with lung and/or nasal airway dysfunction or is (are) anti-sense to the oncogene mRNA, or the corresponding mRNA; or MTAs or combinations thereof; wherein the polypeptides comprise of transcription factors, stimulating or activating peptide factors, cytokines, cytokine receptors, chemokines, chemokine receptors, adenosine receptors, bradykinin receptors, endogenously produced specific or non-specific enzymes, immunoglobulins or antibodies, antibody receptors, central nervous system (CNS) or peripheral nervous or non-nervous system receptors, CNS or peripheral nervous or non-nervous system peptide transmitters, adhesion molecules, defensins, growth factors, vasoactive peptides and receptors, binding proteins, or malignancy associated proteins. 5. The composition of claim 4, wherein the encoded polypeptide(s) comprise(s) one or more adenosine receptors A1, A2a, A2b or A3, bradykinin receptors B1 or B2, NFκB Transcription Factor, Interleukin-8 Receptor (IL-8 R), Interleukin 5 Receptor (IL-5 R), Interleukin 4 Receptor (IL-4 R), Interleukin 3 Receptor (IL-3 R), Interleukin-1β (IL-1β), Interleukin 1β Receptor (IL-1βR), Eotaxin, Tryptase, Major Basic Protein, β2-adrenergic Receptor Kinase, Endothelin Receptor A, Endothelin Receptor B, Preproendothelin, Bradykinin B2 Receptor, IgE High Affinity Receptor, Interleukin 1 (IL-1), Interleukin 1 Receptor (IL-1R), Interleukin 9 (IL-9), Interleukin-9 Receptor (IL-9 R), Interleukin 11 (IL-11), Interleukin-11 Receptor (IL-11 R), Inducible Nitric Oxide Synthase, Cyclo-oxygenase-1 (COX-1), Cyclo-oxygenase-2 (COX-2), Intracellular Adhesion Molecule 1 (ICAM-1) Vascular Cellular Adhesion Molecule (VCAM), Rantes, Endothelial Leukocyte Adhesion Molecule (ELAM-1), Monocyte Activating Factor, Neutrophil Chemotactic Factor, Neutrophil Elastase, Defensin 1, 2 and 3, Muscarinic Acetylcholine Receptors, Platelet Activating Factor, Tumor Necrosis Factor α, 5-lipoxygenase, Phosphodiesterase IV, Substance P, Substance P Receptor, Histamine Receptor, Chymase, CCR-1 CC Chemokine Receptor, CCR-2 CC Chemokine Receptor, CCR-3 CC Chemokine Receptor, CCR-4 CC Chemokine Receptor, CCR-5 CC Chemokine Receptor, Prostanoid Receptors, GATA-3 Transcription Factor, Neutrophil Adherence Receptor, MAP Kinase, Interleukin-9 (IL-9), NFAT Transcription Factors, STAT 4, MIP-1α, MCP-2, MCP-3, MCP-4, Cyclophillins, Phospholipase A2, Basic Fibroblast Growth Factor, Metalloproteinase, CSBP/p38 MAP Kinase, Tryptase Receptor, PDG2, Interleukin-3 (IL-3), Interleukin-1β (IL-1β), Cyclosporin A-Binding Protein, FK5-Binding Protein, α4β1 Selectin, Fibronectin, α4β7 Selectin, Mad CAM-1, LFA-1 (CD11a/CD18), PECAM-1, LFA-1 Selectin, C3bi PSGL-1, E-Selectin, P-Selectin, CD-34, L-Selectin, p150, 95, Mac-1 (CD11b/CD18), Fucosyl transferase, VLA-4, CD-18/CD11a, CD11b/CD18, ICAM2 and ICAM3, C5a, CCR3 (Eotaxin Receptor), CCR1, CCR2, CCR4, CCR5, LTB-4, AP-1 Transcription Factor, Protein kinase C, Cysteinyl Leukotriene Receptor, Tachychinnen Receptors (tach R), IkB Kinase 1 & 2, STAT 6, c-mas or NF-Interleukin-6 (NF-IL-6). 6. The composition of claim 4, wherein the encoded polypeptide(s) comprise(s) a H2A histone family member N, Tubulin, beta polypeptide, ELL gene (11-19 lysine-rich leukemia gene); 7-dehydrocholesterol reductase, ADP-ribosylation factor-like 7, Karyopherin alpha 2 (RAG cohort 1, importin alpha 1), EST (AI038433), EST (AI122689), EST (AI092623), ESTs (AI095492), ESTs (AI138216), ESTs (AI128305), ESTs (AI125228), ESTs (AI041482), ESTs (AI051839), Homo sapiens mRNA; cDNA DKFZp434A1716, ESTs (AI096522), ESTs (AI122807), ESTs (AI041212), EST (AI125651), Enolase 1, (alpha), EST (AI024215), EST (AI034360), Homo sapiens nRNA; cDNA DKFZp564HO764, Homo sapiens mRNA for KIAA1363 protein, partial cds, Potassium voltage-gated channel, shaker-related subfamily, beta member 2, ER-associated DNAJ; ER-associated Hsp40 co-chaperone; hDj9; ERj3, ESTs, Weakly similar to p38 protein [H. sapiens] (AA906703), CGI-142, ESTs (AA463249), Homo sapiens clone 25058 mRNA sequence ESTs (R49144), Squamous cell carcinoma antigen 1, ESTs (AA425700), Myosin X, ESTs (AA459692), Epithelial protein lost in neoplasm beta, CD44 antigen (homing function and Indian blood group system), Coagulation factor III (thromboplastin, tissue factor), ESTs (AA909635), Adducin 1 (alpha), 5′ Nucleotidase (CD73), ESTs, moderately similar to semaphorin C [M. musculus] (AA293300), ESTs (AA278764), ESTs (AA678160), Calmodulin 2 (phosphorylase kinase, delta), ESTs (R42770), Chloride intracellular channel 1, High-mobility group (nonhistone chromosomal) protein 17, Ubiquitin carrier protein, Tubulin, alpha 1 (testis specific), Transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase), Sparc/osteonectin, cwcv and kazal-like domains proteoglycan (testican), Proteasome (prosome, macropain) 26S subunit, non-ATPase, 2, TubuLin, beta polypeptide, Filamin B, beta (actin-binding protein-278), Stanniocalcin, Low density lipoprotein receptor (familial hypercholesterolemia), Plectin 1, intermediate filament binding protein, 500 kD, S100 calcium-binding protein A2, Immediate early response 3, Calpain, large polypeptide L2, Pleckstrin homology-Like domain, family A, member 1, Melanoma adhesion molecule, CD44 antigen (homing function and Indian blood group system), Programmed cell death 5, Hexokinase 1, Vascular endothelial growth factor, Integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor), Calumenin, Syntaxin 11, Diphtheria toxin receptor (heparin-binding epidermal growth factor-like growth factor), Fn14 for type I transmembrane protein, Nef-associated factor 1, High-mobility group (nonhistone chromosomal) protein isoforms I and Y, Catechol-O-methyltransferase, C-terminal binding protein 1, Collagen, type XVII, alpha 1, ESTs (N58473), Farnesyl-diphosphate farnesyltransferase 1 RNA helicase-related protein, Interferon stimulated gene (20 kD), Steroid-5-alpha-reductase, alpha polypeptide 1 (3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1), Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase), Laminin, alpha 3 (nicein (150 kD), kalinin (165 kD), BM600 (150 kD), epilegrin), Collagen, type XVII, alpha 1, Keratin 18, Heparan sulfate (glucosamine) 3-O-sulfotransferase 1, Tubulin, alpha 2, Adenylyl cyclase-associated protein, Forkhead box D1, Cathepsin C, ESTs, Highly similar to AF151802—1 CGI-44 protein [H. sapiens] (T74688), Ribonucleotide reductase M2 polypeptide, Laminin, gamma 2 (nicein (100 kD), kalinin (105 kD), BM600 (100 kD), Herlitz junctional epidermolysis bullosa)), Homo sapiens mRNA; cDNA DKFZp586P1622 (from clone DKFZp586P1622), ESTs, Weakly similar to/prediction (AA284245), or Lactate dehydrogenase A. 7. The composition of claim 1, wherein one or more As of the first active agent is(are) substituted by a universal base comprising a heteroaromatic base that binds to thymidine or uridine but has antagonist activity or less than about 0.3 of the adenosine agonist or antagonist activity at the adenosine A1, A2a, A2b or A3 receptors. 8. The composition of claim 7, wherein the heteroaromatic base(s) comprise(s) pyrimidines or purines, which may be substituted by O, halo, NH2, SH, SO, SO2, SO3, COOH, branched or fused primary or secondary amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl, cycloacyl arylacyl, alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, all of which may be further substituted by O, halo, NH2, primary, secondary or tertiary amine, SH, SO, SO2, SO3, cycloalkyl, heterocycloalkyl or heteroaryl. 9. The composition of claim 7, wherein the purines are substituted at positions 1, 2, 3, 6, and/or 8, the pyrimidines are substituted at positions 2, 3, 4, 5 and/or 6, and the purines and pyrimidines have the chemical formula wherein R1, R2, R3, R4 and R5 are independently H, alkyl, alkenyl or alkynyl and R3 is H, aryl, dicycloalkyl, dicycloalkenyl, dicycloalkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, O-cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH2-alkylamino-ketoxyalkyloxy-aryl, or mono or dialkylaminoalkyl-N-alkylamino-SO2aryl, and R4 and R5 are independently R1 and together are R3, and the pyrimidines and purines optionally comprise theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline or xanthine. 10. The composition of claim 9, wherein the universal base of the first active agent comprises 3-nitropyrrole-2′-deoxynucleoside, 5-nitro-indole, 2-deoxyribosyl-(5-nitroindole), 2-deoxyribofuranosyl-(5-nitroindole), 2′-deoxyinosine, 2′-deoxynebularine, 6H, 8H-3,4 diydropyrimido[4,5-c]oxazine-7-one or 2-amino-6-methoxyaminopurine. 11. The composition of claim 1, wherein if present in the first active agent(s), one or more methylated cytocine(s) (mC) is(are) substituted for a C in or to form one or more CpG dinucleotide(s). 12. The composition of claim 1, wherein one or more mononucleotide(s) of the first active agent(s) is(are) linked or modified by one or more of methylphosphonate, 5′-N-carbamate, phosphotriester, phosphorothioate, phosphorodithioate, boranophosphate, formacetal, thioformacetal, thioether, carbonate, carbamate, sulfate, sulfonate, sulfamate, sulfonamide, sulfone, sulfite, sulfoxide, sulfide, hydroxylamine, methylene(methylmito) (MMI), methoxymethyl (MOM), methoxyethyl (MOE), methyleneoxy(methylimino) (MOMI), 2′-O-methyl, phosphoramidate, or C-5 substituted residues. 13. The composition of claim 12, wherein one or more mononucleotide residue(s) of the first active agent(s) are linked by phosphorothioate residues. 14. The composition of claim 1, wherein the anti-sense oligo of the first active agent(s) comprise(s) about 7 to about 60 mononucleotides. 15. The composition of claim 1, wherein the anti-sense oligo of the first active agent(s) comprise(s) fragments 1, 3, 5, 7 and 8 to 2498 (SEQ ED NOS: 1 through 2498). 16. The composition of claim 1, wherein the anti-sense oligo of the first active agent(s) is(are) operatively linked to, or complexed with, a cell internalized or up-taken agent(s) or a cell targeting agent(s). 17. The composition of claim 15, wherein the cell internalized or up-taken agent comprises transferrin, asialoglycoprotein or streptavidin, and the cell targeting agent comprises a prokaryotic or eukaryotic vector or plasmid. 18. The composition of claim 1, wherein the oligo contains up to about 10% A. 19. The composition of claim 1, wherein the oligo(s) of the first active agent(s) is(are) hybridized to a ribonucleic acid or a deoxyribonucleic acid and delivered as a double stranded agent. 20. The composition of claim 1, wherein the carrier or diluent comprises a gaseous, liquid, or solid carrier or diluent, and the active agents are present in an amount of about 0.01 to about 99.99 w/w of the composition. 21. The composition of claim 20, further comprising an agent selected from other therapeutic agents, surfactants, flavoring or coloring agents, fillers, volatile oils, buffering agents, dispersants, RNA inactivating agents, anti-oxidants, flavoring agents, propellants or preservatives. 22. The composition of claim 21, wherein the other therapeutic or bioactive agent(s) is (are) selected from analgesics, pre-menstrual medications, menopausal agents, anti-aging agents, anti-anxyolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schyzophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti-angyogenic agents, cytokines, growth factors, B-adrenergic receptor agonists, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents, hair growth agents, analgesics, pre-menstrual medications, anti-menopausal agents, hormones, anti-aging agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, other hormones, other anti-inflammatory agents, agents for treating arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Crohn's disease, ulcerative colitis, autoimmune disease, or lupus erythematosus, muscle relaxants, soporific agents, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound and burn healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, agents for reperfusion injury, counteracting appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents or hair growth agents. 23. The composition of claim 22, wherein the surfactant comprises surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidyl choline (other than dipalmitoyl), dipalmitoyl phosphatidyl choline, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl serine; phosphatidic acid, ubiquinones, lysophosphatidyl ethanolamine, lysophosphatidyl choline, palmitoyl-lysophosphatidyl choline, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol glycero-3-phosphocholine, dihydroxy acetone, palmitate, cytidine diphosphate (CDP) diacyl glycerol, CDP choline, choline, choline phosphate; natural or artificial lamellar bodies as carrier surfactant vehicles, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric or polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 or synthetic surfactants ALEC, Exosurf, Survan or Atovaquone. 24. The composition of claim 1, comprising one or more oligo(s), an anti-inflammatory steroid(s) of formula (Ia) or (Ib), a steroid, a surfactant and a carrier or diluent for the oligo. 25. The composition of claim 1, wherein the second active agent comprises CoQn, wherein n is 1 to 10. 26. The composition of claim 1, wherein the second active agent comprises CoQn, wherein n is 6 to 10. 27. The composition of claim 1, wherein the second active agent comprises CoQn wherein n is 10. 28. The composition of claim 1, wherein the second active agent comprises an anti-inflammatory steroid (AIS) of formula (Ia) selected from dehydroepiandrosterone, wherein R and R1 are H and the broken line represents a double bond, 16-alpha bromodehydroepiandrosterone wherein R is Br, R1 is H and the broken line represents a double bond, 16-alphafluorodehydroepiandrosterone wherein R is F, R1 is H and the broken line represents a double bond, etiocholanolone, wherein R and R1 are each hydrogen and the broken line represents a single bond, dehydroepiandrosterone sulfate, wherein R is H, R1 is SO2OM and M is a sulfatide group as defined above, and the broken line represents a double bond, the compound of formula (Ia), R is halogen selected from Br, Cl or F, R1 is H, and the broken line represents a double bond, 16-alpha-fluorodehydro-epiandrosterone, or pharmaceutically or veterinarily acceptable salts thereof. 29. The composition of claim 1, wherein the oligo(s) of the first agent contains up to about 5% A. 30. The composition of claim 1, wherein the oligo(s) of the first agent is A free. 31. The composition of claim 1, wherein the second active agent comprises an anti-inflammatory steroid (AIS) of formula (Ib), wherein R15 and R16 together are ═O; R5 is —OH; R5 is —OSO2R20; R15 and R20 together is H; or pharmaceutically or veterinarily acceptable salts thereof. 32. The composition of claim 1, wherein the second active agent comprises an AIS selected from budesonide, testosterone, progesterone, fluticasone, beclomethasone, prednisone, momethasone, estrogen, dexamethasone, hydrocortisone, triamcinolone, flunisolide, methylprednisolone prednisone, hydrocortisone, or analogues thereof. 33. The composition of claim 1, wherein the active agents are present in an amount of about 0.01 to about 99.99 w/w of the composition. 34. The composition of claim 1, wherein the second active agent comprises an anti-inflammatory steroid (AIS) selected from 21-acetoxypregnenolone ((3β)-21-(acetyloxy)-3-hydroxypregn-5-en-20-one); alclometasone ((7α, 11β, 16α)-7-Chloro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its 17,21-dipropionate form (C28H37ClO7); algestone ((16α)-16,17-dihydroxypregn-4-ene-3,20-dione), its cyclic acetal with acetone form (C24H34O4), or its 16α-methyl ether form (C22H32O4); amcinonide ((11β, 16α)-21-(acetyloxy)-16,17-[cyclopentylidenebis(oxy)]-9-fluoro-11-hydroxypregna-1,4-di-ene-3,20-dione); beclomethasone ((11β,16β)-9-chloro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its dipropionate form (C28H37ClO7), or its monopropionate form; betamethasone ((11β,16β)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO6), its 21-adamantoate form (C33H43FO6), its 17-benzoate form (C29H33FO6), its 17,21-dipropionate form (C28H37FO7), its 17-valerate form (C27H37FO6), or its 21-phospate disodium salt form (C22H28FNa2O8P); budesonide ((11β,16α)-16,17-[butylidenebis(oxy)]-11,21-dihydropregna-1,4-diene-3,20-dione); chloroprednisone ((6α)-chloro-17,21-dihydroxypregna-1,4-diene-3,11,20-trione), or its 21-acetate from (C23H27ClO6); ciclesonide; clobetasol ((11β,16β)-21-chloro-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its 17-propionate form (C25H32ClFO5); clobetasone ((16β)-21-chloro-9-fluoro-17-hydroxy-16-methylpregna-1,4-diene-3,11,20-trione), or its 17-butyrate form (C26H32ClFO5); clocortolone ((6α,11β,16α)-9-chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H30ClFO5), or its 21-pivalate form (C27H36ClFO5); cloprednol ((11β)-6-chloro-11,17,21-trihydroxypregna-1,4,6-triene-3,20-dione); coroxon (phosphoric acid 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl diethyl ester); cortisone (17,21-dihydroxypregn-4-ene-3,11,20-trione), its 21-acetate form (C23H30O6), or its 21-cyclopentanepropionate form (C29H40O6); cortivazol ((11β, 16α)-21-(acetyloxy)-11,17-dihydroxy-6,16-dimethyl-2′-phenyl-2′H-pregna-2,4,6-trieno[3,2-c]pyrazol-20-one); deflazacort ((11β,16β)-21-(acetyloxy)-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-(dione); desonide ((11β,16α)11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione); desoximetasone ((11β,16α)-9-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione); dexamethasone ((11β,16α)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO6), its 21-3,3-dimethylbutyrate) form (C28H39FO6; Chemerda et al., U.S. Pat. No. 2,939,873), its 21-diethylaminoacetate form (C29H41FNO6), its 21-isonicotinate form (C28H41FNO6), its 17,21-dipropionate form (C28H37FNO6), or its 21-palmitate form (C38H59FO6); diflorasone ((6α,11β,16β)-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its diacetate form (C26H32F2O7); diflucortolone ((6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16-methylpregna-1,4-ene-3,20-dione), or its 21-valerate form (C27H36F2O5); difluprednate ((6α,11β)-21-acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione); enoxolone ((3β,20β)-3-hydroxy-11-oxoolean-12-en-29-oic acid), or its 18α-hydrogen form; fluazacort ((11β,16β)-21-acetyloxy)-9-fluoro-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione); flucloronide ((6α,11β,16α)-9,11-dichlro-6-fluoro-21-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); flumethasone ((6α,11β,16α)-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H30F2O6), or its 21-pivalate form (C27H36F2O6); flunisolide ((6α,11β,16α)-6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene) bis(oxy)]pregna-1,4-diene-3,20-dione), or its 21-acetate form (C26H33FO7); fluocinolone acetate((6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); fluocinonide ((6α,11β,16α)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); fluocortin butyl ((6α,11β,16α)-6-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-oic acid butyl ester); fluocortolone ((6α,11β,16α)-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO5), its 21-hexanoate form (C28H39FO5), or its 21-pivalate form (C22H37FO5); fluorometholone ((6α,11β)-9-fluoro-11,17-dihydroxy-6-methylpregana-1,4-diene-3,20-dione), or its 17-acetate form (C24H31FO5); fluperolone acetate([11β,17α,17(S)]-17-[2-(acetyloxy)-1-oxopropyl]-9-fluoro-11,17-dihydroxyandrosta-1,4-dien-3-one); fluprednidene acetate((11β)-21-(acetyloxy)-9-fluoro-11,17-dihydroxy-16-methylenepregna-1,4-diene-3,20-dione); fluprednisolone ((6α,11β)-6-fluoro-11,17,21-trihydroxypregna-1,4-diene-3,20-dione), or its 21-acetate form (C23H29FO6); flurandrenolide ((6α,11β, 16α)-6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione); fluticasone propionate ((6α,11β,16α,17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid S-(fluoromethyl) ester); formocortal ((11β,16α)-21-(acetyloxy)-3-(2-chloroethoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-20-oxopregna-3,5-diene-6-carboxaldehyde); halcinonide ((11β,16α)-21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methyethylidene)bis(oxy)]pregn-4-ene-3,20-dione); halobetasol propionate (6α,11β,16β)-21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)pregna-1,4-diene-3,20-dione); halometasone ((6α,11β,16α)-2-chloro-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its monohydrate form (C22H27ClF2O5.H2O); halopredone acetate((6β,11β)-17,21-bis(acetyloxy)-2-bromo-6,9-difluoro-11-hydroxypregna-1,4-diene-3,20-dione); hydrocortamate (N,N-diethylglycine (11β)-11,17-dihydroxy-3,20-dioxopregn-4-en-21-yl ester), or its hydrochloride form (C27H41NO6.HCl); hydrocortisone ((11β)-11,17,21-trihydroxypregn-4-ene-3,20-dione), its 21-acetate form (C23H32H6), its 17-butyrate form (C25H36O6), its 21-phosphate disodium salt form (C21H29Na2O8P), its 21-sodium succinate form (C25H33NaO8), its 17-valerate form (C26H38O6), or its cypionate form; loteprednol etabonate ((11β, 17α)-17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic acid chloromethyl ester); mazipredone ((11β)-11,17-dihydroxy-21-4-methyl-1-piperazinyl)pregna-1,4-diene-3,20-dione), or its hydrochloride form (C26H38N2O4.HCl); medrysone ((6α, 11β)-11-hydroxy-6-methylpregn-4-ene-3,20-dione); meprednisone ((16β)-17,21-dihydroxy-16-methylpregna-1,4-diene-3,11,20-trione), or its 21-acetate form (C24H30O6); methylprednisolone ((6α,11β)-11,17,21-trihydroxy-6-methylpregna-1,4-diene-3,20-dione; Sebek and Spero, U.S. Pat. No. 2,897,218, and Gould, U.S. Pat. No. 3,053,832), its 21-acetate form (C24H32O6), its 21-phosphate disodium salt form (C22H29Na2O8P), its 21-succinate sodium salt form (C26H33NaO8), or its aceponate form (C27H36O7); mometasone furoate ((11β,16α)-9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methylpregna-1,4-diene-3,20-dione); paramethasone ((6α,11β,16α)-6-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO6), its disodium phosphate form, or a mixture of its 21-acetate and disodium phosphate form; prednicarbate ((11β)-17[(ethoxycarbonyl)oxy]-11-hydroxy-21-(1-oxopropoxy)pregna-1,4-diene-3,20-dione);prednisolone ((11β)-11,17,21-trihydroxypregna-1,4-diene-3,20-dione), its 21-acetate form (C23H30O6), its 21-tert-butylacetate form (C27H38O6; Sarrett), its 21-hydrogen succinate form (C25H32O8), its 21-succinate sodium salt form (C25H31NaO8), its 21-stearoylgylcolate form (C41H64O8), its 21-m-sulfobenzoate sodium salt form (C28H31NaO9S; (11β)-11,17-dihydroxy-21-[(3-sulfobenzoyl)oxy]pregna-1,4-diene-3,20-dione monosodium salt), or its 21-trimethylacetate form (C26H36O6); prednisolone 21-diethylaminoacetate (N,N-diethylglycine (11β)-11,17-dihydroxy-3,20-dioxopregna-1,4-dien-21-yl ester; British Patent No. 862,370), or its hydrochloride form (C27H39NO6.HCl); prednisolone sodium phosphate (11,17-dihydroxy-21-(phosphonooxy)pregna-1,4-diene-3,20-dione disodium salt); prednisone (17,21-dihydroxypregna-1,4-diene-3,11,20-trione), or its 21-acetate form (C23H28O6); prednival ((11β)-11,21 dihydroxy-17-[(1-oxopentyl)oxy]pregna-1,4-diene-3,20-dione;), or its 21-acetate form (C28H38O7); prednylidene ((11β)-11,17,21-trihydroxy-16-methylenepregna-1,4-diene-3,20-dione), or its 21-diethylaminoacetate hydrochloride form (C28H39NO6.HCl); rimexolone ((11β,16α,17β)-11-hydroxy-16,17-dimethyl-17-1-oxopropyl)androsta-1,4-dien-3-one); rofleponide ((22R)-6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione); tipredane ((11β,17α)-17(ethylthio)-9α-fluoro-11β-hydroxy-17-(methylthio) androsta-1,4-dien-3-one); tixocortol ((11β)-11,17-dihydroxy-21-mercaptopregn-4-ene-3,20-dione), or its 21-pivalate form (C26H38O5S; (11β)-21-[(2,2-dimethyl-1-oxopropyl)thio]-11,17-dihydroxypregn-4-ene-3,20-dione); triamcinolone ((11β,16α)-9-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione), or its 16,21-diacetate form (C25H31FO8; (11β,16α)-16,21-bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene-3,20-dione); Triamcinolone acetonide ((11β,16α)-9-fluoro-11,21-dihydroxy-16,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione), its 21-acetate crystal form, its 21-disodium phosphate form (C24H30FNa2O9P), or its 21-hemisuccinate form (C28H35FO9); triamcinolone benetonide ((11β,16α)-21-[3-(benzoylamino)-2-methyl-1-oxopropoxy]-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione); or triamcinolone hexacetonide; ((11β,16α)-21-(3,3-dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione), analogues thereof, or pharmaceutically or veterinarily acceptable salts thereof. 35. The composition of claim 1, wherein the second agent comprises a glucocorticoid steroid selected from budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, or mometasone. 36. The composition of claim 1, wherein the first active agent comprises a single stranded anti-sense DNA oligo. 37. The composition of claim 1, wherein the first active agent comprise(s) a double stranded DNA oligo. 38. The composition of claim 1, wherein the first active agent comprises a single stranded anti-sense RNA oligo(s). 39. The composition of claim 1, wherein the first active agent comprises a double stranded RNA oligo(s) 40. The composition of claim 1, which is a systemic or topical formulation. 41. The formulation of claim 40, selected from oral, intrabuccal, intrapulmonary, rectal, intrauterine, intratumor, intracranial, nasal, intramuscular, subcutaneous, intravascular, intrathecal, inhalable, transdermal, intradermal, intracavitary, implantable, iontophoretic, ocular, vaginal, intraarticular, otical, intravenous, intramuscular, intraglandular, intraorgan, intralymphatic, implantable, slow release or enteric coating formulations. 42. The formulation of claim 41, which is an oral formulation, wherein the carrier is selected from solid or liquid carriers. 43. The formulation of claim 42, in the form of a powder, dragees, tablets, capsules, sprays, aerosols, solutions, suspensions and emulsions, or optionally oil-in-water or water-in-oil emulsions. 44. The formulation of claim 41, which is a topical formulation, in the form of cream, gel, ointment, spray, aerosol, patch, solution, suspension or emulsion. 45. The formulation of claim 41, which is an injectable formulation, in the form of an aqueous or alcoholic solution or suspension, an oily solution or suspension, or an oil-in-water or water-in-oil emulsion. 46. The formulation of claim 41, in the form of a rectal or vaginal formulation, optionally a suppository. 47. The formulation of claim 41, in the form of a transdermal formulation, wherein the carrier comprises an aqueous or alcoholic solution, an oily solution or suspension, or an oil-in-water or water-in-oil emulsion. 48. The formulation of claim 47, in the form of an iontophoretic transdermal formulation, wherein the carrier comprises an aqueous or alcoholic solution, an oily solution or suspension, or an oil-in-water or water-in-oil emulsion, and wherein the formulation further comprises a transdermal transport promoting agent. 49. The formulation of claim 41, in the form of an implant, a capsule, a cartridge or a blister. 50. The formulation of claim 49, in the form of an aqueous or alcoholic solution or suspension, an oily solution or suspension, or an oil-in-water or water-in-oil emulsion. 51. The formulation of claim 40, wherein the carrier comprises a hydrophobic carrier. 52. The formulation of claim 51, wherein the carrier comprises lipid vesicles, optionally liposomes; or particles, optionally microcrystals. 53. The formulation of claim 52, wherein the carrier comprises liposomes, and the liposomes comprise the active agent(s). 54. The formulation of claim 41, which is a respirable or inhalable formulation, optionally aerosolizable or sprayable of particle size about 0.05 to about 10 micron. 55. The formulation of claim 54, having a particle size about 0.1 to about 5 micron. 56. The formulation of claim 41, which is a nasal or intrapulmonary formulation, optionally aerosolizable or sprayable of particle size about 8 to about 200 micron. 57. The formulation of claim 56, of particle size about 10 to about 50 micron. 58. The formulation of claim 41, in single or multiple unit form. 59. The formulation of claim 41, in bulk. 60. A therapeutic or prophylactic kit, comprising a delivery device; in separate containers, the active agent(s) of claim 1; and instructions for adding a carrier and preparing a formulation and for use of the kit. 61. The kit of claim 60, wherein the device delivers single metered doses of the formulation. 62. The kit of claim 60, wherein the formulation is a respirable formulation, and the delivery device comprises a nebulizer or a dry powder inhaler. 63. The kit of claim 62, wherein the device comprises a nebulizer or an insufflator and the formulation is provided in a piercable or openable capsule or cartridge. 64. The kit of claim 60, wherein the delivery device comprises a pressurized inhaler and the agent(s) is (are) provided as a suspension, solution or dry formulation of the active agent(s). 65. The kit of claim 60, further comprising, in a separate container, an agent selected from other therapeutic agents, surfactants, anti-oxidants, flavoring agents, fillers, volatile oils, dispersants, antioxidants, propellants, preservatives, buffering agents, RNA inactivating agents, cell-internalized or up-taken agents or coloring agents. 66. The kit of claim 60, comprising, in separate containers, one or more oligos, one or more AIS of formula (Ia), or (Ib) one or more surfactants, a carrier or diluent, optionally other therapeutic agents, and instructions for scheduling the administration of first and second agents. 67. The kit of claim 66, further comprising one or more ubiquinone(s), and instructions for scheduling the administration of first and second agents. 68. The kit of claim 60, wherein the device is a transdermal delivery device, and the kit further comprises a transdermal delivery agent, a transdermal carrier or diluent, and instructions for preparing and delivering a transdermal delivery formulation. 69. The kit of claim 60, wherein the device is an iontophoretic delivery device, and the kit further comprises an iontophoretic agent(s) and instructions for preparing and delivering an iontophoretic formulation. 70. The kit of claim 60, comprising, in separate containers, one or more oligo(s), one or more ubiquinone(s), one or more surfactants, a carrier or diluent, optionally other therapeutic agents, and instructions for scheduling the administration of first and second agents. 71. A method of preventing or treating a respiratory, lung or malignant disease or condition, comprising simultaneously, sequentially or separately administering to a subject in need of treatment, preventative, prophylactic or therapeutic amounts of the first and second active agents of claim 1. 72. The method of claim 71, wherein the oligo(s) and the AIS are administered in amounts effective for alleviating bronchoconstriction and/or lung inflammation or allergy(ies) and/or surfactant depletion or hyposecretion. 73. The method of claim 71, wherein the oligo(s) and the ubiquinone(s) are administered in amounts effective for alleviating bronchoconstriction, lung inflammation or allergies, or ubiquinone or lung surfactant depletion. 74. The method of claim 71, wherein one or more of the agent(s) is (are) administered as a nasal, inhalable, respirable or intrapulmonary composition(s) into the subject's respiratory system. 75. The method of claim 74, wherein one or more of the agents are administered intrapulmonarily or by inhalation. 76. The method of claim 74, wherein the respirable or inhalable composition(s) comprise(s) particles about 0.05 to about 10 micron in size. 77. The method of claim 74, wherein the nasal or intrapulmonary composition comprises particles about 8 to about 100 micron in diameter. 78. The method of claim 74, wherein the composition(s) is (are) administered as a respirable aerosol. 79. The method of claim 71, wherein the ubiquinone(s) is (are) administered orally, and the oligo(s) and the AIS are administered through the respiratory tract. 80. The method of claim 71, wherein the disease or condition is associated with pulmonary obstruction, bronchoconstriction, lung inflammation or allergy(ies), adenosine hypersensitivity, adenosine or adenosine receptor(s), hyperproduction, or surfactant or ubiquinone hypoproduction. 81. The method of claim 71, wherein the disease or condition comprises pulmonary vasoconstriction, respiratory inflammation or allergies, asthma, impeded respiration, respiratory distress syndrome (RDS), lung pain, cystic fibrosis (CF), allergic rhinitis (AR), apnea, pulmonary hypertension, emphysema, chronic obstructive pulmonary disease (COPD), pulmonary transplantation rejection, pulmonary fibrosis, pulmonary infections, bronchitis, or cancer. 82. The method of claim 71, wherein the disease or condition is associated with respiratory allergies, and the first active agent(s) is anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, or regions within 2 to 10 nucleotides of the junctions of at least one gene(s) encoding, or regulating expression of, an immunoglobulin(s), antibody(ies), or immunoglobulin or antibody receptors, or are anti-sense to the immunoglobulin(s), antibody(ies), or immunoglobulin or antibody receptor mRNA; MTAs of the oligo(s) or combinations thereof. 83. The method of claim 71, wherein the disease or condition is associated with a malignancy or cancer, and the oligo is anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, or regions within 2 to 10 nucleotides of the junctions of an oncogene(s) or at least one gene that regulates expression of, or encodes, a malignancy associated protein, or is(are) anti-sense to the oncogene or malignancy associated mRNA; MTAs or combinations thereof. 84. The method of claim 71, wherein the composition is administered transdermally or systemically. 85. The method of claim 71, wherein the composition is administered orally, intracavitarily, intranasally, intraurethral, intracavernous, intraanally, intravaginally, intrauterally, intraarticularly, transdermally, intrabucally, intravenously, subcutaneously, intramuscularly, intravascularly, intratumorously, intraglandularly, intraocularly, intracranial, into an organ, intravascularly, intrathecally, intralymphatically, intraotically, by implantation, by inhalation, intradermally, intrapulmonarily, intraotically, by slow release, by sustained release and by a pump. 86. The method of claim 71, wherein the mammal(s) is a human or non-human mammal. 87. The method of claim 71, wherein the oligo(s) is (are) administered in amount of about 0.005 to about 150 mg/kg body weight. 88. The method of claim 71, wherein the oligo(s) contain(s) up to about 15% A. 89. The method of claim 71, wherein the oligo(s) is (are) substantially free of A. 90. The method of claim 71, wherein the target comprises transcription factors, stimulating or activating factors, interleukins, interleukin receptors, chemokines, chemokine receptors, endogenously produced specific or non-specific enzymes, immunoglobulins, antibody receptors, central nervous system (CNS) or peripheral nervous or non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensines, growth factors, microbial targets, vasoactive peptides, peptide receptors or binding proteins, or malignancy associated proteins. 91. The method of claim 71, wherein one or more As in the oligo(s) is(are) substituted by a universal base that comprise(s) a heteroaromatic base(s) that bind(s) to thymidine or uridine but has(have) less than about 0.3 of the adenosinebase agonist or antagonist activity at an adenosine A1, A2a, A2b or A3 receptor. 92. The method of claim 91, wherein the heteroaromatic base(s) comprise(s) pyimidines or purines, which may be substituted by O, halo, NH2, SH, SO, SO2, SO3, COOH, branched or fused primary or secondary amino, alkyl alkenyl alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, alkenoxy, acyl cycloacyl, arylacyl alkynoxy, cycloalkoxy, aroyl, arylthio, arylsulfoxyl, halocycloalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkynylcycloalkyl, haloaryl, alkylaryl, alkenylaryl, alkynylaryl, arylalkyl, arylalkenyl, arylalkyl, arylcycloalkyl, all of which may be further substituted by O, halo, NH2, primary, secondary or tertiary amine, SH, SO, SO2, SO3, cycloalkyl, heterocycloalkyl or heteroaryl. 93. The method of claim 91, wherein the purines are substituted at positions 1, 2, 3, 6, and/or 8, the pyrimidines are substituted at positions 2, 3, 4, 5 and/or 6 and have the chemical formula wherein R1, R2, R3, R4 and R5 are independently H, alkyl, alkenyl or alkynyl and R3 is H, aryl dicycloalkyl dicycloalkenyl, dicycloalkynyl cycloakyl, cycloalkenyl, cycloalkynyl, O-cycloalkyl, O-cycloalkenyl, O-cycloalkynyl, NH2-alkylamino-ketoxyalkyloxy-aryl, or mono or dialkylaminoalkyl-N-alkylamino-SO2aryl, and R4 and R5 are independently R1 and together are R3, and the pyrimidines and purines optionally comprise theophylline, caffeine, dyphylline, etophylline, acephylline piperazine, bamifylline, enprofylline or xanthine. 94. The method of claim 93, wherein the universal base(s) comprise(s) 3-nitropyrrole-2′-deoxynucleoside, 5-nitro-indole, 2-deoxyribosyl-(5-nitroindole), 2-deoxyribofuranosyl-(5-nitroindole), 2′-deoxyinosine, 2′-deoxynebularine, 6H, 8H-3,4-dihydropyrimido[4,5-c]oxazine-7-one, or 2-amino-6-methoxyaminopurine. 95. The method of claim 71, wherein the second active agent comprises an AIS of formula (Ia) selected from dehydroepiandrosterone, 16-alphabromodehydroepiandrosterone, 16-alpha-fluorodehydroepiandrosterone, etiocholanolone, dehydroepiandrosterone sulfate or other pharmaceutically or veterinarily acceptable salts thereof. 96. The method of claim 71, wherein the second active agent comprises an AIS formula (Ib), wherein R15 and R16 together are ═O; R5 is —OH; R5 is —SO2R20; R15 and R20 together is H; or pharmaceutically or veterinarily acceptable salts thereof. 97. The method of claim 71, wherein the active agents are present in an amount of about 0.01 to about 99.99 w/w of the composition. 98. The method of claim 71, wherein the second active agent comprises an AIS selected from 21-acetoxypregnenolone ((3β)-21-(acetyloxy)-3-hydroxypregn-5-en-20-one); alclometasone ((7α,11β,16α)-7-Chloro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its 17,21-dipropionate form (C28H37ClO7); algestone ((16α)-16,17 dihydroxypregn-4-ene-3,20-dione), its cyclic acetal with acetone form (C28H34O4), or its 16α-methyl ether form (C22H32O4); amcinonide ((11β, 16α)-21-(acetyloxy)-16,17-[cyclopentylidenebis(oxy)]-9-fluoro-11-hydroxypregna-1,4-di-ene-3,20-dione); beclomethasone ((11β,16β)-9-chloro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its dipropionate form (C28H37ClO7), or its monopropionate form; betamethasone ((11β,16β)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO6), its 21-adamantoate form (C33H43FO6), its 17-benzoate form (C29H33FO6), its 17,21-dipropionate form (C28H37FO7), its 17-valerate form (C27H37FO6), or its 21-phospate disodium salt form (C22H28FNa2O8P); budesonide ((11β,16α)-16,17-[butylidenebis(oxy)]-11,21-dihydropregna-1,4-diene-3,20-dione); chloroprednisone ((6α)-chloro-17,21-dihydroxypregna-1,4-diene-3,11,20-trione), or its 21-acetate from (C23H27CO6); ciclesonide; clobetasol ((11β,16β)-21-chloro-9-fluoro-11,17-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its 17-propionate form (C25H32ClFO5); clobetasone ((16β)-21-chloro-9-fluoro-17-hydroxy-16-methylpregna-1,4-diene-3,11,20-trione), or its 17-butyrate form (C26H32ClFO5); clocortolone ((6α,11β,16α)-9-chloro-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H30ClFO5), or its 21-pivalate form (C27H36ClFO5); cloprednol ((11β)-6-chloro-11,17,21-trihydroxypregna-1,4,6-triene-3,20-dione); coroxon (phosphoric acid 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl diethyl ester); cortisone (17,21-dihydroxypregn-4-ene-3,11,20-trione), its 21-acetate form (C23H30O6), or its 21-cyclopentanepropionate form (C29H40O6); cortivazol ((11β,16α)-21-(acetyloxy)-11,17-dihydroxy-6,16-dimethyl-2′-phenyl-2′H-pregna-2,4,6-trieno[3,2-c]pyrazol-20-one); deflazacort ((11β,16β)-21-(acetyloxy)-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione); desonide ((11β,16α)11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione); desoximetasone ((11β,16α)-9-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione); dexamethasone ((11β,16α)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO6), its 21-(3,3-dimethylbutyrate) form (C28H39FO6; Chemerda et al., U.S. Pat. No. 2,939,873), its 21-diethylaminoacetate form (C28H41FNO6), its 21-isonicotinate form (C28H41FNO6), its 17,21-dipropionate form (C28H37FNO6), or its 21-palmitate form (C38H59FO6); diflorasone ((6α,11β,16β)-6,9-difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its diacetate form (C26H32F2O7); diflucortolone ((6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its 21-valerate form (C27H36F2O5); difluprednate ((6α,11β)-21-(acetyloxy)-6,9-difluoro-11-hydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione); enoxolone ((3β,20β)-3-hydroxy-11-oxoolean-12-en-29-oic acid), or its 18α-hydrogen form; fluazacort ((11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione); flucloronide ((6α,11β,16α)-9,11-dichlro-6-fluoro-21-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); flumethasone ((6α,11β,16α)-6,9 difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H30F2O6), or its 21-pivalate form (C27H36F2O6); flunisolide ((6α,11β,16α)-6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene) bis(oxy)]pregna-1,4-diene-3,20-dione), or its 21-acetate form (C26H33FO7); fluocinolone acetate((6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); fluocinonide ((6α,11β,16α)-21-acetyloxy)-6,9-difluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-pregna-1,4-diene-3,20-dione); fluocortin butyl((6α,11β,16α)-6-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-21-oic acid butyl ester); fluocortolone ((6α,11β,16α)-6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H31FO5), its 21-hexanoate form (C28H39FO5), or its 21-pivalate form (C22H37FO5); fluorometholone ((6α,11β)-9-fluoro-11,17-dihydroxy-6-methylpregana-1,4-diene-3,20-dione), or its 17-acetate form (C24H31FO5); fluperolone acetate([11β,17α,17(S)]-17-[2-(acetyloxy)-1-oxopropyl]-9-fluoro-11,17-dihydroxyandrosta-1,4-dien-3-one); fluprednidene acetate((11β)-21-(acetyloxy)-9-fluoro-11,17-dihydroxy-16-methylenepregna-1,4-diene-3,20-dione); fluprednisolone ((6α,11β)-6-fluoro-11,17,21-trihydroxypregna-1,4-diene-3,20-dione), or its 21-acetate form (C23H29FO6); flurandrenolide ((6α,11β,16α)-6-fluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregn-4-ene-3,20-dione); fluticasone propionate ((6α, 11β, 16α, 17α)-6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(1-oxopropoxy)androsta-1,4-diene-17-carbothioic acid S-(fluoromethyl) ester); formocortal ((11β,16α)-21-(acetyloxy)-3-(2-chloroethoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]-20-oxopregna-3,5-diene-6-carboxaldehyde); halcinonide ((11β,16α)-21-chloro-9-fluoro-11-hydroxy-16,17-[(1-methyethylidene)bis(oxy)]pregn-4-ene-3,20-dione); halobetasol propionate (6α,11β,16β)-21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17-(1-oxopropoxy)pregna-1,4-diene-3,20-dione); halometasone ((6α,11β,16α)-2-chloro-6,9 difluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), or its monohydrate form (C22H27ClF2O5.H2O); halopredone acetate((6β,11β)-17,21-bis(acetyloxy)-2-bromo-6,9-difluoro-11-hydroxypregna-1,4-diene-3,20-dione); hydrocortamate (N,N-diethylglycine (11β)-11,17-dihydroxy-3,20-dioxopregn-4-en-21-yl ester), or its hydrochloride form (C27H41NO6.HCl); hydrocortisone ((11β)-11,17,21-trihydroxypregn-4-ene-3,20-dione), its 21-acetate form (C23H32O6), its 17-butyrate form (C25H36O6), its 21-phosphate disodium salt form (C21H29Na2O8P), its 21-sodium succinate form (C25H33NaO8), its 17-valerate form (C26H38O6), or its cypionate form; loteprednol etabonate ((11β,17α)-17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic acid chloromethyl ester); mazipredone ((11β)-11,17-dihydroxy-21-(4-methyl-1-piperazinyl)pregna-1,4-diene-3,20-dione), or its hydrochloride form (C26H38N2O4.HCl); medrysone ((6α,11β)-11-hydroxy-6-methylpregn-4-ene-3,20-dione); meprednisone ((16β)-17,21-dihydroxy-16-methylpregna-1,4-diene-3,11,20-trione), or its 21-acetate form (C24H30O6); methylprednisolone ((6α,11β)-11,17,21-trihydroxy-6-methylpregna-1,4-diene-3,20-dione; Sebek and Spero, U.S. Pat. No. 2,897,218, and Gould, U.S. Patent No. 3,053,832), its 21-acetate form (C24H32O6), its 21-phosphate disodium salt form (C22H29Na2O8P), its 21-succinate sodium salt form (C26H33NaO8), or its aceponate form (C27H36O7); mometasone furoate ((11β,16α)-9,21-dichloro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methylpregna-1,4-diene-3,20-(ione); paramethasone ((6α,11β,16α)-6-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), its 21-acetate form (C24H34FO6), its disodium phosphate form, or a mixture of its 21-acetate and disodium phosphate form; prednicarbate ((11β)-17[(ethoxycarbonyl)oxy]-11-hydroxy-21-(1-oxopropoxy)pregna-1,4-diene-3,20-dione); prednisolone ((11β)-11,17,21-trihydroxypregna-1,4-diene-3,20-dione), its 21-acetate form (C23H30O6), its 21-tert-butylacetate form (C27H38O6; Sarrett), its 21-hydrogen succinate form (C25H32O8), its 21-succinate sodium salt form (C25H31NaO8), its 21-stearoylgylcolate form (C41H64O8), its 21-m-sulfobenzoate sodium salt form (C28H31,NaO9S; (11β)-11,17-dihydroxy-21-[(3-sulfobenzoyl)oxy]pregna-1,4-diene-3,20-dione monosodium salt), or its 21-trimethylacetate form (C26H36O6); prednisolone 21-diethylaminoacetate(N,N-diethylglycine (11β)-11,17-dihydroxy-3,20-dioxopregna-1,4-dien-21-yl ester; British Patent No. 862,370), or its hydrochloride form (C27H39NO6.HCl); prednisolone sodium phosphate (11,17-dihydroxy-21-(phosphonooxy)pregna-1,4-diene-3,20-dione disodium salt); prednisone (17,21-dihydroxypregna-1,4-diene-3,11,20-trione), or its 21-acetate form (C23H28O6); prednival ((11β)-11,21-dihydroxy-17-[(1-oxopentyl)oxy]pregna-1,4-diene-3,20-dione;), or its 21-acetate form (C28H38O7); prednylidene ((11β)-11,17,21-trihydroxy-16-methylenepregna-1,4-diene-3,20-dione), or its 21-diethylaminoacetate hydrochloride form (C28H39NO6.HCl); rimexolone ((11β,16α,17β)-11-hydroxy-16,17-dimethyl-17-(1-oxopropyl)androsta-1,4-dien-3-one); rofleponide ((22R)-6α,9α-Difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxypregn-4-ene-3,20-dione); tipredane ((11β, 17α)-17-(ethylthio)-9α-fluoro-11β-hydroxy-17-(methylthio) androsta-1,4-dien-3-one); tixocortol ((11β)-11,17-dihydroxy-21-mercaptopregn-4-ene-3,20-dione), or its 21-pivalate form (C26H38O5S; (11β)-21-[(2,2-dimethyl-1-oxopropyl)thio]-11,17-dihydroxypregn-4-ene-3,20-dione); triamcinolone ((11β,16α)-9-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,20-dione), or its 16,21-diacetate form (C25H31FO8; (11β,16α)-16,21-bis(acetyloxy)-9-fluoro-11,17-dihydroxypregna-1,4-diene-3,20-dione); Triamcinolone acetonide ((11β,16α)-9-fluoro-11,21-dihydroxy-16,17-[1-methylethylidenebis(oxy)]pregna-1,4-diene-3,20-dione), its 21-acetate crystal form, its 21-disodium phosphate form (C24H30FNa2O9P), or its 21-hemisuccinate form (C28H35FO9); triamcinolone benetonide ((11β, 16α)-21-[3-(benzoylamino)-2-methyl-1-oxopropoxy]-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione); or triamcinolone hexacetonide; ((11β,16α)-21-(3,3-dimethyl-1-oxobutoxy)-9-fluoro-11-hydroxy-16,17-[(1-methylethylidene) bis(oxy)]pregna-1,4-diene-3,20-dione), or pharmaceutically or veterinarily acceptable salts thereof. 99. The method of claim 71, wherein the second active agent comprises an AIS selected from budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, or mometasone. 100. A method of enhancing the prophyllactic or therapeutic respiratory effect of an anti-inflammatory steroid in a subject, comprising administering to the subject, in addition to the AIS, the oligonucleotide(s) (oligo(s)) of claim 1, the AIS and the oligo(s) being administered in amounts effective for reducing or depleting levels of, or reducing sensitivity to, adenosine, reducing levels of adenosine receptors, producing bronchodilation, increasing levels of ubiquinone or lung surfactant in a subject's tissue (s), or treating bronchoconstriction, lung inflammation or lung allergies or a respiratory or lung disease or condition. 101. The method of claim 100, further administering to the subject a ubiquinone of the chemical formula. 102. The method of claim 100, wherein the steroid comprises budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone, beclomethasone, betamethasone, dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, or mometasone 103. The method of claim 100, wherein the oligo(s) is anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, and regions within 2 to 10 nucleotides of the junctions of at least one oncogene(s) and a gene(s) enclding or regulating expression of a target polypeptide(s) associated with lung airway dysfunction, or anti-sense to the corresponding mRNA and the polypeptide mRNA; combinations, MTAs or mixtures of the oligos; the polypeptides comprising peptide factors and transmitters, antibodies, cytokines or chemokines, enzymes, binding proteins, adhesion molecules, their receptors, or malignancy associated proteins. 104. The method of claim 100, further comprising administering to the subject other therapeutic or bioactive agents selected from analgesics, pre-menstrual medications, menopausal agents, anti-aging agents, anti-anxyolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schyzophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti-angyogenic agents, cytokines, growth factors, B-adrenergic receptor agonists, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents, hair growth agents, analgesics, premenstrual medications, anti-menopausal agents, hormones, anti-aging agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, other hormones, other anti-inflammatory agents, agents for treating arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Crohn's disease, ulcerative colitis, autoimmune disease, or lupus erythematosus, muscle relaxants, soporific agents, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound and burn healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, agents for reperfusion injury, counteracting appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents or skin renewal agents. 105. The method of claim 100, wherein the oligo(s) and/or the steroid(s) is(are) administered with surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidyl choline (other than dipalmitoyl), dipalmitoyl phosphatidyl choline, phosphatidyl choline, phosphatidyl glycerol phosphatidyl inositol, phosphatidyl ethanolamine, phosphatidyl serine; phosphatidic acid, ubiquinones, lysophosphatidyl ethanolamine, lysophosphatidyl choline, palmitoyl-lysophosphatidyl choline, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxy acetone, palmitate, cytidine diphosphate (CDP) diacyl glycerol, CDP choline, choline, choline phosphate; natural or artificial lamellar bodies as carrier surfactant vehicles, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric or polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35, Triton X-100 or synthetic surfactants ALEC, Exosurf, Survan or Atovaquone. 106. The method of claim 100, wherein the AIS comprises a steroid of chemical formula (Ia) or (Ib). 107. The method of claim 106, wherein the AIS is selected from budesonide, testosterone, progesterone, fluticasone, beclomethasone, prednisone, momethasone, estrogen, dexamethasone, hydrocortisone, triamcinolone, flunisolide, methylprednisolone prednisone, hydrocortisone, or analogues thereof. 108. The method of claim 100, wherein the first and second active agents are administered systemically or topically. 109. The method of claim 100, wherein the first and second active agents are administered as an oral intrabuccal, intrapulmonary, rectal, intrauterine, intratumor, intracranial, nasal, intramuscular, subcutaneous, intravascular, intrathecal, inhalable, transdermal, intradermal, intracavitary, implantable, iontophoretic, ocular, vaginal, intraarticular, otical intravenous, intramuscular, intraglandular, intraorgan, intralymphatic, implantable, slow release or enteric coating formulation. 110. The method of claim 101, wherein the ubiquinone is administeredorally. 107. The method of claim 106, wherein the oligo(s) and the AIS is(are) administered intrapulmonarily, into the respiration, nasally, or by inhalation. 108. The method of claim 106, wherein the oligo(s) or the AIS is(are) administered as a respirable or inhalable formulation, optionally an aerosol of particle size about 0.05 to about 10 micron. 109. The method of claim 107, wherein the formulation comprises an oligo(s) or AIS of particle size about 0.1 micron to about 5 micron. 110. The method of claim 106, wherein the oligo(s) or the AIS is(are) administered nasallym intrapulmonarily, optionally an aerosol of particle size about 8 to about 100 micron. 111. The method of claim 109, wherein the oligo(s) or the AIS has(have) a particle size about 10 to about 50 micron. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention concerns itself with compositions, formulations and kits employed for the administration of active agents that are effective for treating respiratory and pulmonary diseases including bronchoconstriction, impaired airways, decreased lung surfactant, asthma, rhinitis, acute respiratory distress syndrome (ARDS), infantile or maternal RDS, chronic obstructive pulmonary disease (COPD), allergies, impeded respiration, lung pain, cystic fibrosis (CF), infectious diseases, cancers such as leukemias, lung and colon cancer, and the like, and diseases whose secondary effects afflict the lungs. The active agents, anti-sense oligonucleotides and steroid agents and/or ubiquinones may be administered preventatively, prophylactically or therapeutically as a single therapy or in conjunction with other therapies. 2. Background of the Invention Respiratory ailments, associated with a variety of diseases and conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1% of all health care costs. An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the depletion reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood. Respiratory and pulmonary diseases such as asthma, allergic rhinitis, Acute Respiratory Distress Syndrome (ARDS), including that occurring in pregnant mothers and in premature born infants, pulmonary fibrosis, cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and cancer, among others, are common diseases in industrialized countries. In the United States alone they account for extremely high health care costs, and their incidence has recently been increasing at an alarming rate, both in terms of prevalence, morbidity and mortality. In spite of this, their underlying causes still remain poorly understood. Asthma is a condition characterized by variable, in many instances reversible obstruction of the airways. This process is associated with lung inflammation and in some cases lung allergies. Many patients have acute episodes referred to as “asthma attacks,” while others are afflicted with a chronic condition. The asthmatic process is triggered in some cases by inhalation of antigens by hypersensitive subjects. This condition is generally referred to as “extrinsic asthma.” Other asthmatics have an intrinsic predisposition to the condition, which is thus referred to as “intrinsic asthma,” and may be comprised of conditions of different origin, including those mediated by the adenosine receptor(s), allergic conditions mediated by an immune IgE-mediated response, and others. All asthmas have a group of symptoms, which are characteristic of this condition: bronchoconstriction, lung inflammation and decreased lung surfactant. Existing bronchodilators and anti-inflammatories are currently commercially available and are prescribed for the treatment of asthma. The most common anti-inflammatories, corticosteroids, have considerable side effects but are commonly prescribed nevertheless. Most of the drugs available for the treatment of asthma are, more importantly, barely effective in a small number of patients. Acute Respiratory Distress Syndrome (ARDS), or stiff lung, shock lung, pump lung and congestive atelectasis, is believed to be caused by fluid accumulation within the lung which, in turn, causes the lung to stiffen. The condition is triggered within 48 hours by a variety of processes that injure the lungs such as trauma, head injury, shock, sepsis, multiple blood transfusions, medications, pulmonary embolism, severe pneumonia, smoke inhalation, radiation, high altitude, near drowning, and others. In general, ARDS occurs as a medical emergency and may be caused by other conditions that directly or indirectly cause the blood vessels to “leak” fluid into the lungs. In ARDS, the ability of the lungs to expand is severely decreased and produces extensive damage to the air sacs and lining or endothelium of the lung. ARDS' most common symptoms are labored, rapid breathing, nasal flaring, cyanosis blue skin, lips and nails caused by lack of oxygen to the tissues, breathing difficulty, anxiety, stress, tension, joint stiffness, pain and temporarily absent breathing. ARDS is commonly diagnosed by testing for symptomatic signs, for example by a simple chest auscultation or examination with a stethoscope that may reveal abnormal symptomatic breath sounds. A preliminary diagnosis of ARDS may be confirmed with chest X-rays and the measurement of arterial blood gas. In some cases ARDS appears to be associated with other diseases, such as acute myelogenous leukemia, with acute tumor lysis syndrome (ATLS) developed after treatment with, e.g. cytosine arabinoside. In general, however, ARDS appears to be associated with traumatic injury, severe blood infections such as sepsis, or other systemic illness, high dose radiation therapy and chemotherapy, and inflammatory responses which lead to multiple organ failure, and in many cases death. In premature babies (“premies”), the lungs are not quite developed and, therefore, the fetus is in an anoxic state during development. Moreover, lung surfactant, a material critical for normal respiration, is generally not yet present in sufficient amounts at this early stage of life; however, premies often hyper-express the adenosine A 1 receptor and/or underexpress the adenosine A 2a receptor and are, therefore, susceptible to respiratory problems including bronchoconstriction, lung inflammation and ARDS, among others. When Respiratory Distress Syndrome (RDS) occurs in premies, it is an extremely serious problem. Preterm infants exhibiting RDS are currently treated by ventilation and administration of oxygen and surfactant preparations. When premies survive RDS, they frequently develop bronchopulmonary dysplasia (BPD), also called chronic lung disease of early infancy, which is often fatal. The systemic administration of adenosine was found useful for treating SVT, and as a pharmacologic means to evaluate cardiovascular health via an adenosine stress test commonly administered by hospitals and by doctors in private practice. Adenosine administered by inhalation, however, is known to cause bronchoconstriction in asthmatics, possibly due to mast cell degranulation and histamine release, effects which have not been observed in normal subjects. Adenosine infusion has caused respiratory compromise, for example, in patients with COPD. As a consequence of the untoward side effects observed in many patients, caution is recommended in the prescription of adenosine to patients with a variety of conditions, including obstructive lung disease, emphysema, bronchitis, etc, and complete avoidance of its administration to patients with or prone to bronchoconstriction or bronchospasm, such as asthma. In addition, the administration of adenosine must be discontinued in any patient who develops severe respiratory difficulties. It would be of great help if a formulation were to be made available for joint use when adenosine administration is required. Allergic rhinitis afflicts one in five Americans, accounting for an estimated $4 to 10 billion in health care costs each year, and occurs at all ages. Because many people mislabel their symptoms as persistent colds or sinus problems, allergic rhinitis is probably underdiagnosed. Typically, IgE combines with allergens in the nose to produce chemical mediators, induction of cellular processes, and neurogenic stimulation, causing an underlying inflammation. Symptoms include nasal congestion, discharge, sneezing, and itching, as well as itchy, watery, swollen eyes. Over time, allergic rhinitis sufferers often develop sinusitis, otitis media with effusion, and nasal polyposis that may exacerbate asthma, and is associated with mood and cognitive disturbances, fatigue and irritability. Degranulation of mast cells results in the release of preformed mediators that interact with various cells, blood vessels, and mucous glands to produce the typical rhinitis symptoms. Most early- and late-phase reactions occur in the nose after allergen exposure. The late-phase reaction is seen in chronic allergic rhinitis, with hypersecretion and congestion as the most prominent symptoms. Repeated exposure may cause hypersensitivity to one or many allergens. Sufferers may also become hyperreactive to non-specific triggers, such as cold air or strong odors. Non-allergic rhinitis may be induced by infections, such as viral infections, or associated with nasal polyps, as occurs in patients with aspirin idiosyncrasy. In addition, pregnancy, hypothyroidism, and exposure to occupational factors or medications may cause rhinitis, as well. NARES syndrome, a non-allergic type of rhinitis associated with eosinophils in nasal secretions, typically occurs in middle-aged individuals and is accompanied by loss of smell. Saline is often recommended to improve nasal stuffiness, sneezing, and congestion, since saline sprays usually relieve mucosal irritation or dryness associated with various nasal conditions, minimize mucosal atrophy, and dislodge encrusted or thickened mucus, while causing no side effects, and may be used freely in pregnant patients. In addition, if used immediately before intra-nasal corticosteroid dosing, saline helps prevent local irritation. Anti-histamines often serve as a primary therapy. Terfenadine and astemizole, two non-sedating anti-histamines, however, have been associated with a ventricular arrhythmia known as Torsades de Points, usually in interaction with other medications such as ketoconazole and erythromycin, or secondary to an underlying cardiac problem. Up to date, loratadine, another nonsedating anti-histamine, and cetirizine have not been associated with serious adverse cardiovascular events. Cetirizine's most common side effect, however, is drowsiness. Clartin, for example, may be effective in relieving sneezing, runny nose, and nasal, ocular and palatal itching in a low percentage of patients, although not approved for this indication or asthma. Anti-histamines are typically combined with a decongestant to help relieve nasal congestion. Sympathomimetic medications are used as vasoconstrictors and decongestants, the most common being pseudoephedrine, phenylpropanolamine and phenylephrine. These agents, however, often cause hypertension, palpitations, tachycardia, restlessness, insomnia and headache. Topical decongestants are recommended for limited periods because their overuse results in nasal dilatation. Anti-cholinergic agents, such as cromolyn, have a role in patients with significant rhinorrhea or in specific cases, such as “gustatory rhinitis”, which is usually associated with ingestion of spicy foods, and have been used on the common cold Sometimes the Cromolyn spray produces sneezing, transient headache, and even nasal burning. Topical and nasal spray corticosteroids such as Vancenase are effective agents in the treatment of rhinitis, especially for symptoms of congestion, sneezing and runny nose, but sometimes may cause irritation stinging, burning, sneezing, and local bleeding. Topical steroids are generally more effective than Cromolyn sodium, particularly in the treatment of NARES, but side effects sometimes limit their usefulness. Immunotherapy, while expensive and inconvenient, often provides substantial benefits, especially the use of drugs such as blocking antibodies, and those that alter cellular histamine release, and result in decreased IgE. Presently available treatments, such as propranolol, verapamil, and adenosine, may help to minimize symptoms. Verapamil is most commonly used but it has several shortcomings, since it causes or exacerbates systemic hypotension, congestive heart failure, bradyarrhythmias, and ventricular fibrillation. Verapamil, however, crosses the placenta and has been shown to cause fetal bradycardia, heart block, depression of contractility, and hypotension. Adenosine has several advantages over verapamil, including rapid onset, brevity of side effects, theoretical safety, and probable lack of placental transfer, but may not be administered to a variety of patients. Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is generally caused by chronic bronchitis, emphysema, or both. Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is characterized by chronic cough, mucus production, or both, for at least three months for at least two successive years where other causes of chronic cough have been excluded. COPD characteristically affects middle aged and elderly people, and is one of the leading causes of morbidity and mortality worldwide. In the United States it affects about 14 million people and is the fourth leading cause of death, and both its morbidity and mortality rates are still rising. This contrasts with the decline over the same period in age-adjusted mortality from all causes, and from cardiovascular diseases. COPD, however, is preventable, since it is believed that its main cause is exposure to cigarette smoke. The disease is rare in lifetime non-smokers, in whom exposure to environmental tobacco smoke will explain at least some of the airways obstruction. Other proposed etiological factors include airway hyper-responsiveness or hypersensitivity, ambient air pollution, and allergy. The airflow obstruction in COPD is usually progressive in people who continue to smoke. This results in early disability and shortened survival time. Stopping smoking reverts the decline in lung function to values for non-smokers. Many patients will use medication chronically for the rest of their lives, with the need for increased doses and additional drugs during exacerbations. Amongst the currently available treatments for COPD, short-term benefits were found, as opposed to long term effects on progression, from anti-cholinergic drugs, β2 adrenergic agonists, and oral steroids. The effects of anti-cholinergic drugs and β2 adrenergic agonists, however, are not seen in all people with COPD, and the two agents combined are only slightly more effective than either alone. Their adverse effects and the need for frequent monitoring of blood concentrations limit the usefulness of theophyllines. There is no evidence that anti-cholinergic agents affect the decline in lung function, and mucolytics have been shown to reduce the frequency of exacerbations but with a possible deleterious effect on lung function. The long-term effects of β2 adrenergic agonists, oral corticosteroids, and antibiotics have not yet been evaluated, and up to the present time no other drug has been shown to affect the progression of the disease or survival. Thus, there is very little currently available to alleviate symptoms of COPD, prevent exacerbations, preserve optimal lung function, and improve daily living activities an quality of life. Thus, there is very little currently available to alleviate symptoms of COPD, prevent exacerbations, preserve optimal lung function, and improve daily living activities an quality of life. Interstitial lung disease (ILD), interstitial pulmonary fibrosis, or simply pulmonary fibrosis are terms that include more than 130 chronic lung disorders that affect the lung in at least three ways: lung tissue is damaged in some known or unknown way, walls of the air sacs in the lung become inflamed, and scarring or fibrosis begins in the interstitium (or tissue between the air sacs), and the lung becomes stiff. Breathlessness during exercise may be one of the first symptoms of these diseases, and a dry cough may be present. Neither the symptoms nor X rays are often sufficient to tell apart different types of pulmonary fibrosis. Some pulmonary fibrosis patients have known causes and some have unknown or idiopathic causes. Interstitial lung disease (or pulmonary fibrosis) is named after he tissue between the air sacs of the lungs because this is the tissue affected by fibrosis or scarring. The course of this disease is generally unpredictable. If they progress the lung tissue thickens and becomes stiff, breathing becomes more difficult and demanding, and inflammation occurs. Some people may need oxygen therapy as part of their treatment. Microbial infections are extremely common, and may be caused by viruses, bacteria, and other forms of life. They are generally treated with anti-viral agents, antibiotics, and other specific therapeutic drugs. However, some infections may either go unnoticed, or produce secondary effects such as inflammation, pulmonary and airway obstructions, and other pulmonary ailments. Cancer is one of the most prevalent and feared diseases of our times. It generally results from the carcinogenic transformation of normal cells of different epithelia. Two of the most damaging characteristics of carcinomas and other types of malignancies are their uncontrolled growth and their ability to create metastases in distant sites of the host particularly a human host. It is usually these distant metastases that cause serious consequences to the host since frequently the primary carcinoma may be, in most cases, removed by surgery. The treatment of cancer presently relies on surgery, irradiation therapy and systemic therapies such as chemotherapy, different immunity-boosting medicines and procedures, hyperthermia and systemic, radioactively labeled monoclonal antibody treatment immunotoxins and chemotherapeutic drugs. Adenosine may constitute an important mediator in the lung for various diseases, including bronchial asthma, COPD, CF, RDS, rhinitis, pulmonary fibrosis, and others. Its potential role was suggested by the finding that asthmatics respond favorably to aerosolized adenosine with marked bronchoconstriction whereas normal individuals do not. An asthmatic rabbit animal model, the dust mite allergic rabbit model for human asthma, responded in a similar fashion to aerosolized adenosine with marked bronchoconstriction whereas non-asthmatic rabbits showed no response. More recent work with this animal model suggested that adenosine-induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be mediated primarily through the stimulation of adenosine receptors. Adenosine has also been shown to cause adverse effects, including death, when administered therapeutically for other diseases and conditions in subjects with previously undiagnosed hyper reactive airways. Adenosine is a purine involved in intermediary metabolism, and may constitute an important natural mediator of many of diseases. Adenosine plays a unique role in the body as a regulator of cellular metabolism. It can raise the cellular level of AMP, ADP and ATP which are the energy intermediates of the cell. Adenosine can stimulate or down regulate the activity of adenylate cyclase and hence regulate cAMP levels. cAMP, in turn, plays a role in neurotransmitter release, cellular division and hormone release. Adenosine's major role appears to be to act as a protective injury autocoid. In any condition in which ischemia, low oxygen tension or trauma occurs adenosine appears to play a role. Defects in synthesis, release, action and/or degradation of adenosine have been postulated to contribute to the over activity of the brain excitatory amino acid neurotransmitters, and hence various pathological states. Adenosine has also been implicated as a primary determinant underlying the symptoms of bronchial asthma and other respiratory diseases, the induction of bronchoconstriction and the contraction of airway smooth muscle. Moreover, adenosine causes bronchoconstriction in asthmatics but not in non-asthmatics. Other data suggest the possibility that adenosine receptors may also be involved in allergic and inflammatory responses by reducing the hyperactivity of the central dopaminergic system. It has been postulated that the modulation of signal transduction at the surface of inflammatory cells influences acute inflammation. Adenosine is said to inhibit the production of super-oxide by stimulated neutrophils. Recent evidence suggests that adenosine may also play a protective role in stroke, CNS trauma, epilepsy, ischemic heart disease, coronary by-pass, radiation exposure and inflammation. Overall, adenosine appears to regulate cellular metabolism through ATP, to act as a carrier for methionine, to decrease cellular oxygen demand and to protect cells from ischemic injury. Adenosine is a tissue hormone or inter-cellular messenger that is released when cells are subject to ischemia, hypoxia, cellular stress, and increased workload, and or when the demand for ATP exceeds its supply. Adenosine is a purine and its formation is directly linked to ATP catabolism. It appears to modulate an array of physiological processes including vascular tone, hormone action, neural function, platelet aggregation and lymphocyte differentiation. It also may play a role in DNA formation, ATP biosynthesis and general intermediary metabolism. It is suggested that it regulates the formation of cAMP in the brain and in a variety of peripheral tissues. Adenosine regulates cAMP formation through two receptors A 1 and A 2 . Via A 1 receptors, adenosine reduces adenylate cyclase activity, while it stimulates adenylate cyclase at A 2 receptors. The adenosine A 1 receptors are more sensitive to adenosine than the A 2 receptors. The CNS effects of adenosine are generally believed to be A 1 -receptor mediated, where as the peripheral effects such as hypotension, bradycardia, are said to be A 2 receptor mediated. Anti-sense oligonucleotides have received considerable theoretical consideration as potential useful pharmacological agents in human disease. One important impediment to their effective application has been a difficulty in finding an appropriate route of administration to deliver them to their site of action. The administering of anti-sense oligonucleotides directly to specific regions of the brain, for example, necessarily has limited clinical utility due to its invasive nature. Finding practical and effective applications for these agents in actual models of human disease have been few and far between, particularly because they had to be administered in large doses. The systemic administration of anti-sense oligonucleotides as pharmacological agents, such as oral and parenteral administration, has been found to have also significant problems, including the inherent difficulty in targeting specific tissues due to their dilution in the circulatory system. The bioavailability of orally administered anti-sense oligonucleotides is very low, of the order of less than about 5%. The present inventor previously pioneered the administration of oligonucleotides via the respiratory system, and successfully treated asthma, bronchoconstriction and lung inflammation and allergies, and applied the technology to the treatment of other conditions. The route of administration, thus was found to be of importance, particularly for treating localized conditions. As described in more detail below, the lung is an excellent target for the direct administration of anti-sense oligonucleotides and provides a non-invasive and a tissue-specific route. The respiratory system, and in particular the lung, as the ultimate port of entry into the organism provides an excellent route of administration for anti-sense oligonucleotides. This is so not only for the treatment of lung disease, but also when utilizing the lung as a means for delivery, particularly because of its non-invasive and tissue-specific nature. Thus, local delivery of anti-sense oligos directly to the target tissue enables an optimal delivery for the therapeutic use of these compounds. Fomivirsen (ISIS 2922) is an example of a local drug delivery into the eye to treat cytomegalovirus (CMV) retinitis, for which a new drug application has been filed by ISIS. The administration of a drug through the lung offers the further advantage that inhalation is non-invasive whereas direct injection into the vitreous of the eye is invasive. Steroids are naturally occurring compounds of varied activities. In mammals, they serve different functions, some being associated with sexual cycles and reproduction, others with regulation of endogenous levels of various compounds. Some of these have anti-inflammatory activity, Steroid hormones are potent chemical messengers that exert dramatic effects on cell differentiation, homeostasis, and morphogenesis. These molecules diverse in structure share a mechanistically similar mode of action. The effector molecules diffuse across cellular membranes and bind to specific high affinity receptors in the target cell nuclei. This interaction results in the conversion of an inactive receptor to one that can interact with the regulatory regions of target genes and modulate the rate of transcription of specific gene sets. Upon ligand binding, these receptors generate both rapid and long lasting responses. Steroids can act through two basic mechanisms: genomic and non-genomic. The classical genomic action is mediated by specific intracellular receptors, whereas the primary target for the non-genomic one is the cell membrane. Many clinical symptoms seem to be mediated through the non-genomic route. Furthermore, membrane effects of steroid and other factors can interfere with the intranuclear receptor system inducing or repressing steroid-and receptor-specific genomic effects. These signalling pathways may lead to unexpected hormonal or anti-hormonal effects in patients treated with certain drugs. Steroid receptors are members of a large family of nuclear transcription factors that regulate gene expression by binding to their cognate steroid ligands, to the specific enhancer sequences of DNA (steroid response elements) and to the basic transcription machinery. Steroid receptors are basically localized in the nucleus, regardless of hormonal status, and considerable-amounts of unliganded steroid receptors may be present in the cytoplasm of target cells in exceptional cases Most steroid receptors are phosphoproteins, which are further phosphorylated after ligand binding. The role of phosphorylation in receptor transaction is complex and may not be uniform to all steroid receptors. However, pliosphorylation and/or dephosphorylation is believed to be a key event regulating the transcriptional activity of steroid receptors. Steroid receptor activities can be affected by the amount of steroid receptor in the cell nuclei, which is modified by the rate of transcription and translation of the steroid receptor gene as well as by proteolysis of the steroid receptor protein. There is an auto- and heteroregulation of receptor levels. Some of the steroid receptors appear to bind specific protease inhibitors and exhibit protease activity. Some steroid receptors are expressed as two or more isoforms, which may have different effects on transcription. Receptor isoforms are different translation or transcription products of a single gene. Isoform A of the progesterone receptor is a truncated form of PR isoform B originating from the same gene, but it is able to suppress not only the gene enhancing activity of PR-B but also that of other steroid receptors. Before hormone binding, the receptors are part of a complex with multiple chaperones which maintain the receptor in its steroid binding conformation. Following hormone binding, the complex dissociates and the receptors bind to steroid response elements in chromatin. Regulation of gene expression by hormones involves an interaction of the DNA-bound receptors with other sequence-specific transcription factors and with the general transcription factors, which is partly mediated by co-activators and co-repressors. The specific array of cis regulatory elements in a particular promoter/enhancer region, as well as the organization of the DNA sequences in nucleosomes, specifies the network of receptor interactions. Depending on the nature of these interactions, the final outcome can be induction or repression of transcription. Adrenocortical hormones are steroid hormones classified as glucocorticoids, mineralocorticoids and sex hormones. Glucocorticoids moderate the metabolism of sugar, fat and protein and may raise the resistance to the adverse stimulation of the body by these substances. Many of the clinically useful steroids belong to this group, including cortisone, hydrocortisone, and their pharmaceutical derivatives such as prednisone, dexamethasone, etc. Although glucocorticoids were originally so called because of their infuence on glucose metabolism, they are currently defined as steroids that exert their effects by binding to specific cytosolic receptors that mediate the actions of these hormones. These glucocorticoid receptors are present in virtually all tissues, and glucocorticoid-receptor interactions are responsible for most of the known effects of these steroids. Alteration in the structure of these glucocorticoids has led to the development of synthetic compounds with greater glucocorticoid activity. The increased activity of these compounds is due to increased affinity for the glucocorticoid receptors and/or delayed plasma clearance, which increases tissue exposure. In addition, many of these synthetic glucocorticoids evidence negligible mineralocortocoid effects and thus do not result in sodium retention, hypertension, and/or hypokalemia. Glucocorticoid action is initiated by entry of the steroid into the cell and binding to the cytosolic glucocorticoid receptor proteins. After binding, activated hormone-receptor complexes enter the nucleus and interact with nuclear chromatin acceptor sites. These events cause the expression of specific genes and the transcription of specific mRNAs. The resulting proteins affect the response to the glucocorticoids, which may be inhibitory or stimulatory depending on the specific tissue affected. Although glucocorticoid receptors are similar in many tissues, the proteins synthesized vary widely and are the result of expression of specific genes in different cell types. Mineralocorticoids and sex hormones are non-glucocorticoid steroids, e.g., adrenal androgens. Adrenal androgens, such as androstenediones, dehydroepiandrosterone (DHEA), and DHEA sulfate function as precursors for the peripheral conversion to androgenic hormones, such as testosterone and dihydrotestosterone. DHEA sulfate secreted by the adrenal undergoes limited conversion to DHEA, and both the peripheral DHEA and DHEA secreted by the adrenal cortex may be further converted in peripheral tissues to androstenedione, the immediate precursor of the active androgens. Dehydroepiandrosterone (DHEA) is a naturally occurring steroid secreted by the adrenal cortex with apparent chemoprotective properties. Epidemiological studies have shown that low endogenous levels of DHEA correlate with increased risk of developing some forms of cancer, such as pre-menopausal breast cancer in women and bladder cancer in both sexes. The ability of DHEA and DHEA analogues, e.g. dehydroepiandrosterone sulfate (DHEA-S), to inhibit carcinogenesis is believed to result from their uncompetitive inhibition of the activity of the enzyme glucose 6-phosphate dehydrogenase (G6PDH). G6PDH is the rate limiting enzyme of the hexose monophosphate pathway, a major source of intracellular ribose-5-phosphate and NADPH. Ribose-5 phosphate is a necessary substrate for the synthesis of both ribo- and deoxyribonucleotides required for the synthesis of RNA and DNA. NADPH is a cofactor also involved in nucleic acid biosynthesis and the synthesis of hydroxmethylglutaryl Coenzyme A reductase (HMG CoA reductase). HMG CoA reductase is an unusual enzyme that requires two moles of NADPH for each mole of product, mevalonate, produced. Thus, it appears that HMG CoA reductase would be ultrasensitive to DHEA-mediated NADPH depletion, and that DHEA-treated cells would rapidly show the depletion of intracellular pools of mevalonate. Mevalonate is required for DNA synthesis, and DHEA arrests human cells in the G1 phase of the cell cycle in a manner closely resembling that of the direct HMG CoA. Because G6PDH produces mevalonic acid used in cellular processes such as protein isoprenylation and the synthesis of dolichol, a precursor for glycoprotein biosynthesis, DHEA inhibits carcinogenesis by depleting mevalonic acid and thereby inhibiting protein isoprenylation and glycoprotein synthesis. Mevalonate is a central precursor for the synthesis of cholesterol, as well as for the synthesis of a variety of non-sterol compounds involved in post-translational modification of proteins, such as farnesyl pyrophosphate and geranyl pyrophosphate. Mevalonate is also a central precursor for the synthesis of dolichol, a compound that is required for the synthesis of glycoproteins involved in cell-to-cell communication and cell structure. Mevalonate is also central to the manufacture of ubiquinone, an anti-oxidant with an established role in cellular respiration. It has long been known that patients receiving steroid hormones of adrenocortical origin at pharmacologically appropriate doses show increased incidence of infectious disease. DHEA, also known as 3β-hydroxyandrost-5-en-17-one or dehydroepiandrosterone, is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones found in mammals. Although DHEA appears to serve as an intermediary in gonadal steroid synthesis, the primary physiological function of DHEA has not been fully understood. It has been known, however, that levels of this hormone begin to decline in the second decade of life, reaching 5% of the original level in the elderly.) Clinically, DHEA has been used systemically and/or topically for treating patients suffering from psoriasis, gout, hyperlipemia, and it has been administered to post-coronary patients. In mammals, DHEA has been shown to have weight optimizing and anti-carcinogenic effects, and it has been used clinically in Europe in conjunction with estrogen as an agent to reverse menopausal symptoms and also has been used in the treatment of manic depression, schizophrenia, and Alzheimer's disease. DHEA has also been used clinically at 40 mg/kg/day in the treatment of advanced cancer and multiple sclerosis. Mild androgenic effects, hirsutism, and increased libido were the side effects observed. These side effects can be overcome by monitoring the dose and/or by using analogues. The subcutaneous or oral administration of DHEA to improve the hosts response to infections is known, as is the use of a patch to deliver DHEA. DHEA is also known as a precursor in a metabolic pathway that ultimately leads to more powerful agents that increase immune response in mammals. That is, DHEA acts as a biphasic compound: it acts as an immuno-modulator when converted to androstenediol or androst-5-ene-3β,17β-diol (βAED), or androstenetriol or androst-5-ene-3β,7β,17β-triol (βAET). However, in vitro DHEA has certain lymphotoxic and suppressive effects on cell proliferation prior to its conversion to βAED and/or βAET. It is, therefore, believed that the superior immunity enhancing properties obtained by administration of DHEA result from its conversion to more active metabolites. Adequate ubiquinone levels have been found to be essential for maintaining proper cardiac function, and the administration of exogenous ubiquinone has recently been shown to have beneficial effect in patients with chronic heart failure. Ubiquinone depletion has been observed in humans and animals treated with lovastatin, a direct HMG CoA reductase inhibitor. Such lovastatin-induced depletion of ubiquinone has been shown to lead to chronic heart failure, or to a shift from low heart failure into life-threatening high grade heart failure. DHEA, unlike lovastatin, inhibits HMG CoA reductase indirectly by inhibiting G6PDH and depleting NADPH, a required cofactor for HMG CoA reductase. However, DBEA's indirect inhibition of HMG CoA reductase suffices to deplete intracellular mevalonate. This effect adds to the depletion of ubiquinone, and may result in chronic heart failure following long term usage. Thus, although DHEA was once considered a safe drug, it is now predicted that with long term administration of DHEA or its analogues, chronic heart failure may occurs as a complicating side effect. Further, some analogues of DHEA produce this side effect to a greater extent because, in general, they are more potent inhibitors of G6PDH than DHEA. A handful of medicaments have been used for the treatment of respiratory diseases and conditions, although in general they all have limitations. Amongst them are corticoid steroids with glucocorticoid activity, leukotriene inhibitors, anti-cholinergic agents, anti-histamines, oxygen therapy, theophyllines, and mucolytics. Corticosteroids are the ones with the most widespread use in spite of their well documented side effects. Most of the available drugs are nevertheless effective in a small number of cases, and not at all when it comes to the treatment of asthma. No treatments are currently available for many of the other respiratory diseases. Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist that was reported to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits. A selective adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was also reported to inhibit adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. The therapeutic and preventative applications of currently available adenosine A 1 receptor-specific antagonists are, nevertheless, limited by their toxicity. Theophylline, for example, has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. DPCPX is far too toxic to be useful clinically. The fact that, despite decades of extensive research, no specific adenosine receptor antagonist is available for clinical use attests to the general toxicity of these agents. For many years, two classes of compounds have dominated the treatment of asthma: corticosteroids having glucocorticoid activity and bronchodilators. Examples of corticosteroids are beclomethasone and corticoid 21-sulfopropionates. Examples of a bronchodilator are an older β2 adrenergic agonist such as albuterol, and a newer one such as salmeterol. In general, when glucocorticosteroids are taken daily either by inhalation or orally, they attenuate inflammation. The β2 adrenergic agonists, on the other hand, primarily alleviate bronchoconstriction. Whereas glucocorticosteroids are not useful in general for acute settings, bronchodilators are used in acute care, such as in the case of asthma attacks. At the present time, many asthma patients require daily use of both types of agents, a glucocorticosteroid to contain pulmonary inflammation, and a bronchodilator to alleviate bronchoconstriction. More recently, fluticasone propionate, a corticosteroid was combined with β2 adrenergic agonists in one therapeutic formulation said to have greater efficiency in the treatment of asthma. However, glucocorticosteriods, particularly when taken for prolonged periods, have extremely deleterious side effects that, although somewhat effective, make their chronic use undesirable, particularly in children. Clearly, there exists a well defined need for novel and effective therapies for treating respiratory, lung and cancer ailments that cannot presently be reasonably treated, or at least for which no therapies are available that are effective and devoid of significant detrimental side effects. Moreover, there is a definite need for treatments that have prophylactic and therapeutic applications, and require low amounts of active agents, and are less costly and less prone to detrimental side effects. Furthermore, it is readily apparent that anti-inflammatory steroids (“AIS”), including adrenal androgens, androgens and their derivatives, etc, corticoid and non-glucocorticoid steroids, ubiquinones and their respective salts, as well as specifically targeted anti-sense oligonucleotides (oligos) are each alone useful for the treatment of respiratory, lung, and cancer. This patent provides their joint effects that evidence unexpected superior results over each agent alone. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention generally relates to a pharmaceutical or veterinary composition, comprising a pharmaceutically or veterinarily acceptable carrier or diluent, and first and second active agents. The first active agent comprises an oligonucleotide(s) (oligo(s)) that may be anti-sense to one or more targets, and a second active agent comprising anti-inflammatory steroids (“AIS”) and/or a ubiquinone, in amounts effective for alleviating airway, lung, and microbial and/or cancer diseases associated with, for example, bronchoconstriction, impeded respiration, dispnea, emphysema, asthma, COPD, ARDS, CF, allergic rhinitis, pulmonary hypertension and fibrosis, lung inflammation, allergies, surfactant depletion or hyposecretion, and cancers, among others. The oligo preferably contains about 0 to about 15% adenosine (A) and is anti-sense to the initiation codon, the coding region, the 5′-end or the 3′-end genomic flanking regions, the 5′ or 3′ intron-exon junctions, or regions within 2 to 10 nucleotides of the junctions of at least one gene regulating or encoding a target polypeptide associated with lung or airway dysfunction or cancer, or that is anti-sense to the corresponding mRNA, and the composition may comprise also combinations or mixtures of the oligos. The targets are typically molecules associated with airway disease, cancer, etc., such as transcription factors, stimulating and activating peptide factors, cytokines, cytokine receptors, chemokines, chemokine receptors, adenosine receptors, bradykinin receptors, endogenously produced specific and non-specific enzymes, immunoglobulins and antibodies, antibody receptors, central nervous system (CNS) and peripheral nervous and non-nervous system receptors, CNS and peripheral nervous and non-nervous system peptide transmitters, adhesion molecules, defensins, growth factors, vasoactive peptides and receptors, binding proteins, and malignancy associated proteins, among others. In one embodiment the first active agent comprises a nucleic acid wherein the oligo is anti-sense to more than one target. These are called within the four corners of this patent multiple target anti-sense oligonucleotides or MTAS. The second active agent comprises an anti-inflammatory steroid such as an adrenal androgen of the chemical formula wherein R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 and R 19 are independently H, OR, halogen, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene, (C 1 -C 10 ) alkyne, (C 1 -C 10 ) alkoxy, or two or more of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 and R 19 can be linked by combination of the atoms of C, O, N, S, P and Si to form a 3 to 15 member ring(s), in the α- and/or β-configuration; R 5 , R 6 , R 10 , and R 11 are independently OH, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO 2 R 20 , —OPOR 20 R 21 , (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene, (C 1 -C 10 ) alkyne or OR 23 , wherein, R 23 is hydrogen or SO 2 OM, wherein M is selected from H, Na, sulfatide; or phosphatide wherein R 24 and R 25 , which may be the same or different, are straight or branched (C 1 -C 20 ) alkyl, (C 1 -C 20 ) alkene, (C 1 -C 20 ) alkyne, sugar, polyethyleneglycol (PEG) or glucuronide R 5 and R 6 taken together are ═O; R 10 and R 11 , taken together are ═O; R 15 is (1) H, halogen, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene, (C 1 -C 10 ) alkyne, or (C 1 -C 10 ) alkoxy when R 16 is —C(O)OR 22 , (2) H, halogen, OH, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene or (C 1 -C 10 ) alkyne, when R 16 is halogen, OH, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene or (C 1 -C 10 ) alkyne, (3) H, halogen, (C 1 -C 10 ) alkyl(C 1 -C 10 ) alkenyl, (C 1 -C10) alkynyl, formyl, (C 1 -C 10 ) alkanoyl or epoxy when R 16 is OH, (4) OR, SR, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO 2 R 20 or —OPOR 20 R 21 when R 16 is H, or R 15 and R 16 taken together are ═O; R 17 and R 18 is are independently (1) H, —OH, halogen, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene, (C 1 -C 10 ) alkyne or —(C 1 -C 10 ) alkoxy when R 6 is H OR, halogen, (C 1 -C 10 ) alkyl or —C(O)OR 22 , (2) H, (C 1 -C 10 alkyl) n amino, (C 1 -C 10 alkene) n amino, (C 1 -C 10 alkyne) n amino, ((C 1 -C 10 )alkyl) n amino-(C 1 -C 10 ) alkyl, ((C 1 -C 10 )alkene) n amino-C 1 -C 10 )alkyl, ((C 1 -C 10 ) alkyne) n amino-(C 1 -C 10 ) alkyl, ((C 1 -C 10 )alkyl) n amino-(C 1 -C 10 ) alkene, ((C 1 -C 10 )alkene) n amino-(C 1 -C 10 ) alkene, ((C 1 -C 10 )alkyne) n amino-(C 1 -C 10 )alkene, ((C 1 -C 10 )alkyl) n amino-(C 1 -C 10 )alkyne, ((C 1 -C 10 ) alkene) n amino-(C 1 -C 10 ) alkyne, ((C 1 -C 10 )alkyne) n amino-(C 1 -C 10 )alkyne, (C 1 -C 10 )alkoxy, hydroxy-(C 1 -C 10 )alkyl, hydroxy-(C 1 -C 10 ) alkene, hydroxy-(C 1 -C 10 )alkyne, (C 1 -C 10 )alkoxy-(C 1 -C 10 )alkyl, (C 1 -C 10 ) alkoxy-(C 1 -C 10 ) alkene, (C 1 -C 10 ) alkoxy-(C 1 -C 10 ) alkyne, (halogen) m (C 1 -C 10 ) alkyl, (halogen) m (C 1 -C 10 ) alkene, (halogen) m (C 1 -C 10 ) alkyne, (C 1 -C 10 ) alkanoyl, formyl, (C 1 -C 10 ) carbalkoxy or (C 1 -C 10 ) alkanoyloxy when R 15 and R 16 taken together are ═O, (3) R 17 and R 18 taken together are ═O; (4) R 17 and R 18 is taken together with the carbon to which they are attached form a 3-6 member ring containing 0 or 1 oxygen atom; or (5) R 15 and R 17 taken together with the carbons to which they are attached form an epoxide ring; R 20 and R 21 are independently OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether; R 22 is H, (halogen) m (C 1 -C 10 ) alkyl, (halogen) m (C 1 -C 10 ) alene, (halogen) m (C 1 -C 10 ) alkyne, (C 1 -C 10 ) alkyl, (C 1 -C 10 ) alkene or (C 1 -C 10 ) alkyne; n is 0, 1 or 2; and m is 1, 2 or 3, or pharmaceutically or veterinarily acceptable salts thereof; and/or a ubiquinone of the chemical formula wherein n=1 to 12, the agent being present in an amount effective for treating respiratory lung diseases and conditions, or for reducing levels of, or sensitivity to, adenosine or for increasing surfactant or ubiquinone levels in a subject's tissue (s), or pharmaceutically acceptable salts thereof. The oligos and the anti-inflamatory steroids (“AIS”) and/or ubiquinones (the second agent) are provided in the form of separate compositions and formulations together with a carrier or diluent, and optionally with other therapeutic agents and formulation additives. The first and second active agents are also provided as a single composition in combination with a carrier and other ingredients known in the art, and may be provided jointly or separately contained in a capsule or cartridge, and in the form of a kit. The drawings accompanying this patent form part of the disclosure of the invention, and further illustrate some aspects of the present invention as discussed below. |
Composition, formulations and kit for treatment of respiratory and lung disease with non-glucocorticoid steroids and/or ubiquinone and a bronchodilating agent |
A pharmaceutical or veterinary composition, comprises a first active agent selected from a non-glucocorticoid steroid or analogues, a ubiquinone, or salts thereof, and a second active agent comprising a bronchodilator. The composition is provided in various formulations and in the form of a kit The products of this patent are applied to the prophylaxis and treatment of respiratory, lung and malignant diseases. |
1. A pharmaceutical composition, comprising a pharmaceutically or veterinarily acceptable carrier and amounts of the first and second active agents effective to treat a respiratory, lung or malignant disease, (a) the first active agent being selected from a non-glucocorticoid steroid having the chemical formula wherein the broken line represents a single or a double bond; R is hydrogen or a halogen; the H at position 5 is present in the alpha or beta configuration or the compound of chemical formula I comprises a racemic mixture of both configurations; and R1 is hydrogen or SO2OM, wherein M is selected from the group consisting of H, Na, sulfatide and phosphatide wherein R2 and R3, which may be the same or different, are straight or branched (C1-C14) alkyl or glucuronide or a non-glucocorticoid steroid of the chemical formula wherein R1, R2, R3, R4, R5, R7, R8, R9, R10, R12, R13, R14 and R19 are independently H, OR, halogen (C1-C10) alkyl or (C1-C10) alkoxy, R5 and R11 are independently OH, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20, —OPOR20R21 or (C1-C10) alky, R5 and R6 taken together are ═O, R10 and R11 taken together are ═O; R15 is (1) H, halogen, (C1-C10) alkyl, or (C1-C10) alkoxy when R16 is —C(O)OR22,(2) H, halogen, OH or (C1-C10) alkyl when R16 is halogen, OH or (C1-C10) alkyl, (3) H halogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, formyl, (C1-C10) alkanoyl or epoxy when R16 is OH, (4) OR, SH, H, halogen, pharmaceutically acceptable ester, pharmaceutically acceptable thioester, pharmaceutically acceptable ether, pharmaceutically acceptable thioether, pharmaceutically acceptable inorganic esters, pharmaceutically acceptable monosaccharide, disaccharide or oligosaccharide, spirooxirane, spirothirane, —OSO2R20 or —OPOR20R21 when R16 is H, or R15 and R16 taken together are ═O; R17 and R18 independently (1) H, —OH, halogen, (C1-C10) alkyl or —(C1-C10) alkoxy when R6 is H OR, halogen. (C1-C10) alkyl or —C(O)OR22, (2) H, (C1-C10 alkyl).amino, ((C1-C10) alkyl)n amino-(C1-C10) alkyl, (C1-C10) alkoxy, hydroxy —(C1-C10) alkyl, (C1-C10) alkoxy —(C1-C10) alkyl, (halogen)m (C1-C10) alkyl, (C1-C10) alkanoyl, formyl, (C1-C10) carbalkoxy or (C1-C10) alkanoyloxy when R15 and R16 taken together are ═O, (3) R17 and R18 taken together are ═O; (4) R17 or R18 taken together with the carbon to which they are attached form a 3-6 member ring containing 0 or 1 oxygen atom; or (5) R15 and R17 taken together with the carbons to which they are attached form an epoxide ring; R20 and R21 are independently OH, pharmaceutically acceptable ester or pharmaceutically acceptable ether; R22 is H, (halogen)m (C1-C10) alkyl or (C1-C10) alkyl; n is 0, 1 or 2; and m is 1, 2 or 3; or pharmaceutically or veterinarily acceptable salts thereof; and/or a ubiquinone or pharmaceutically or veterinarily acceptable salt thereof, wherein the ubiquinone has the chemical formula wherein n is 1 to 12; and (b) the second active agent comprising a bronchodilating agent. 2. The composition of claim 1, wherein the first active agent has the formula COQn, wherein n is 1 to 10. 3. The composition of claim 1, wherein the first active agent has the formula CoQn, wherein n is 6 to 10. 4. The composition of claim 1, wherein the first active agent has the formula CoQn, wherein n is 10. 5. The composition of claim 1, comprising about 0.01 to about 99.9% w/w first and second active agent. 6. The composition of claim 5, comprising about 1 to about 20% w/w first and second active agents. 7. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (1), wherein R and R1 are each hydrogen and the broken line represents a double bond, or dehydroepiandrosterone. 8. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is Br, R1 is H, and the broken line represents a double bond, or 16-alpha bromoepiandrosterone. 9. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is F, R1 comprises H and broken line represents a double bond, or 16-alpha-fluoro epiandrosterone. 10. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R and R1 are each hydrogen and the broken line represents a double bond, or etiocholanolone. 11. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), wherein R is H, R1 is SO2OM and M is a sulfatide group as defined above, and the broken line represents a single bond, or dehydroepiandrosterone sulfate. 12. The composition of claim 1, wherein in the compound of formula (I), R is halogen selected from Br, Cl or F, R1 is H, and the broken line represents a double bond. 13. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (I), which is 16-alpha-fluoro epiandrosterone or 16-alpha-bromo epiandrosterone. 14. The composition of claim 1, wherein first active agent comprises the compound of formula (III), wherein R15 and R161together from =0. 15. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (m) or (IV), wherein R5 is OH. 16. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (III) or (IV), wherein R5 is OSO2R20. 17. The composition of claim 1, wherein the first active agent comprises a non-glucocorticoid steroid of formula (III) or (TV), wherein R20 is H. 18. The composition of claim 1, wherein the second active agent is selected from β2 adrenergic agonists, anti-cholinergic agents, anti-histaminic agents, adenosine receptor antagonists or glucocorticosteroids. 19. The composition of claim 18, wherein the second active agent comprises a β2 adrenergic agonist selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide. 20. The composition of claim 18, wherein the second active agent comprises a glucocorticosteroid. 21. The composition of claim 18, wherein second active agent comprises an anti-cholinergic agent. 22. The composition of claim 18, wherein the second active agent comprises a theophylline. 23. The composition of claim 1, further comprising an agent selected from other therapeutic or bioactive agents, preservatives, anti-oxidants, flavoring agents, volatile oils, buffering agents, dispersants or surfactants. 24. The composition of claim 23, wherein the other therapeutic or bioactive agents are selected from analgesics, pre-menstrual medications, menopausal agents, anti-aging agents, anti-anxyolytic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schyzophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound healing agents, anti-angyogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents, hair growth agents, analgesics, pre-menstrual medications, anti-menopausal agents, hormones, anti-aging agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Crohn's disease, ulcerative colitis, autoimmune disease, lupus erythematosus, muscle relaxants, steroids, soporific agents, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmitter regulating agents, wound and burn healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, anti-histaminic agents, anti-bacterial agents, anti-viral agents, anti-gas agents, agents for reperfusion injury, counteracting appetite suppressants, sun screens, emollients, skin temperature lowering products, radioactive phosphorescent or fluorescent contrast diagnostic or imaging agents, libido altering agents, bile acids, laxatives, anti-diarrheic agents, skin renewal agents or hair growth agents. 25. The composition of claim 1, which is a systemic or topical formulation, and wherein the carrier comprises a gaseous, solid or liquid carrier. 26. The formulation of claim 25, selected from an oral, nasal, inhalable, topical, parenteral or transdermal formulation. 27. The formulation of claim 26, selected from oral, intrabuccal, intrapulmonary, respirable, inhalable, nasal, rectal, intrauterine, vaginal, intratumor, intracranial, subcutaneous, intravascular, sublingual, intravenous, intrathecal, transdermal, intradermal, intracavitary, implantable, iontophoretic, intraocular, ophthalmic, intraarticular, otical, intravenous, intramuscular, intraglandular, intraorgan, intralymphatic, slow release or enteric coating formulations. 28. The formulation of claim 26, which is an oral formulation. 29. The oral formulation of claim 28, which is selected from capsules, cachets, lozenges, tablets, powder, granules, solutions, suspensions or emulsions. 30. The oral formulation of claim 28, further comprising an enteric coating. 31. The formulation of claim 26, which is a solution, suspension or emulsion selected from aqueous or non-aqueous liquid solutions or suspensions, or oil-in-water or water-in-oil emulsions. 32. The formulation of claim 26, which is a buccal or sub-lingual formulation. 33. The formulation of claim 26, which is a parenteral formulation. 34. The parenteral formulation of claim 33, in injectable form. 35. The formulation of claim 26, which is a topical formulation. 36. The formulation of claim 35, which is selected from ointments, creams, lotions, pastes, gels, sprays, aerosols or oils; and may further comprise a carrier selected from vaseline, lanoline, polyethylene glycols, alcohols or trans-dermal enhancers. 37. The formulation of claim 26, which is a transdermal formulation. 38. The transdermal formulation of claim 37, which is in the form of a patch. 39. The transdermal formulation of claim 37, which is an iontophoretic formulation. 40. The iontophoretic formulation of claim 39, which is selected from iontophoretic solutions, suspensions or emulsions, and which may further comprise a buffer. 41. The formulation of claim 26, which is a nasal, inhalable, respirable, intrapulmory or intratracheal formulation. 42. The nasal, inhalable, respirable, intrapulmonary or intratracheal formulation of claim 41, which is an aerosol or spray comprising liquid or solid powdered particles. 43. The inhalable or respirable formulation of claim 41, comprising particles of about 0.05 to about 10 μm in size. 44. The inhalable or respirable formulation of claim 43, comprising particles about 1 to about 5 μm in size. 45. The nasal, intrapulmonary or intratracheal formulation of claim 41, comprising particles about 10 to about 100 μm in size. 46. The nasal, intrapulmonary or intratracheal formulation of claim 45, comprising particles about 20 to about 50 μm in size. 47. The composition of claim 1, in bulk or in single- or multi-dose form. 48. The single- or multi-dose form of the composition of claim 47, which is provided in sealed ampoules, vials, cartridges or blisters. 49. The composition of claim 1, which is freeze-dried or lyophilized. 50. A kit, comprising a delivery device, and the formulation of claim 41. 51. The kit of claim 48, wherein the delivery device comprises an aerosol or spray generator. 52. The kit of claim 51, wherein the aerosol generator comprises an inhaler. 53. The kit of claim 51, wherein the inhaler delivers individual pre-metered doses of the formulation 54. The kit of claim 52, wherein the inhaler comprises a nebulizer or insufflator. 55. The kit of claim 50, wherein the delivery device comprises a compression inhaler, and the formulation comprises a suspension or solution in an aqueous, or non-aqueous liquid, or an oil-in-water, or water-in-oil emulsion. 56. The kit of claim 50, wherein the formulation is provided in a capsule, cartridge or blister, which may be a pierceable or openable capsule, cartridge or blister. 57. The kit of claim 50, wherein the delivery device is pressurized and it operates with the aid of a propellant. 58. A method for treatment of a respiratory, lung or malignant disorder or condition, or for reducing levels of, or sensitivity to, adenosine or adenosine receptors, or for increasing surfactant or ubiquinone levels in a subject in need of treatment, comprising simultaneously, sequentially or separately administering to a subject in need of treatment prophylactically or therapeutically effective amounts of the first and second active agents of claim 1. 59. The method of claim 58, wherein the disorder or condition comprises asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), dispnea, emphysema, wheezing, pulmonary hypertension, pulmonary fibrosis, hyper-responsive airways, increased adenosine or adenosine receptor levels, adenosine hyper-sensitivity, infectious diseases, pulmonary bronchoconstriction, respiratory tract inflammation or allergies, lung surfactant or ubiquinone depletion, chronic bronchitis, bronchoconstriction, difficult breathing, impeded or obstructed lung airways, adenosine test for cardiac function, pulmonary vasoconstriction, impeded respiration, Acute Respiratory Distress Syndrome (ARDS), administration of adenosine or adenosine level increasing drugs, infantile Respiratory Distress Syndrome (infantile RDS), pain, allergic rhinitis, cancer, or chronic bronchitis. 60. The method of claim 58, wherein the first active agent comprises a non-glucocorticoid steroid formula (I), (III) or (IV), or salt thereof, and is administered in an amount of about 0.05 to about 2000 mg/kg body weight/day. 61. The method of claim 60, wherein the non-glucocorticoid steroid of formula (I), (III) or (IV), or salt thereof, is administered in an amount of about 1 to about 500 mg/kg/day. 62. The method of claim 61, wherein the non-glucocorticoid steroid of formula (I), (III) or (IV), or salt thereof, is administered in an amount of about 2 to about 100 mg/kg/day. 63. The method of claim 58, wherein the first active agent is a ubiquinone of formula (II) or salt thereof, and it is administered in an amount of about 1 to 150 mg/kg body weight/day. 64. The method of claim 63, wherein the ubiquinone of formula (II) or salt thereof is administered in an amount of about 30 to about 100 mg/kg/day. 65. The method of claim 64, wherein the ubiquinone of formula (II) or salt thereof is administered in an amount of about 5 to about 50 mg/kg/day. 66. The method of claim 58, wherein the respiratory or lung disease or condition is associated with an infectious disease, respiratory tract allergies or surfactant depletion. 67. The method of claim 58, wherein the disorder or condition comprises COPD. 68. The method of claim 58, wherein the disorder or condition comprises asthma. 69. The method of claim 58, wherein the disorder or condition comprises RDS. 70. The method of claim 58, wherein the disorder or condition comprises allergic rhinitis. 71. The method of claim 58, wherein the disorder or condition comprises pulmonary fibrosis. 72. The method of claim 58, wherein the disorder or condition comprises bronchoconstriction, wheezing, difficulty breathing or hypoxia. 73. The method of claim 58, wherein the respiratory or lung disease or condition comprises cystic fibrosis. 74. The method of claim 58, wherein the respiratory or lung disease or condition comprises emphysema. 75. The method of claim 58, wherein the respiratory or lung disease or condition comprises dyspnea. 76. The method of claim 58, wherein the first active agent comprises DHEA or DHEA-S and ubiquinone, and the second active agent comprises a β2 adrenergic agonist selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide. 77. The method of claim 58, wherein the subject is a human or a non-human animal. 78. The method of claim 58, which is a prophylactic method. 79. The method of claim 58, which is a therapeutic method. 80. The method of claim 58, wherein the respiratory disease comprises bronchoconstriction, lung inflammation or allergies, decreased lung surfactant or decreased ubiquinone, or DHEA or DHEA-S levels. 81. The method of claim 58, wherein the first active agent comprises a ubiquinone; and the second active agent comprises a β2 adrenergic agonist agent selected from ephedrine, isoproterenol, isoetharine, epinephrine, metaproterenol, terbutaline, fenoterol, procaterol, albuterol, salbutamol, pirbuterol, formoterol, biloterol, bambuterol, salmeterol or seretide. 82. The method of claim 58, wherein the first active agent comprises DHEA; and is administered in an amount of about 2 to about 200/mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 pg per day wherein the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day. 83. The method of claim 58, wherein the first active agent comprises DHEA Sulfate (DHEA-S) and is administered in an amount of about 1 to about 150 /mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day. 84. The method of claim 58, wherein the first agent comprises a ubiquinone of formula (II), or salt thereof, and it is administered in an amount about 0.1 to about 1200 mg/kg/day; and the second active agent comprises salmeterol or a salt thereof, and is administered in an amount about 25 to about 500 μg per day. 85. The method of claim 58, wherein the first and second active agents are administered by inhalation, into the airways or respiration, intrapulmonarily, nasally, orally, bucally, rectally, vaginally, into a tumor or fibroma, parenterally, sublingually, transdermally, topically, iontophorically, intracavitarily, by implant, sub-lingually, opthalmically, otically, intraarticularly, intralymphatically, by slow or sustained release or interically coated. 86. The method of claim 85, wherein the agents are administered nasally, intrapulmonarily, by inhalation or into the respiratory airways. 87. The method of claim 86, wherein the agents are administered as a liquid or powdered aerosol or spray of particle size about 0.05 to about 10 μm. 88. The method of claim 87, wherein the agents are administered as a liquid or powdered aerosol or spray of particle size about 10 to about 50 μm. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates to a composition and formulations comprising a non-glucocorticoid steroid including DHEA, DHEA salts such as DHEA Sulfate, and analogues and salts thereof, and a bronchodilating agent, and optionally other bioactive agents. These products are useful in the treatment of conditions where a reduction of adenosine levels, or adenosine hyper-responsiveness, or where an increase in ubiquinone or lung surfactant levels is beneficial, or in the treatment of respiratory and lung diseases in general. 2. Description of the Background Respiratory ailments, associated with a variety of conditions, are extremely common in the general population, and more so in certain ethnic groups, such as African Americans. In some cases they are accompanied by inflammation, which aggravates the condition of the lungs. Asthma, for example, is one of the most common diseases in industrialized countries. In the United States it accounts for about 1% of all health care costs. An alarming increase in both the prevalence and mortality of asthma over the past decade has been reported, and asthma is predicted to be the preeminent occupational lung disease in the next decade. While the increasing mortality of asthma in industrialized countries could be attributable to the depletion reliance upon beta agonists in the treatment of this disease, the underlying causes of asthma remain poorly understood. Diseases such as asthma, allergic rhinitis, and Acute Respiratory Distress Syndrome (ARDS), including RDS in pregnant mothers and in premature born infants, among others, are common diseases in industrialized countries, and in the United States alone, they account for extremely high health care costs. These diseases have recently been increasing at an alarming rate, both in terms of prevalence, morbidity and mortality. In spite of this, their underlying causes still remain poorly understood. Asthma is a condition characterized by variable, in many instances reversible obstruction of the airways. This process is associated with lung inflammation and in sum cases lung allergies. Many patients have acute episodes referred to as “asthma attacks,” while others are afflicted with a chronic condition. The asthmatic process is believed to be triggered in some cases by inhalation of antigens by hypersensitive subjects. This condition is generally referred to as “extrinsic asthma.” Other asthmatics have an intrinsic predisposition to the condition, which is thus referred to as “instrinsic asthma,” and may be comprised of conditions of different origin, including those mediated by the adenosine receptor(s), allergic conditions mediated by an immune IgE-mediated response, and others. All asthmas have a group of symptoms, which are characteristic of this condition: bronchoconstriction, lung inflammation and decreased lung surfactant. Existing bronchodilators and anti-inflammnatories are currently commercially available and are prescribed for the treatment of asthma. The most common anti-inflammatories, corticosteroids, have considerable side effects but are commonly prescribed nevertheless. Most of the drugs available for the treatment of asthma are, more importantly, barely effective in a small number of patients. Acute Respiratory Distress Syndrome (ARDS), or stiff lung, shock lung, pump lung and congestive atelectasis, is believed to be caused by fluid accumulation within the lung which, in turn, causes the lung to stiffen. The condition is triggered within 48 hours by a variety of processes that injure the lungs such as trauma, head injury, shock, sepsis, multiple blood transfusions, medications, pulmonary embolism, severe pneumonia, smoke inhalation, radiation, high altitude, near drowning, and others. In general, ARDS occurs as a medical emergency and may be caused by other conditions that directly or indirectly cause the blood vessels to “leak” fluid into the lungs. In ARDS, the ability of the lungs to expand is severely decreased and produces extensive damage to the air sacs and lining or endothelium of the lung. ARDS' most common symptoms are labored, rapid breathing, nasal flaring, cyanosis blue skin, lips and nails caused by lack of oxygen to the tissues, breathing difficulty, anxiety, stress, tension, joint stiffness, pain and temporarily absent breathing. ARDS is commonly diagnosed by testing for symptomatic signs, for example by a simple chest auscultation or examination with a stethoscope that may reveal abnormal symptomatic breath sounds. A preliminary diagnosis of ARDS may be confirmed with chest X-rays and the measurement of arterial blood gas. In some cases ARDS appears to be associated with other diseases, such as acute myelogenous leukemia, with acute tumor lysis syndrome (ATLS) developed after treatment with, e.g. are, therefore, susceptible to respiratory problems including bronchoconstriction, lung inflammation and ARDS, among others. When Respiratory Distress Syndrome (RDS) occurs in premies, it is an extremely serious problem. Preterm infants exhibiting RDS are currently treated by ventilation and administration of oxygen and surfactant preparations. When premies survive RDS, they frequently develop bronchopulmonary dysplasia (BPD), also called chronic lung disease of early infancy, which is often fatal. The systemic administration of adenosine was found useful for treating SVT, and as a pharmacologic means to evaluate cardiovascular health via an adenosine stress test commonly administered by hospitals and by doctors in private practice. Adenosine administered by inhalation, however, is known to cause bronchoconstriction in asthmatics, possibly due to mast cell degranulation and histamine release, effects which have not been observed in normal subjects. Adenosine infusion has caused respiratory compromise, for example, in patients with COPD. As a consequence of the untoward side effects observed in many patients, caution is recommended in the prescription of adenosine to patients with a variety of conditions, including obstructive lung disease, emphysema, bronchitis, etc, and complete avoidance of its administration to patients with or prone to bronchoconstriction or bronchospasm, such as asthma. In addition, the administration of adenosine must be discontinued in any patient who develops severe respiratory difficulties. It would be of great help if a formulation were to be made available for joint use when adenosine administration is required. Allergic rhinitis afflicts one in five Americans, accounting for an estimated $4 to 10 billion in health care costs each year, and occurs at all ages. Because many people mislabel their symptoms as persistent colds or sinus problems, allergic rhinitis is probably underdiagnosed. Typically, IgE combines with allergens in the nose to produce chemical mediators, induction of cellular processes, and neurogenic stimulation, causing an underlying inflammation. Symptoms include nasal congestion, discharge, sneezing, and itching, as well as itchy, watery, swollen eyes. Over time, allergic rhinitis sufferers often develop sinusitis, otitis media with effusion, and nasal polyposis, and may exacerbate asthma, and is associated with mood and cognitive disturbances, fatigue and irritability. Degranulation of mast cells results in the release of preformed mediators that interact with various cells, blood vessels, and mucous glands to produce the typical rhinitis symptoms. Most early- and late-phase reactions occur in the nose after allergen exposure. The late-phase reaction is seen in chronic allergic rhinitis, with hypersecretion and congestion as the most prominent symptoms. Repeated exposure causes a hypersensitivity reaction to one or many allergens. Sufferers may also become hyperreactive to nonspecific triggers such as cold air or strong odors. Nonallergic rhinitis may be induced by infections, such as viruses, or associated with nasal polyps, as occurs in patients with aspirin idiosyncrasy. In addition, pregnancy, hypothyroidism, and exposure to occupational factors or medications can cause rhinitis, as well. NARES syndrome, a non-allergic type of rhinitis associated with eosinophils in the nasal secretions, typically occurs in middle-aged individuals and is accompanied by loss of smell. Saline is often recommended to improve nasal stuffiness, sneezing, and congestion, and saline sprays usually relieve mucosal irritation or dryness associated with various nasal conditions, minimize mucosal atrophy, and dislodge encrusted or thickened mucus, while causing no side effects, and may be tried first in pregnant patients. Also, if used immediately before intranasal corticosteroid dosing, saline helps prevent local irritation. Anti-histamines often serve as a primary therapy. Terfenadine and asternizole, two non-sedating anti-histamines, however, have been associated with a ventricular arrhythmia known as Torsades de Points, usually in interaction with other medications such as ketoconazole and erythromycin, or secondary to an underlying cardiac problem. To date loratadine, another nonsedating anti-histamine, and cetirizine have not been associated with serious adverse cardiovascular events, the most common side effect of cetirizine being drowsiness. Claritin, for example, may be effective in relieving sneezing, runny nose, and nasal, ocular and palatal itching in a low percentage of patients, although not approved for this indication or asthma. Anti-histamines are typically combined with a decongestant to help relieve nasal congestion. Sympathomimetic medications are used as vasoconstrictors and decongestants, the three most common decongestants being pseudoephedrine, phenylpropanolamine and phenylephrine. These agents, however, cause hypertension, palpitations, tachycardia, restlessness, insomnia and headache. Topical decongestants are recommended for a limited period of time, as their overuse results in nasal dilatation. Anti-cholinergic agents, such as Cromolyn, have a role in patients with significant rhinorrhea or for specific entities such as “gustatory rhinitis”, which is usually associated with ingestion of spicy foods, and have been used on the common cold. Sometimes the Cromolyn spray produces sneezing, transient headache, and even nasal burning. Topical and nasal spray corticosteroids such as Vancenase are effective agents in the treatment of rhinitis, especially for symptoms of congestion, sneezing, and runny nose, but often cause irritation, stinging, burning, sneezing, local bleeding and septal perforation. Topical steroids are generally more effective than Cromolyn Sodium, particularly in the treatment of NARES, but side effects limit their usefulness except for temporary therapy in patients with severe symptoms. Immunotherapy, while expensive and inconvenient, often can provide substantial benefits, especially the use of drugs that produce blocking antibodies, alter cellular histamine release, and result in decreased IgE. Presently available treatments, such as propranolol, verapamil, and adenosine, may help to minimize symptoms. Verapamil is most commonly used but it has several shortcomings, since it causes or exacerbates systemic hypotension, congestive heart failure, bradyarrhythmias, and ventricular fibrillation. In addition, verapamil readily crosses the placenta and has been shown to cause fetal bradycardia, heart block, depression of contractility, and hypotension. Adenosine has several advantages over verapamil, including rapid onset, brevity of side effects, theoretical safety, and probable lack of placental transfer, but may not be administered to a variety of patients. Chronic obstructive pulmonary disease (COPD) is characterized by airflow obstruction that is generally caused by chronic bronchitis, emphysema, or both. Emphysema is characterized by abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is characterized by chronic cough, mucus production, or both, for at least three months for at least two successive years where other causes of chronic cough have been excluded. COPD characteristically affects middle aged and elderly people, and is one of the leading causes of morbidity and mortality worldwide. In the United States it affects about 14 million people and is the fourth leading cause of death. Both morbidity and mortality, however, are rising. The estimated prevalence of this disease in the United States has risen by 41% since 1982, and age adjusted death rates rose by 71% between 1966 and 1985. This contrasts with the decline over the same period in age-adjusted mortality from all causes (which fell by 22%), and from cardiovascular diseases (which fell by 45%). COPD, however, is preventable, since it is believed that its main cause is exposure to cigarette smoke. The disease is rare in lifetime non-smokers, in whom exposure to environmental tobacco smoke will explain at least some of the airways obstruction. Other proposed etiological factors include airway hyper-responsiveness or hypersensitivity, ambient air pollution, and allergy. The airflow obstruction in COPD is usually progressive in people who continue to smoke. This results in early disability and shortened survival time. Stopping smoking reverts the decline in lung function to values for non-smokers. Many patients will use medication chronically for the rest of their lives, with the need for increased doses and additional drugs during exacerbations. Amongst the currently available treatments for COPD, short term benefits, but not long term effects, were found on its progression, from administration of anti-cholinergic drugs, β2 adrenergic agonists, and oral steroids. Neither anti-cholinergic drugs nor β2 adrenergic agonists have an effect on all people with COPD; nor do the two agents combined. The adverse effects of theophyllines and the need for frequent monitoring limit their usefulness. There is no evidence that anti-cholinergic agents affect the decline in lung function, and mucolytics have been shown to reduce the frequency of exacerbations but with a possible deleterious effect on lung function. The long-term effects of β32 adrenergic agonists, oral corticosteroids, and antibiotics have not yet been evaluated, and up to the present time no other drug has been shown to affect the progression of the disease or survival. Thus, there is very little currently available to alleviate symptoms of COPD, prevent exacerbations, preserve optimal lung function, and improve daily living activities an quality of life. Pulmonary fibrosis, interstitial lung disease (ILD), or interstitial pulmonary fibrosis, include more than 130 chronic lung disorders that affect the lung by damaging lung tissue, and producing inflammation in the walls of the air sacs in the lung, scarring or fibrosis in the interstitium (or tissue between the air sacs), and stiffening of the lung, thus the name of the disease. Breathlessness during exercise may be one of the first symptoms of these diseases, and a dry cough may be present. Neither the symptoms nor X-rays are often sufficient to tell apart different types of pulmonary fibrosis. Some pulmonary fibrosis patients have known causes and some have unknown or idiopathic causes. The course of this disease is generally unpredictable. Its progression includes thickening and stiffening of the lung tissue, inflammation and difficult breathing. Some people may need oxygen therapy as part of their treatment. Cancer is one of the most prevalent and feared diseases of our times. It generally results from the carcinogenic transformation of normal cells of different epithelia. Two of the most damaging characteristics of carcinomas and other types of malignancies are their uncontrolled growth and their ability to create metastases in distant sites of the host, particularly a human host. It is usually these distant metastases that may cause serious consequences to the host since, frequently, the primary carcinoma is removed by surgery. The treatment of cancer presently relies on surgery, irradiation therapy and systemic therapies such as chemotherapy, different immunity-boosting medicines and procedures, hyperthermia and systemic, radioactively labeled monoclonal antibody treatment, immunotoxins and chemotherapeutic drugs. Dehydroepiandrosterone (DHEA) is a naturally occurring steroid secreted by the adrenal cortex with apparent chemoprotective properties. Epidemiological studies have shown that low endogenous levels of DHEA correlate with increased risk of developing some forms of cancer, such as pre-menopausal breast cancer in women and bladder cancer in both sexes. The ability of DHEA and DHEA analogues such as DHEA-S sulfate derivative to inhibit carcinogenesis is believed to result from their uncompetitive inhibition of the activity of the enzyme glucose 6-phosphate dehydrogenase (G6PDH). G6PDH is the rate limiting enzyme of the hexose monophosphate pathway, a major source of intracellular ribose-5-phosphate and NADPH. Ribose-5 phosphate is a necessary substrate for the synthesis of both ribo- and deoxyribonucleotides required for the synthesis of RNA and DNA. NADPH is a cofactor also involved in nucleic acid biosynthesis and the synthesis of hydroxmethylglutaryl Coenzyme A reductase (HMG CoA reductase). HMG CoA reductase is an unusual enzyme that requires two moles of NADPH for each mole of product, mevalonate, produced. Thus, it appears that HMG CoA reductase would be ultrasensitive to DHEA-mediated NADPH depletion, and that DHEA-treated cells would rapidly show the depletion of intracellular pools of mevalonate. Mevalonate is required for DNA synthesis, and DHEA arrests human cells in the GI phase of the cell cycle in a manner closely resembling that of the direct HMG CoA. Because G6PDH produces mevalonic acid used in cellular processes such as protein isoprenylation and the synthesis of dolichol, a precursor for glycoprotein biosynthesis, DHEA inhibits carcinogenesis by depleting mevalonic acid and thereby inhibiting protein isoprenylation and glycoprotein synthesis. Mevalonate is the central precursor for the synthesis of cholesterol, as well as for the synthesis of a variety of non-sterol compounds involved in post-translational modification of proteins such as farnesyl pyrophosphate and geranyl pyrophosphate; for dolichol, which is required for the synthesis of glycoproteins involved in cell-to-cell communication and cell structure; and for ubiquinone, an anti-oxidant with an established role in cellular respiration. It has long been known that patients receiving steroid hormones of adrenocortical origin at pharmacologically appropriate doses show increased incidence of infectious disease. DHEA, also known as 3β-hydroxyandrost-5-en-17-one or dehydroiso-androsterone, is a 17-ketosteroid which is quantitatively one of the major adrenocortical steroid hormones found in mammals. Although DHEA appears to serve as an intermediary in gonadal steroid synthesis, the primary physiological function of DHEA has not been fully understood. It has been known, however, that levels of this hormone begin to decline in the second decade of life, reaching 5% of the original level in the elderly.) Clinically, DHEA has been used systemically and/or topically for treating patients suffering from psoriasis, gout, hyperlipemia, and it has been administered to post-coronary patients. In mammals, DHEA has been shown to have weight optimizing and anti-carcinogenic effects, and it has been used clinically in Europe in conjunction with estrogen as an agent to reverse menopausal symptoms and also has been used in the treatment of manic depression, schizophrenia, and Alzheimer's disease. DHEA has been used clinically at 40 mg/kg/day in the treatment of advanced cancer and multiple sclerosis. Mild androgenic effects, hirsutism, and increased libido were the side effects observed. These side effects can be overcome by monitoring the dose and/or by using analogues. The subcutaneous or oral administration of DHEA to improve the host's response to infections is known, as is the use of a patch to deliver DHEA. DHEA is also known as a precursor in a metabolic pathway which ultimately leads to more powerful agents that increase immune response in mammals. That is, DHEA acts as a biphasic compound: it acts as an immuno-modulator when converted to androstenediol or androst-5-ene-3β, 17β-diol (βAED), or androstenetriol or androst-5-ene-3β,7β,17β-triol (βAET). However, in vitro DHEA has certain lymphotoxic and suppressive effects on cell proliferation prior to its conversion to βAED and/or βAET. It is, therefore, believed that the superior immunity enhancing properties obtained by administration of DHEA result from its conversion to more active metabolites. Adequate ubiquinone levels have been found to be essential for maintaining proper cardiac function, and the administration of exogenous ubiquinone has recently been shown to have beneficial effect in patients with chronic heart failure. Ubiquinone depletion has been observed in humans and animals treated with lovastatin, a direct HMG CoA reductase inhibitor. Such lovastatin-induced depletion of ubiquinone has been shown to lead to chronic heart failure, or to a shift from low heart failure into life-threatening high grade heart failure. DHEA, unlike lovastatin, inhibits HMG CoA reductase indirectly by inhibiting G6PDH and depleting NADPH, a required cofactor for HMG CoA reductase. However, DHEA's indirect inhibition of HMG CoA reductase suffices to deplete intracellular mevalonate. This effect adds to the depletion of ubiquinone, and may result in chronic heart failure following long term usage. Thus, although DHEA is considered a safe drug, chronic heart failure may occur as a complicating side effect of its long term administration. Further, some analogues of DHEA produce this side effect to a greater extent because, in general, they are more potent inhibitors of G6PDH than DHEA. Adenosine is a purine involved in intermediary metabolism, and may constitute an important mediator in the lung for various diseases, including bronchial asthma, COPD, CF, RDS, rhinitis, pulmonary fibrosis, and others. Its potential role was suggested by the finding that asthmatics respond to aerosolized adenosine with marked bronchoconstriction whereas normal individuals do not. An asthmatic rabbit animal model, the dust mite allergic rabbit model for human asthma, responded in a similar fashion to aerosolized adenosine with marked bronchoconstriction whereas non-asthmatic rabbits showed no response. More recent work with this animal model suggested that adenosine-induced bronchoconstriction and bronchial hyperresponsiveness in asthma may be mediated primarily through the stimulation of adenosine receptors. Adenosine has also been shown to cause adverse effects, including death, when administered therapeutically for other diseases and conditions in subjects with previously undiagnosed hyper-reactive airways. Adenosine plays a unique role in the body as a regulator of cellular metabolism. It can raise the cellular level of AMP, ADP and ATP that are the energy intermediates of the cell. Adenosine can stimulate or down regulate the activity of adenylate cyclase and hence regulate cAMP levels. cAMP, in turn, plays a role in neurotransmitter release, cellular division and hormone release. Adenosine's major role appears to be to act as a protective injury autocoid. In any condition in which ischemia, low oxygen tension or trauma occurs adenosine appears to play a role. Defects in synthesis, release, action and/or degradation of adenosine have been postulated to contribute to the over activity of the brain excitatory amino acid neurotransmitters, and hence various pathological states. Adenosine has also been implicated as a primary determinant underlying the symptoms of bronchial asthma and other respiratory diseases, the induction of bronchoconstriction and the contraction of airway smooth muscle. Moreover, adenosine causes bronchoconstriction in asthmatics but not in non-asthmatics. Other data suggest the possibility that adenosine receptors may also be involved in allergic and inflammatory responses by reducing the hyperactivity of the central dopaminergic system. It has been postulated that the modulation of signal transduction at the surface of inflammatory cells influences acute inflammation. Adenosine is said to inhibit the production of super-oxide by stimulated neutrophils. Recent evidence suggests that adenosine may also play a protective role in stroke, CNS trauma, epilepsy, ischemic heart disease, coronary by-pass, radiation exposure and inflammation. Overall, adenosine appears to regulate cellular metabolism through ATP, to act as a carrier for methionine, to decrease cellular oxygen demand and to protect cells from ischemic injury. Adenosine is a tissue hormone or inter-cellular messenger that is released when cells are subject to ischemia, hypoxia, cellular stress, and increased workload, and or when the demand for ATP exceeds its supply. Adenosine is a purine and its formation is directly linked to ATP catabolism. It appears to modulate an array of physiological processes including vascular tone, hormone action, neural function, platelet aggregation and lymphocyte differentiation. It also may play a role in DNA formation, ATP biosynthesis and general intermediary metabolism It is suggested that it regulates the formation of cAMP in the brain and in a variety of peripheral tissues. Adenosine regulates cAMP formation through two receptors A 1 and A 2 . Via Al receptors, adenosine reduces adenylate cyclase activity, while it stimulates adenylate cyclase at A 2 receptors. The adenosine A 1 receptors are more sensitive to adenosine than the A 2 receptors. The CNS effects of adenosine are generally believed to be A 1 -receptor mediated, where as the peripheral effects such as hypotension, bradycardia, are said to be A 2 receptor mediated. A handful of medicaments have been used for the treatment of respiratory diseases and conditions, although in general they all have limitations. Amongst them are glucocorticoid steroids, leukotriene inhibitors, anti-cholinergic agents, anti-histamines, oxygen therapy, theophyllines, and mucolytics. Glucocorticoid steroids are the ones with the most widespread use in spite of their well documented side effects. Most of the available drugs are nevertheless effective in a small number of cases, and not at all when it comes to the treatment of asthma. No treatments are currently available for many of the other respiratory diseases. Theophylline, an important drug in the treatment of asthma, is a known adenosine receptor antagonist which was reported to eliminate adenosine-mediated bronchoconstriction in asthmatic rabbits. A selective adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was also reported to inhibit adenosine-mediated bronchoconstriction and bronchial hyperresponsiveness in allergic rabbits. The therapeutic and preventative applications of currently available adenosine A1 receptor-specific antagonists are, nevertheless, limited by their toxicity. Theophylline, for example, has been widely used in the treatment of asthma, but is associated with frequent, significant toxicity resulting from its narrow therapeutic dose range. DPCPX is far too toxic to be useful clinically. The fact that, despite decades of extensive research, no specific adenosine receptor antagonist is available for clinical use attests to the general toxicity of these agents. For many years, two classes of compounds have dominated the treatment of asthma: glucocorticosteroids and bronchodilators. Examples of glucocorticosteroids are beclomethasone and corticoid 21-sulfopropionates. Examples of a bronchodilator are an older β2 adrenergic agonist such as albuterol, and a newer one such as salmeterol. In general, when glucocorticosteroids are taken daily either by inhalation or orally, they attenuate inflammation. The β2 adrenergic agonists, on the other hand, primarily alleviate bronchoconstriction. Whereas glucocorticosteroids are not useful in general for acute settings, bronchodilators are used in acute care, such as in the case of asthma attacks. At the present time, many asthma patients require daily use of both types of agents, a glucocorticosteroid to contain pulmonary inflammation, and a bronchodilator to alleviate bronchoconstriction. More recently, fluticasone propionate, a glucocorticoid steroid was combined with β2 adrenergic agonists in one therapeutic formulation said to have greater efficiency in the treatment of asthma. However, glucocorticosteriods, particularly when taken for prolonged periods of time, have extremely deleterious side effects that, although somewhat effective, make their chronic use undesirable, particularly in children. Clearly, there exists a well defined need for novel and effective therapies for treating respiratory, lung and cancer ailments that cannot presently be treated, or at least for which no therapies are available that are effective and devoid of significant detrimental side effects. This is the case of ailments afflicting the respiratory tract, and more particularly the lung and the lung airways, including respiratory difficulties, bronchoconstriction, lung inflammation and allergies, depletion or hyposecretion of surfactant, etc. Moreover, there is a definite need for treatments that have prophylctic and therapeutic applications, and require low amounts of active agents, which makes them both less costly and less prone to detrimental side effects. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a composition and formulations and treatments employing a first active agent comprising a non-glucocorticoid steroid such as an epiandrosterone (EA) or analogue thereof and/or a ubiquinone (CoEnzyme Q) and/or their salts in combination with a second active agent comprising a bronchodilator, and optionally other bioactive agents and formulation ingredients. These compositions and formulations are useful for treating lung and respiratory diseases and conditions associated with brochoconstriction, lung inflammation and allergies, and other respiratory and lung diseases. The drawings accompanying this patent form part of the disclosure of the invention, and further illustrate some aspects of the present invention as discussed below. |
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