A method for performing an opinion poll with a mobile communication system having a data processing block, a plurality of recipient mobile stations comprising a wireless communication block and a display, and service center having a buffer. A query message is entered to the data processing block, a predetermined answering period is defined, and the buffer is provided with the query message. This is followed by attempting to send wirelessly the query message from the buffer substantially simultaneously to the recipient mobile stations, attempting again if necessary, and storing at least temporarily the query message at the recipient mobile stations. The query messages are then presented at recipient mobile stations and their users are allowed, at a convenient moment, to enter a written answer message to the mobile station. The written answer messages are sent wirelessly to the service center, forwarded from the service center to the data processing block; and processed by the data processing block, if received by the processing block within the answering period.

The present invention relates to a method for transmitting messages and the processing of received answers to the transmitted messages. A further object of the invention is a system for transmitting messages and the processing of received answers to the transmitted messages, which system comprises a communicator""s (message sender""s) data processing system comprising means for selecting a target group, for transmitting a message and for receiving answers, a service center comprising means for transferring the message and the answer, and a telecommunication device for receiving messages.
The invention relates in particular to making small-size opinion polls, but it is possible to utilize the method according to the invention also in other two-way communication. In the following the invention is through explained in an exemplary way in particular in connection with making opinion polls.
Opinion polls have traditionally been made by mailing a questionnaire to the answering party, by making personal on-site interviews, by making personal interviews by telephone and by requesting in television and/or radio broadcasts the interviewees to call certain telephone numbers, in which case the opinion is expressed by dialing a telephone number corresponding to the opinion or by entering DTMF-signals, i.e. by pushing the telephone keys based upon a voice or a vocal message heard from the called-up telephone number. In publication WO 88 05 239 xe2x80x9cImproved polling systemxe2x80x9d it is explained a system operating in the fixed telephone network, in which system by utilizing programmable units and a voice messages a data system is made to call the interviewees, who answer the questions using their telephone devices according to the instructions of the voice message.
A letter poll can be directed to a certain area, in which case the persons selected to be interviewed are selected based upon their area of residence. A letter poll cannot be directed to persons who were in a certain area at a certain moment.
The problem of a letter poll is also its slowness. The preparing of the material, mailing and the passage of mail itself to both directions all consume their own time. The slowness is increased by the fact that the transfer of the answer information to the enquirer""s data processing system for analyzing involves a delay. Another disadvantage is also that a letter poll is delivered to an interviewee""s address or to an address into which the interviewee has redirected his/her mail, independent of where the interviewee is at the moment. A further problem of a letter poll from a recipient""s point of view is that if he/she does not check his/her mail during the answering period, an outdated enquiry cannot be removed from his/her mail. Answering a letter poll further requires that the interviewee takes his/her answer to a letter box.
Personal on-site interviews can be directed to a certain area. Additionally, they can be directed to persons being in this area during a certain period. The period must however be rather long. Normally there are so many persons in an area that only a small part of them is reached. Interviewees selected based upon their place of residence are only reached when at home, in which case an interviewer may have to make several visits. The problem is, independent of the selecting criterion, that the coverage of a poll is highly dependent on the number of persons present on the site. A further problem is that the interviewees cannot be reached simultaneously. From an interviewee""s point of view the disadvantage is that he/she should have time to answer the questions just at the time of an interview. Also slowness is a problem of an on-site interview. The preparing of material, printing, an eventual selecting of the interviewers and the interviewers"" moving to the site of interview, the interview itself, delivering the answers to the subscriber of the poll and transferring the answer information into the enquirer""s data processing systems consume time. In addition to above, the problem of an on-site personal interview is that an interviewer may unconsciously, or even consciously, influence the answers given by the interviewee with his/her body language and/or by presenting the question using his/her own words.
Telephone interviews can be directed to a certain area. In this case the persons selected to be interviewed are selected based upon their place of residence. In prior known methods enquiries cannot be directed to persons who were in a certain place at a certain moment. Even the telephone interview method utilizing a voice message and several telephone lines simultaneously, which was presented in publication WO 88 05 239, has shortcomings. If there is no answer in a telephone number or it is busy, it must be called again, possibly even a number of times during the interview period. In addition to that the number of telephone lines connected to a xe2x80x9cpolling centerxe2x80x9d limits the number of interviewees who can be reached simultaneously. Because in the method the answering is done using the dialing equipment of a telephone, the questions are limited to multiple-choice questions only. From the point of view of an interviewee who has answered the phone, the problem of the method is that he/she should have just at the moment of enquiry time to answer the questions.
An opinion poll, in which answers are requested over a television and/or radio broadcast to call certain telephone numbers or to express their opinions in another way, has the problem of limiting the target group and the geographical focusing of a poll. It is possible to try to limit the target group through selecting the media and the broadcasting time, but it is not possible to select the target group demographically. The problem in geographic focusing is that even the smallest area to which a poll can be focused, is geographically a quite large one (e.g. the coverage of a local radio broadcast).
U.S. Pat. No. 5,226,177 (Nickerson) discloses an opinion poll system utilising a radio link connection between central station and user stations. The system comprises plurality of dedicated handsets for transmission of user responses to a local base station. The opinion poll questions are delivered over a common TV-broadcast. The system offers real-time answering and updating opinion poll charts. Updated charts can further be broadcasted and shown also to the audience with handsets. While the system has advantages of real-time opinion polls with wireless handsets, it has several disadvantages such as: 1. The user""s station is not capable for receiving and displaying only a short index (question reference) of maximum 3 digits. 2. The user""s station must be relatively close to the central station to confirm a wireless link (radio link or wireless infrared- or optical link etc.) to the central station and therefore the system is basically for local use only. 3. The purpose of the handset according to this system is to provide the user with possibility to answer questions shown in an on-line or off-line media (TV, radio, and newspapers). The handsets are therefore not likely to become popular and thus the system can not offer substantial percentage of voters among a large population.
The publication of WO patent application 89 09 530 discloses a real time automated interactive mass communications system. The system is arranged to make telephone calls to a number of telephone subscribers. Once a recipient answers a call, a recorded audio message will be played to present the question(s). The user can give an answer by means of dialling certain number by and ordinary telephone device used to answer the telephone call. An automated system gathers the results from the various users. As the system uses an on-line telephone method, it suffers from the same disadvantages as mentioned before in case of WO 88 05 239.
U.S. Pat. No. 5,036,389 discloses a system, where a satellite TV-program carries the question of an opinion poll and a user is equipped with special devices providing a possibility to reply to an opinion poll question over a satellite link. While this system can offer a large coverage area, each participant of an opinion poll must follow a satellite TV-program to be able to see the question and answer it, and answering must be done almost instantaneously, while the question is shown in the TV-program. The required satellite television equipment also makes this system fairly complicated and expensive, which inherently restricts the possible number of users.
U.S. Pat. No. 5,311,507 xe2x80x9cAutomated interactive mass communications systemxe2x80x9d utilises automated on-line interview very similar to the same inventor""s patent WO 89/09530 referred above.
The problem of all above presented methods is that they are very poorly suited for making a small poll with at most a few questions.
The object of this invention is to solve the above problems and to provide a quick method, which reaches one target group at one time and offers versatile geographic focusing possibilities and normal other selecting criterion and which is well suited for even small opinion polls. This goal is achieved with the method according to the invention, which method is characterized in that a message is entered from a communicator""s data system through a service center utilizing wireless data transmission connection essentially simultaneously to at least two recipients to the recipients"" telecommunication devices, which service center buffers said message for sending it later if any of recipient""s telecommunication devices is unable to receive said message, the recipients are allowed to view said message on a display of said devices and are allowed to reply at a moment suitable for the recipient, whereby the interviewees use their telecommunication devices to feed the answer to the message through the service center utilizing wireless data transmission back to the communicator""s data system, which expects the answers for a certain, predetermined time, and the information contained in each answer is processed in a predetermined way in the communicator""s data system.
The concept essentially simultaneously means in this context that small differences may occur in the time of transmitting a message, which differences are due to delays connected with data processing and data transfer caused by the executing equipment and/or software for example because of eventually required database searches.
A further object of the invention is a system in which the method according to the invention can be utilized. A system according to the invention is for transmitting messages and for the processing of the answers arrived to the questions, which system comprises
a communicator""s data processing system, comprising means for selecting a target group, for transmitting a message and for receiving answers,
a service center comprising means for transferring the message and the answer, and
a telecommunication device for receiving messages, is characterized in that
the communicator""s data processing system, comprises means for feeding the message to the service center, and means for receiving each answer to the message from the service center and means for analyzing the information contained in the answers in the communicator""s data processing system,
the service center comprises means for receiving the message from the communicator""s data processing system and means for transferring the message over a wireless telecommunication system substantially simultaneously to the telecommunication devices of at lease two recipients, wherein said means for transferring the message are arranged to buffer said message for sending said message later if any of said telecommunication devices is unable to receive said message, and said service center further comprises means for receiving the recipients"" answers and for transferring them further to the communicator""s data processing system, and
the telecommunication device comprises means for receiving the message, a user interface for presenting the information contained in the message to the recipient, means for entering the answer to the telecommunication device, and means for transmitting the answer entered at a moment suitable for the recipient by the recipient using the user interface having a display, utilizing the service center, over the wireless data transmission connection to the communicator""s data processing system.
The concept message means in this context any message containing at least one question, which a recipient is desired to answer. A message can thus be an opinion poll with one or several questions or some other opinion enquiry, an official communication containing a question or an advertisement containing a question.
The concept communicator means in this context a sender of a message who makes the inquiries for himself or as a research assignment.
The concept service center means in this context a center belonging to a telecommunication network, which center is capable of attending to the transmitting of messages to right recipients in a format suitable for the latter and of transferring the answers to the communicator in a correct format. Such a service center can be e.g. the short message service center of a GSM-mobile communication network.
The concept telecommunication device means in this context any device suited for wireless communication, with the help of which a recipient can both receive a message and send an answer to the message. Such a telecommunication device can be for example any radio transmitter, such as e.g. a mobile telephone operating over base stations or eventually over a satellite or e.g. a two-way-pager or e.g. a device of PDA (Personal Digital Assistant)-type.
The concept user interface means in this context those parts of a telecommunication device or a part or sub-unit connected to a telecommunication device, by using which the communication is executed. Such a user interface is e.g. the entity formed by the display and keypad of a mobile telephone.
The invention is based upon the concept that polls can be made quickly thanks to the wireless telecommunication, effectively and using little manpower by focusing a poll according to the present selecting criterion (e.g. area of residence, demographic factors) or based upon the location of a telecommunication device at a given moment (e.g. a superstore). The invention is very well suited for small-form polls including a few questions. The most significant advantages of the solution according to the invention are thus the simultaneous distribution of the message to an unlimited amount of recipients, the reaching of the recipients based upon their location at the moment of reception, and that the message can be answered when it is best suited for the recipient and the answer can be sent from the recipient""s present location, and that it is possible to select persons who have been in a certain area at a given moment as a target group, and that said area can be limited to be very small by utilizing the cellular structure of the telecommunication system, and that a message can be provided with a time stamp, in which case an outdated message is automatically removed, and that the invention offers the possibility of crediting an interviewee""s account with an answering fee.
In a preferable embodiment of the invention the GSM-mobile telephone system is used as the wireless telecommunication system. This embodiment according to the invention is very advantageous, because its short messages can be delivered even if a telecommunication device is busy. In addition to it, its short message service center takes care of delivering a message during the validity of the message, if a recipient""s telecommunication device, i.e. a mobile telephone of the GSM-system, has not been in connection with the mobile telephone network at the moment a message was transmitted.

Opinion poll utilizing a wireless data transmission connection


Rosacea is treated by application of a composition containing lipoic acid and/or a lipoic acid derivative such as dihydrolipoic acid, a lipoic or dihydrolipoic acid ester, a lipoic or dihydrolipoic acid amide, a lipoic or dihydrolipoic acid salt, and mixtures of any of these. Preferred compositions further comprise xcex1-hydroxy acids or acid derivatives such as glycolic and/or lactic acid. Other embodiments also contain fatty acid esters of ascorbic acid such as ascorbyl palmitate, and/or tocotrienol.

Not Applicable
1. Field of the Invention
This invention relates primarily to methods and compositions for the treatment of rosacea. Rosacea is a chronic inflammatory disorder affecting the blood vessels and pilosebaceous units of the face in middle-aged individuals, afflicting as many as 13 million Americans. Patients with rosacea have papules and pustules superimposed on diffuse erythema and telangiectasia (visible blood vessels) over the central portion of the face. Hence, the clinical features are facial redness, swelling, papules, pustules, and telangiectasias. An important component of the patients"" history is often easy flushing and blushing of the face, and this is often accentuated when alcohol, caffeine-containing, or hot spicy foods are ingested. Hyperplasia of the sebaceous glands, connective tissue, and vascular bed of the nose sometimes causes rhinophyma, or a large, red, bulbous nose in addition to the other signs. Ocular complications occur in a small but significant number of rosacea patients; these include blepharitis, chalazion, conjunctivitis, and keratinitis. Progressive keratinitis can lead to scarring and blindness.
Rosacea and the eye complications are usually responsive to tetracycline, but the antibiotic must be continued for life (at the lowest dose that suppresses the condition) because rosacea recurs when therapy is interrupted. In addition to the undesirability of the more prevalent use of antibiotics in general, a disadvantage to such treatments are the possible side effects associated with long-term use of oral antibiotics, such as nausea, gastrointestinal upset, phototoxicity, enhanced susceptibility to yeast infection, and interactions with other medications. Oral antibiotics may also lessen the effectiveness of oral contraceptives. High-potency topical corticosteroid preparations may induce or aggravate pre-existing rosacea and should not be used for long periods of time on the face. Instead, topical metronidazole is sometimes prescribed for reducing skin redness and the number of pimples on the face of patients with rosacea. Laser therapy has been used to reduce the telangiectasia and redness in some cases. (See Wilkin J K: Rosacea: Pathophysiology and Treatment. Archives of Dermatology, 1994, 130 :359-362; this and subsequent references are expressly incorporated herein by reference.) It would be desirable to have alternate treatments for rosacea.
2. Description of Related Art.
Lipoic acid was originally identified as a bacterial growth factor present in the water-soluble fraction of liver and yeast. It was found to be necessary for the oxidative decarboxylation of pyruvic acid by Streptococcus fecalis and for the growth of Tetrahymena gelii, and replaced acetate for the growth of Lactobacillus casei. It has been variously known as acetate replacing factor, protogen A, and pyruvate oxidation factor.
Subsequent research showed that lipoic acid (LA) was a growth factor for many bacteria and protozoa, and it served as a prosthetic group, coenzyme, or substrate in plants, microorganisms, and animal tissues. Elucidation of its structure and function determined that it is a co-factor for aketo-dehydrogenase complexes, typically bound as lipoamide, that participates in acyl transfer reactions. Its reduced form, dihydrolipoic acid (DHLA), is a potent sulfhydryl reductant. In aqueous systems, both LA and DHLA exhibit antioxidant actions (reviewed by Packer, L., et al., Free Rad. Biol. Med., 1995, 19: 227-250 (1995)). LA has been shown to maintain microsomal protein thiols, protect against hemolysis, and protect against neurological disorders. The protective effect of dietary supplementation of LA against ischemia/reperfusion injury in the Langendorff isolated heart model has also been demonstrated. LA has been suggested for treating systemically, or as adjuvant systemic medication for, liver cirrhosis, atheroschlerosis, diabetes, neurodegenerative diseases, heavy metal poisoning, and Chagas disease (ibid.). It has also been used as an antidote to poisonous mushrooms (ibid., particularly Amanita species, Merck Index, 11th ed., 1989, entry 9255).
Few references suggest the use of lipoic acid in dermatological compositions. In a 1988 Japanese patent publication (JP 63008315), lipoic acid in cosmetics at concentrations of 0.01% to 1%, preferably 0.05% to 0.5%, or in topical xe2x80x9cquasi-drugsxe2x80x9d at concentrations of 0.1% to 1.5%, preferably 0.5% to 1.0%, were suggested for inhibiting tyrosinase, and thus melanin formation, to whiten skin.
In 1995, Rawlings, et al., disclosed a composition and method for xe2x80x9cimproving or preventing the appearance of dry, flaky wrinkled, aged, photodamaged skin and treating skin disordersxe2x80x9d (U.S. Pat. No. 5,472,698, column 2, lines 51 to 54) using a synergistic combination of serine and/or N-acetyl serine and a thiol, an xe2x80x9cS-esterxe2x80x9d, and/or a disulfide (id., lines 28 to 33). Lipoic acid was mentioned as encompassed by the latter ingredient (column 3, lines 29 to 30). However, the patent""s terminology was confusing. Thiols and S-esters were disclosed as preferable over disulfides (column 4, lines 1 to 4). Though lipoic acid is a disulfide, it""s listed as a thiol in the patent (column 3, lines 29 to 30); perhaps what is referred to as xe2x80x9clipoic acidxe2x80x9d is, instead, dihydrolipoic acid. This supposition is reinforced by the fact that a Sigma product was employed in some examples (column 7, line 63). Both oxidized lipoic acid and reduced, i.e., dihydrolipoic acid, are available from that chemical company, so DHLA may have been used. Unfortunately, there is more uncertainty about the effects of DHLA when compared to LA (see Packer, et a/., cited above, 231-234). The only illustrations of alternate sulfur-containing ingredients were acylated cysteine derivatives, including glutathione.
More importantly, the focus of the patent was stimulation of sphingolipid synthesis in skin to improve it (see column 1 at lines 21 to 23 and column 2 at lines 12 to 13). The examples reported that assays monitored ceramide production in cultured human keratinocytes and porcine skin. In the studies, lipoic acid had no effect in compositions without serine. On the contrary, in every reported assay, the lipoic acid values were identical to controls; see Tables 2 and 3. And, though increasing concentrations of lipoic in the presence of a constant amount of serine boosted ceramide production at certain levels of serine (Table 7), other thiols worked equally well (Tables 1, 4, 5, 6, 8, and 9). Read as a whole, the reference teaches away from LA as an active ingredient, and suggests DHLA of efficacy only with serine or N-acetyl serine.
A year later, in U.S. Pat. No. 5,569,670 to Weischer, et al., pharmaceutical compositions containing a synergistic combination of xcex1-lipoic acid and/or dihydrolipoic acid with specific enantiomers of these, together with some vitamins, including C and E (column 1, lines 3 to 15), were disclosed as useful, primarily for treating diabetes (see the claims). However, anti-inflammatories (abstract, line 8 and column 2 at line 16) as well as treatments for retroviruses and other pathological conditions were included, with an emphasis on veterinary applications (column 13, lines 42 to 62). In a test model for inflammation (observing rat edema), the R-enantiomer of lipoic acid was superior to lipoic alone or to vitamin E alone (column 3, lines 37 to 40). Suggested administration was oral, parenteral or intravenous (column 7, line 31 to end, et seq.), preferably oral (column 11, line 42), but application to skin and mucous membranes was mentioned (column 12, lines 58 to 60). Antioxidants could be employed in some embodiments (column 16, lines 47 to 55), and the list included ascorbic acid, ascorbyl xe2x80x9cpalmiratexe2x80x9d [sic] and tocopherols. The examples combined lipoic and/or dihydrolipoic acid with tocopherols (Examples 1, 2, 5, and 6) or ascorbic acid (Examples 3, 4, and 7). An ointment was disclosed in Example 6; the others described suppositories, capsules, ampules, and tablets.
Similarly, U.S. Pat. No. 5,693,664 to Wessel, et al., from the same research group, was directed to diabetes treatments, particularly where insulin resistance is observed (column 1, lines 10 to 14 and the claims) by use of the Renantiomer of xcex1-lipoic acid. Again, one enantiomer, not a racemate, was employed (column 6, lines 18 to 19). Indeed, the S-enantiomer decreased the effect of insulin in an experimental study reported (column 3, lines 61 to 65). Suggested administration was primarily oral (column 6, lines 61 to 66), though parenteral and intravenous are mentioned (ibid., and column 3, lines 7 to 8).
U.S. Pat. No. 5,728,735 to Ulrich, et al., again from the same group, stressed use of an enantiomer (column 1, lines 28 to 54), particularly the Renantiomer (see the claims), and not a racemate, for combatting pain and inflammation in a variety of conditions (id., lines 58 to 59; inflammations are listed in column 5, line 64 to column 6, lines 9 and include neurodermatitis and psoriasis). Suggested administrations were oral, intravenous, or infusions (column 3, lines 28 to 30, 51, 62 to 63 and 65), but solutions and emulsions for topical application were mentioned (column 6, lines 29 to 34 and 65 to 68, and column 8, lines 16 to 18). Only tablets and ampules were illustrated. All the reported findings of the group are complicated by the fact that the metabolic effects of the R- and S-enantiomers are now known to be different, as are the enzymes that process the enantiomers in cytosolic and mitrochondrial systems (Haramaki, N., et a/., Free Rad. Biol. Med. 22: 535-542 (1997)). Moreover, different stereospecific reduction by intact cells and tissues has also been observed (ibid.).
More recently, Perricone suggested the use of lipoic acid in dermatological compositions for the treatment of skin damage, particularly inflammation and aging (U.S. Pat. No. 5,709,868). As explained in that reference, the antioxidant activity of lipoic acid appears to prevent free radical damage to cells and cell components. Free radical damage is most evident in cellular membranes because of the density of the molecular structure of the membranes. It is currently hypothesized that cell membrane aging leads to all of the various cellular changes seen in aging, such as decreased RNA production, decreased protein production, and faulty enzyme action.
Inflammation in skin is mediated by several active chemicals and metabolites of arachidonic acid. Arachidonic acid is oxidized by cyclo-oxygenase and lipoxygenase to active metabolites such as the leukotrienes and 5- and 12-hydroxyeicosatetraenoic acid (HETES). Within the arachidonic acid cascade, many free radicals are generated, which both perpetuate and magnify the inflammatory cascade, resulting in skin damage and manifested clinically as erythema. The redox state of the cell determines gene expression. Transcription factor nuclear factor kappa-B (NFxcexa-B) is inactive in the cytosol under a normal redox state of the cell. When the cell undergoes oxidative stress, i.e., ultraviolet radiation, ionizing radiation, infection, and free radicals created by metabolism, the inhibitory fraction of NFxcexa-B is dissociated from the molecule. Once the inhibitory fraction is dissociated from the NFxcexaB molecule, it then migrates to the nucleus of the cell, begins transcription, and subsequent production of inflammatory mediators, including cytokines such as tumor necrosis factor alpha (TFxcex1) and various interleukins, as well as many of the pro-inflammatory interleukins. These pro-inflammatory and inflammatory products of transcription then enter the cell cytoplasm effecting all parts of the cell including the mitochondria and cell membrane. Arachidonic acid is released, which is oxidized to biologically active mediators. When arachidonic acid is oxidized via the cyclooxygenase or lipoxygenase pathways, for example, prostaglandins, leukotrines, and hydroxyeicosatetraenoic acid (HETE) are produced, which cause erythema, edema, and free radical production. Lipoic acid is a powerful inhibitor of the activation of NFxcexa-B, and therefore can act as an anti-inflammatory as well as an antioxidant. It would be useful to employ this substance in the treatment of chronic skin conditions such as rosacea.
It is an objective of this invention to provide compositions and methods for the treatment and inhibition of rosacea.
It is another and more specific objective of the invention to provide topical compositions and methods for rosacea treatment based upon the topical application of compositions containing lipoic acid and/or lipoic acid derivatives, typically in association with a dermatologically acceptable carrier or vehicle, to skin exhibiting signs of rosacea.
These and other objectives are accomplished by the present invention, which provides compositions and methods for the treatment and/or inhibition of rosacea, which comprises topical application to skin areas exhibiting rosacea of an effective amount of lipoic acid, lipoic acid derivatives or mixtures thereof. Preferred embodiments also contain an xcex1-hydroxy acid such as glycolic acid in addition to lipoic acid. Typical embodiments involve the topical application of compositions containing active ingredient(s) in a dermatologically acceptable carrier.
Ascorbic acid, particularly fat-soluble fatty acid esters of ascorbic acid such as ascorbyl palmitate, can, optionally, also be utilized for further enhancing the efficacy of the therapeutic or prophylactic treatment. In other embodiments, tocotrienols or derivatives thereof or vitamin E compositions enriched with tocotrienols or tocotrienol derivatives such as tocotrienol-enriched fractions of natural oils are included in the lipoic acid composition with or without an ascorbic acid ingredient.
As summarized above, in a preferred practice of the invention, effective amounts of lipoic acid (and/or derivative) is applied in admixture with glycolic or another xcex1-hydroxy acid in a dermatologically acceptable carrier or vehicle (e.g., as a lotion, cream, ointment, soap, or the like) so as to facilitate topical application and, in some cases, provide additional therapeutic effects as might be brought about, e.g., by moisturizing of the affected skin areas. As noted, other ingredients, particularly ascorbyl palmitate and/or tocotrienol, can be advantageously included in the compositions.
The amount of lipoic acid or derivative thereof (hereinafter referred to collectively as lipoic acid for ease of reference) necessary to treat rosacea is not fixed per se, and necessarily is dependent upon the identity and form of lipoic acid employed, the amount and type of any additional ingredients used, particularly xcex1-hydroxy acids such as glycolic acid, but also ascorbyl esters and/or tocotrienol, the user""s skin type, and the severity and extent of the patient""s rosacea. In some typical embodiments, the composition contains from about 0.1% to about 7 weight %, lipoic acid or dihydrolipoic acid, more narrowly from about 0.25 to about 5 weight %. In one embodiment, about 2% to 5% lipoic acid is employed. xcex1-Hydroxy acids are employed in concentration ranges of from about 1% to about 10%, more narrowly from about 1% to about 5%, by weight.
This invention is based upon the finding that lipoic acid and/or its derivatives are useful for the treatment of rosacea.
As used herein, the term xe2x80x9clipoic acidxe2x80x9d encompasses thioctic acid (1,2-dithiolane-3-pentanoic acid; 1,2-dithiolane-3-valeric acid), C8H14O2S2, formula weight 206.32. It has been variously known as acetate replacing factor, protogen A, and pyruvate oxidation factor. Elucidation of its structure and function determined that it is a co-factor for xcex1-keto-dehydrogenase complexes, typically bound as lipoamide, that participates in acyl transfer reactions. Its reduced form, dihydrolipoic acid, is a potent sulfhydryl reductant. In aqueous systems, both LA and dihydroLA exhibit antioxidant action.
Lipoic acid derivatives include thioctic acid esters, particularly alkyl esters such as fatty acid esters, amides, particularly those isolated from or mimicking naturally occurring lipoamides, salts, particularly alkali metal salts, anhydrides and specifically includes the reduced form, dihydrolipoic acid and its esters, amides and salts. One particularly efficacious derivative that exhibits increased cellular uptake and biological activity useful in the practice of the invention is N,N-dimethyl,N-2-amidoethyl lipoate recently described by Sen, C. K., et al. (Free Radical Biol. Med., 1998, 25: 89) and called lipoic acid plus (LA-Plus). Since lipoic acid is both fat- and water-soluble, it is an advantage of the invention that it can be used in either lipid or aqueous-based compositions, and it readily crosses cellular membranes and disperses in extracellular and intracellular tissue components. Derivatives may also include those involving other reactive groups known to those skilled in the art. As used herein, the term xe2x80x9cderivativesxe2x80x9d includes metabolic precursors of lipoic acid. Where lipoic acid derivatives are employed, they must be functionally equivalent to lipoic acid.
As mentioned above, lipoic acid is fat-soluble. Therefore, lipoic acid preparations can be applied neat to skin tissue. It is an advantage of the invention that the active compound is fatty so that it physically contributes to the lubrication of affected skin areas to which it is applied.
However, only effective amounts of lipoic acid are needed to treat rosacea, so generally topical application to exposed or affected skin sites is accomplished in association with a carrier, and particularly one in which the active ingredient is soluble per se or is effectively solubilized (e.g., as an emulsion or microemulsion). Where employed, the carrier is inert in the sense of not bringing about a deactivation of the lipoic acid or derivative, and in the sense of not bringing about any adverse effect on the skin areas to which it is applied.
Suitable carriers include water, alcohols, oils and the like, chosen for their ability to dissolve or disperse lipoic acid and any other ingredients used in the treatment. Generally, even low concentrations of active ingredients in a carrier are suitable, depending upon the application regimen and adjunct ingredients employed. Many embodiments contain from about 0.1% to about 7% by weight, more narrowly from about 0.25 to about 5% by weight, LA or LA derivative. Many embodiments contain more than 1 weight % lipoic acid and/or lipoic acid derivative, e.g., from about 1.1% to about 3 to 5 weight % LA. One efficacious embodiment contains from about 2% to about 5% by weight. Examples are illustrated hereafter.
While the carrier for lipoic acid can consist of a relatively simple solvent or dispersant, it is generally preferred that the carrier comprise a composition more conducive to topical application, and particularly one which will form a film or layer on the skin to which it is applied so as to localize the application and provide some resistance to perspiration and/or one which aids in percutaneous delivery and penetration of the active ingredients into lipid layers of the scarred area. Many such compositions are known in the art, and can take the form of lotions, creams, gels or even solid compositions (e.g., stick-form preparations). Typical compositions include lotions containing water and/or alcohols and emollients such as hydrocarbon oils and waxes, silicone oils, hyaluronic acid, vegetable, animal or marine fats or oils, glyceride derivatives, fatty acids or fatty acid esters or alcohols or alcohol ethers, lanolin and derivatives, polyhydric alcohols or esters, wax esters, sterols, phospholipids and the like, and generally also emulsifiers (nonionic, cationic or anionic), although some of the emollients inherently possess emulsifying properties. These same general ingredients can be formulated into a cream rather than a lotion, or into gels, or into solid sticks by utilization of different proportions of the ingredients and/or by inclusion of thickening agents such as gums or other forms of hydrophillic colloids. Such compositions are referred to herein as dermatologically acceptable carriers. Most preferred for skin are those carriers which are fat-soluble, i.e., those which can effectively penetrate skin layers and deliver LA to all skin layers.
As summarized above, many preferred embodiments of this invention contain at least one other ingredient in addition to lipoic acid, preferably xcex1-hydroxy acids and/or their derivatives. As used herein, the terminology xe2x80x9cxcex1-hydroxy acidxe2x80x9d has reference to and encompasses the general class of organic compounds containing at least one hydroxy group and at least one carboxyl group, and wherein at least one hydroxyl group is located on the xcex1-carbon atom. Typically, the compounds are organic acids having at least one carboxylic acid group and at least one hydroxyl group on the xcex1-carbon atom, and may contain other functional groups including additional hydroxyl and carboxylic acid moieties. Most typically, xcex1-hydroxy acids will have a basic structure of lower aliphatic compounds having from two to six carbon atoms.
The xe2x80x9cderivativesxe2x80x9d of these xcex1-hydroxy acids most typically will involve derivatives related to the carboxyl functionality, i.e., wherein the hydrogen or hydroxyl portion of the carboxyl moiety is substituted by metallic ions (to form salts), alkoxy groupings (to form esters), ammonium ions (to form ammonium salts), as well as other substitution reactions and products leading to formation of corresponding lactones, anhydrides or amines. However, the derivatives may also include reactions involving the xcex1-hydroxyl group, most notably ketone formation, to form corresponding xcex1-keto carboxylic acids.
Among the hydroxy acids and derivative compounds useful in the present invention are hydroxy monocarboxylic acids such as glycolic acid, hydroxymethylglycolic acid, lactic acid, glucuronic acid, galacturonic acid, gluconic acid, glucoheptonic acid, xcex1-hydroxybutyric acid, xcex1-hydroxyisobutyric acid, xcex1-hydroxyvaleric acid, xcex1-hydroxyisovaleric acid, xcex1-hydroxycaproic acid, and xcex1-isocaproic acid. Also included are di- and tri-carboxylic hydroxy acids such as tartronic acid, tartaric acid, malic acid, hydroxyglutaric acid, hydroxyadipic acid, hydroxypimelic acid, muric acid, citric acid, isocitric acid, saccharic acid, dihydroxymaleic acid, dihydroxytartaric acid, and dihydroxyfumaric acid. Derivatives involving keto groups include keto acids and keto esters such as pyruvic acid, methyl pyruvate, ethyl pyruvate, isopropyl pyruvate, benzoylformic acid, methyl benzoylformate, and ethyl benzoylformate. In some preferred embodiments, xcex1-hydroxy acids having an aliphatic backbone of 2 to 3 carbons such as glycolic and/or lactic acid or their derivatives are employed. Glycolic acid is especially efficacious.
As with the other active ingredient, lipoic acid, preferred compositions contain effective amounts of xcex1-hydroxy acids. Typcal concentrations range from about 1% to about 10% by weight, more narrowly from about 1% to about 5%, by weight xcex1-hydroxy acid.
Fat-soluble fatty acid esters of ascorbic acid (vitamin C) may be added to the lipoic acid composition for treating rosacea in some embodiments. The more oxidation-resistant saturated fatty acid esters of ascorbic acid are preferred, including, but not limited to, ascorbyl laurate, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, and ascorbyl behenate. Ascorbyl palmitate is used in one embodiment. As denoted herein, where fatty acid esters are described, e.g., ascorbyl stearate, compositions having predominantly that ester, e.g., predominantly stearate, are included. The esters may be prepared using hydrogenated oils or fats, or fractions thereof, and contain small amounts of another ester. Ascorbyl stearate prepared using canola, for example, commonly contain about 4% ascorbyl palmitate.
Tocotrienol may also be added to lipoic acid compositions of the invention, alone or in combination with an ascorbyl esters and/or xcex1-hydroxy acids or their derivatives in some embodiments. The term xe2x80x9ctocotrienolxe2x80x9d encompasses natural and/or synthetic counterparts of tocopherol (vitamin E) that bear unsaturated tails, and include, but not limited to, xcex1-, xcex2-, xcex3-, and xcex4-tocotrienols, tocotrienol P25, desmethyl-tocotrienol, didesmethyl-tocotrienol, their synthetic counterparts, their counterparts having methylated or demethylated chroman rings, and mixtures thereof. The double bonds may be cis or trans or mixtures thereof.
Tocotrienol useful in compositions of the invention may be tocotrienol-enriched vitamin E preparations obtained from natural or synthetic sources, such as those obtained by removal of tocopherol from vitamin E compositions. Many embodiments employ tocotrineol isolated from natural sources such as tocotrienol-enriched fractions obtained from sunflower seed, wheat germ, bran, palm, or other vegetable oils by high performance liquid chromatography or other methods, or tocotrienol-enriched extracts obtained from barley, brewer""s grains oats, and other tocotrienol-containing natural products by alcohol extraction, molecular distillation and the like. Useful tocotrienols can be tocotrienol-enriched fractions or extracts, or mixtures of these with vitamin E fractions. As used herein, the term xe2x80x9ctocotrienolsxe2x80x9d includes all of these tocotrienolrich fractions and extracts obtained from these natural products as well as the pure compounds and mixtures of any of these.
As with other vitamin E preparations, tocotrienol or tocotrienol-enriched preparations include those containing tocotrienol and, in some cases, tocopherol derivatives, particularly stabilized derivatives. These typically include derivatives related to the phenolic hydroxyl functionality, i.e., wherein it is acylated with an organic acid to form an ester. Examples of such stabilized tocotrienols include, but are not limited to, tocotrienol acetate, tocotrienol succinate, and mixtures thereof. However, the derivatives may also include those involving other reactive groups known to those skilled in the art. Where tocotrienol derivatives are employed, they must be functionally equivalent to tocotrienol. Preferred derivatives contain both the chromanol nucleus and three double bonds in the hydrocarbon tail.
While not wishing to be bound to any theory, it is possible that lipoic acid is efficacious in the treatment of rosacea because it is both fat- and water-soluble and readily disperses in cell membranes and other cellular components. Because of its solubility, it is sometimes referred to as a universal antioxidant. It acts as a free radical scavenger and neutralizer, and prevents the cross-linking of cell membranes that is often seen in rosacea. By the same token, LA modulation of free radicals and other oxidative species affects gene expression, including expression of nuclear factor xcexa-B (NF-xcexaB), nitric oxide synthetase and other mediators at all stages of proinflammation and inflammation. Lipoic acid""s alteration of lipid peroxidation, protein cross-linking, growth factor stimulation, and membrane permability may explain its negative effect on the symptoms of rosacea.
Generally in the practice of the method of the invention, the composition is topically applied to the affected skin areas in a predetermined or as-needed regimen either at intervals by application of a lotion or the like, it generally being the case that gradual improvement is noted with each successive application. Insofar as has been determined based upon clinical studies to date, no adverse side effects are encountered. Though two patients reported a slight stinging within the first four days of a study, it was immediately resolved, and there were no reports or observations of irritation, erythema, irritant dermatitis or other side effects.
The following examples are presented to further illustrate and explain the present invention and should not be taken as limiting in any regard. Unless otherwise indicated, all percentages are by weight.


The chain comprises a plurality of external links (2), each defined by a pair of parallel external plates (4, 5) and by two rotation pivots (6) interpositioned between the two external plates (4, 5). The chain also comprises a plurality of internal links (3), each defined by a pair of parallel internal plates (7, 8) and by two bushes (9) interpositioned between the plates and each internal link (3). Each of the rotation pivots (6) is inserted coaxially in a bush (9) and so defines an alternated succession of external links (2) and internal links (3) and defines with the bush (9) a spherical coupling surface. The chain also comprises anti-rotation elements (12) for reducing a possibility of rotation with respect to an alignment direction of each pair of adjacent links (2, 3).

As is known, the chains usually used for bicycle transmissions are composed of articulated links. The links are made up of parallel bushes mounted rotatingly on cylindrical pivots. Each bush is solidly connected at each end thereof to a plate, and each pivot is solidly connected at each end thereof to another plate. The pivot exhibits a greater length than the bush, and the two plates connected to the bush are in an internal position with respect to the two plates connected to the pivot, in order that the first end of the plates connected to the bush is superposed on the second end of the plates connected to the pivot. A further bush is solidly connected to the second end of the internal plates; a further pivot is housed internally of the further bush, which pivot is solidly connected to the first ends of two further external plates, defining a complete internal chain link.
Similarly, an external link is defined by two pivots connected at the two ends thereof respectively to the first and the second ends of two external plates, so that the chain is closed by alternatingly connecting numerous internal links to numerous external links. In order to prevent scraping between the chain and the cogwheels on which the chain is mounted, the prior art teaches rotating rollers coupled externally to the bushes, or rotatingly engaging the bushes to the internal plates so that they take on a direct roller function.
Thanks to the rotating coupling between pivots and bushes, each link is free to rotate with respect to the contiguous links on a perpendicular plane to the longitudinal axes of the pivots, enabling the chain to transmit drive between pairs of cogwheels of different dimensions.
The two wheels between which drive is transmitted may not be perfectly coplanar, i.e. because the chain is mounted on bicycles having known systems for gear couple variations between driven cog, or pinion, and drive cog, known as the crown wheel, in which the chain is made to translate transversally on several concentrically-arranged cogwheels. In these geared systems, the chain must be provided with a certain degree of transversal deformability. In traditional chains this deformability is achieved by including a predetermined degree of play in the coupling between each pivot and the bush in which the pivot is housed. Thanks to this play, the pivot can shift into an inclined position with respect to the bush it is housed in. In this way, each internal link, apart from being free to rotate longitudinally with respect to the two contiguous external links on a perpendicular axis to the pivot axes, can also rotate transversally, within certain limits, on a plane containing the longitudinal axis of the pivot belonging to a contiguous external link. In the rotated configuration, the contact between the pivot and the corresponding bush is no longer distributed along a straight line, but is rather concentrated at certain points, giving rise to very high pressures which can lead to considerable problems of wear.
Furthermore, in the tracts where the chain is enmeshed with the cogwheels it is aligned and has the links thereof arranged at a standard distance between one another, due to the coupling between each bush on the chain and the recess between each cog on the cogwheel. Therefore the de-alignment between the external links occurs brusquely at the moment where the links leave the cogwheel, which moment also includes the utilisation of the play in the chain between the pivots and bushes—and the play is taken in equally brusquely when the chain links enter the cogs on the gearing cogwheels and re-aligns.
These sharp changes of link configuration create a certain level of noise in the transmission, and accentuate wear on the parts in relative motion. This wear also increases the degree of play between the pivots and the bushes, so that the bushes become able to assume even more inclined positions with respect to the bushes. The inclinations bring the internal links to exert a lever action on the external links they are connected to, and in effect push the external links further outwards. This can end with the external links becoming detached from the pivots, causing the chain to break.
To overcome these drawbacks, and especially to enable transversal inclinations greater than those that can be obtained with traditional chains, while eliminating the play between pivot and bush and therefore shocks, and ensuring that contact between the bushes and pivots always occurs along a surface even when the chain is not working axially, thus obtaining a more silent and less wearing operation, the present applicant, in a previous patent application, proposed a new and original technical solution consisting in defining, between each bush and respective pivot, a spherical reciprocal coupling surface for enabling a rotation between two adjacent links about perpendicular axes to a corresponding main rotation axis.
The longitudinal axis of each pivot and the longitudinal axis of each bush, which in reciprocal alignment identify the main rotation axis, are free to rotate reciprocally about the centre of the spherical coupling surface. This freedom of movement is translated into the possibility of rotation and inclination with respect to the longitudinal direction of alignment of one link to another according to an angle which can exceed four degrees and which can in any case be defined during the design stage by suitably sizing the elements constituting the chain.
In other words, for each pair of contiguous external and internal links, thanks to the presence of the spherical contact and coupling surface between each pivot and the corresponding bush, both reciprocal torsional rotation, about a rotation axis which coincides with a longitudinal alignment axis of the ling couple, and reciprocal transversal rotation, about a transversal rotation axis which is perpendicular to the longitudinal plane containing the main rotation axis, are possible.
The prior art, as summed-up above, includes some limitations and drawbacks. In particular, the rotation possibility between each contiguous pair of links, as described above, is useful in some industrial applications, where it is necessary to transmit drive between cogwheels with skewed axes, but when applied to bicycles it can give rise to snagging between the chain and cogwheels at the moment where each cog inserts in the little space between two rollers and the respective internal or external plates; this is because each of the spaces may be imperfectly aligned with the cog.
This snagging phenomenon, which causes a drop in pedalling fluency when occurring in bicycles, emerges most frequently during gear changing, i.e. when the chain is caused to translate transversally from one gearing cogwheel to another.
However, even during normal power drive transmission, when the chain is not subject to changing from one gearing to another, the cogwheels may not be coplanar and since the spaces formed by the external links are slightly wider than the spaces defined by the internal links, with a consequently greater cog-space play in the external links, a certain degree of irregularity is present in the orientation, and there is a continuous slight transversal oscillation of the chain due to the alternation of successive insertions and removals of the cogs into and out of the non-uniformly-wide spaces.
It is also worth noting that the slight transversal oscillations of the chain may induce torsional rotations, and therefore may accentuate the problems caused thereby, as has already been mentioned.
The technical aim of the present invention is therefore to provide an articulated chain which obviates the above-described drawbacks.
An important aim of the invention is to provide an articulated chain for bicycles in which each bush and respective pivot exhibit a spherical coupling surface, which surface functions more regularly and with lower friction than prior-art surfaces, especially during stages of transfer of the chain from one cogwheel to another and during work done in highly-inclined configurations.
The specified aim 1s attained by a an articulated chain which is characterised in that it comprises one or more of the technical solutions claimed herein below.
With reference to the figures of the drawings, 1 denotes an articulated chain according to the present invention.
The articulated chain 1 comprises a first plurality of links which will hereinafter be defined as external links 2 because of their arrangement, and a second plurality of links, or internal links 3, which are rotatably and consecutively connected about respective main axes of rotation X, which are axes of rotation of a link with respect to a next link when the two links lie in a same plane.
More precisely, as clearly illustrated in FIG. 1, the chain 1 is formed by an alternating succession of external links 2 and internal links 3.
In particular, each of the external links 2 exhibits a first external plate 4 having a first end 4a and a second end 4b and a second external plate 5, parallel to the first external plate 4 and having a first end 5a and a second end 5b.
The two external plates 4 and 5 of each first link 2 are solidly connected by two rotation pivots 6 interpositioned between the first and second external plates 4, 5 at the first ends 4a, 5a and the second ends 4b, 5b thereof.
In particular, the two external plates 4, 5 exhibit a same double-lobed shape and are provided with an end hole 4d, 5d at each lobe into which ends 6a, 6b of each pivot 6 will insert.
Similarly, each internal link 3 exhibits a first internal plate 7 having a first end 7a and a second end 7b, and a second internal plate 8 parallel to the first internal plate 7 and having a first end 8a and a second end 8b.
The internal plates 7, 8 of the internal link 3 exhibit a double-lobed shape. In an intermediate portion comprised between the two lobes, the plates 7, 8 exhibit a bevelling which has the effect of thinning down the section thereof in proximity of the edge, which has the effect of improving the enmeshing of the chain with the cogs. The first and second internal plates 7, 8 of each internal link 3 are reciprocally coupled through two bushes 9 interpositioned between the first ends 7a, 8a, and the second ends 7b, 8b.
More precisely, with reference to FIG. 2, the bush 9 exhibits two collars 10 which can be inserted in special holes 11 afforded in the first ends 7a, 8a and the second ends 7b, 8b.
Each of the rotation pivots 6 belonging to the external links 2 is inserted coaxially in a respective bush 9, to define an alternated succession of external links 2 and internal links 3 (FIG. 1) which are rotatably and consecutively connected about respective main rotation axes X.
Each pivot 6 projects from the respective bush 9 at ends 6a, 6b of the pivot 6, and the bush 9 remains comprised between the plates 4, 5 of the external link 2. Advantageously, each rotation pivot 6 exhibits a barrel shape having a spherical profile and the bush 9 exhibits a seating a having a barrel-shaped spherical shape which is complementary to the profile of the pivot 6.
Each of the pivots 6 defines, with the respective bush 9, a spherical coupling surface, which allows not only rotation about the main rotation axis X but also a rotation between two adjacent links about perpendicular axes to the main rotation axis X.
Each of the bushes 9 is free to rotate between two extreme positions on any plane containing the longitudinal axis of the pivot 6 it is mounted on.
In particular, the spherical coupling surface allows a disalignment between the longitudinal axis of the pivot 6 and the longitudinal axis of the respective bush 9 which, in the position of reciprocal alignment, identifies the main rotation axis X.
The longitudinal axis of the pivot 6 and the longitudinal axis of the bush 9 are free to rotate reciprocally about the centre of the spherical surface.
The freedom of movement is in fact a freedom to rotate and to incline, with respect to the alignment direction, of one link with respect to a contiguous link, according to an angle α lying on a perpendicular plane to the longitudinal axis Y. The chain 1 comprises anti-rotation elements 12 which reduce the possibility of rotation with respect to the longitudinal direction of alignment of each pair of adjacent links 2, 3.
More precisely, the anti-rotation elements 12 comprise, in turn, spacers 13a, 13b interpositioned between the external plates 4, 5 of each external link 2 and the internal plates 7, 8 of each internal link 3 at the respective ends 4a, 5a, 7b, 8b and 4b, 5b, 7b and 8b.
The spacers 13a, 13b reduce the possibility of reciprocal torsional rotation between each consecutive pair of external links 2 and internal links 3 about a longitudinal axis y of alignment of the pair of links which is perpendicular to the corresponding main rotation axis X.
Furthermore, the spacers 13a, 13b comprise, for each main rotation axis X, a first pair of spacers 13a interpositioned between the first external plate 4 and the first internal plate 7 and a second pair of spacers 13b interpositioned between the second external plate 5 and the second internal plate 8.
Both the spacer elements 13a of the first pair and the spacer elements 13b of the second pair are arranged in proximity of the edges of the respective external plates 4, 5 and internal plates 7, 8 in a position which is symmetrically opposite to the longitudinal axis Y of the corresponding link.
For correct chain operation, it is sufficient that the spacers 13a and 13b comprise, for each main rotation axis X, a first spacer 13a interpositioned between the first external plate 4 and the first internal plate 7 and a second spacer 13b interpositioned between the second external plate 5 and the second internal plate 8. The first spacer 13a and the second spacer 13b are in this case arranged in proximity of the edges of the respective external and internal plates and are aligned along a straight line parallel to the corresponding main rotation axis X. Each spacer 13a 13b has a convex conformation, with a spherical profile, and is obtained by plastic deformation of an edge zone of the external plate 4, 5 or the corresponding internal plate 7, 8. The plastic deformation can be localized, producing a shaped surface as illustrated in FIGS. 1, 2 and 3, or it can be a fold in the edge itself, which has the effect of raising an edge zone of the plate with respect to the surface of the plate itself, as illustrated in FIGS. 4, 5 and 6.
Alternatively, each spacer 13a, 13b can be defined by a shaped element connected to an edge zone of the corresponding external plate 4, 5 or internal plate 7, 8. The shaped element can be realised in various materials, according to the desired resistance characteristics and friction coefficient.
The spacers 13a, 13b in effect reduce the play between the external plates 4, 5 and the internal plates 7, 8 in a perpendicular plane to the longitudinal axis y passing through the main rotation axis X, and strike against the external faces of the internal plates 7, 8, limiting transversal rotation only when a reciprocal rotation movement between adjacent external and internal links occurs.
Thanks to their position, the spacers 13a and 13b do not limit transversal rotation between two adjacent links, which are the rotations that permit the chain to deform transversally, a necessary condition when the cogwheels the chain is wound around are not coplanar. Also, the presence of the spacers 13a and 13b constitutes a precise reference for the relative positions between each pivot 6 and bush 9 in the direction of the respective main rotation axis X. Thus no other reference elements are necessary to perform this function, considerably simplifying chain assembly operations. In greater detail, the presence of the anti-rotation elements 12 means that only one of the pivot 6 and the bush 9 in each coupling need be provided with a spherical profile. In a first embodiment, each rotation pivot 6 exhibits a barrel-shape having a spherical profile, and the respective bush 9 exhibits a seating a having a straight profile. In a second embodiment each bush 9 exhibits a seating a having a spherical profile that projects in an internal direction and the respective pivot 6 exhibits a straight cylindrical shape having a straight profile. The spherical profile can be directly afforded on the surface of each rotation pivot 6 or each bush 9, as illustrated in FIGS. 7 and 8, or it can be defined by an annular element 20 associated to each rotation pivot 6 or each bush 9.
Advantageously the anti-rotation elements 12 further comprise swells 14a, 14b, which are respectively solidly constrained to the external plates 4,5 or each external link 2 and are arranged centrally on the external links 2.
The swells 14a, 14b project internally of a chamber 15 comprised between the external plates 4, 5, and are of a size which is sufficient to reduce the breadth of the chamber 15 in central portions 4c, Sc of the external plates 4, 5 to the breadth of a like chamber 16 comprised between the internal plates 7, 8.
The swells 14a, 14b also exhibit a convex conformation, with a spherical profile, and are obtained by plastic deformation of the central portions 4c, 5c of the external plates 4, 5. Alternatively the swells 14a, 14b can be obtained by etching and plastic deformation of central portions 4c, 5c of the external plates 4, 5, creating small tabs projecting from the external plates 4, 5.
In a further embodiment, the swells 14a, 14b are defined by shaped elements, which can be made of various materials, connected to central portions 4c, Sc of the external plates 5.
The swells 14a, 14b guide the entrance of the cogs of a cogwheel into the chambers 15 of the external links 2, limiting the play of the cogs with the internal faces of the external plates 4, 5 to levels which are similar to the play on the internal links 3.
Finally, to reduce relative dragging between the bushes 9 and the cogwheels, rotatable rollers 17 are included, rotatingly coupled externally of the bushes 9.
The invention offers important advantages.
The anti-rotation elements arranged on the external plates and at the ends and central part thereof limit or rather enable a precise definition at the design stage of the torsional rotation between the links of an articulated chain according to the invention; this has the effect of rendering the positioning of each chamber of the chain precise and regular at the moment in which each cog of a cogwheel inserts into the chamber, resulting in a cogwheel-chain coupling that is more fluid and free of snagging.
The anti-rotation elements are arranged centrally on the external links and thus make the play between the cogs and the external plates of the external links equal to the play between the cogs and the internal plates of the internal links. This considerably smooths disalignments that occur brusquely when the links exit the cogwheels and re-alignments that take place when the links enter the cogs of the gear wheels.
Finally, the greater regularity of the chain motion is very useful in improving the precision of the derailments required for gear changes involving cogged gearing wheels.

Articulated chain for drive transmission in bicycles


A formulation for the treatment of a parasitic skin disease includes a parasiticide to kill the parasite. The formulation also includes a polymer effective to increase retention of the formulation on the skin, and to reduce absorption of the formulation into the skin. Alternatively, the formulation may include a polymer such as a beta-sheet breaker peptide which is effective to increase absorption of the insecticide into the head lice and/or the eggs of the head lice. The formulation also includes a vehicle for the polymer and the parasiticide.

This invention relates to treatments for parasitic skin diseases such as infestations with lice or mites, and in particular to improved treatments for such diseases that contain a polymer delivery system.
Parasitic skin diseases, such as infestations with lice or mites, cause much suffering in both humans and animals. For example, head lice is a persistent problem, especially among elementary school-aged children. It was reported that six million U.S. school children will become infested with head lice in one year, that is one out of every four students in elementary schools (Consumer Reports, February 1998). The total number of people in the U.S. infested with head lice in one year is about ten million when all ages are accounted for. The incidence of head lice is only slightly improved from the reported incidence in 1940, which was prior to the advent of insecticides and xe2x80x9csuperiorxe2x80x9d knowledge by the medical establishment.
Infestation with head lice typically causes itching of the scalp. In some cases, a person may develop lesions or papules on the scalp, swollen glands in the neck or under the arms, or other symptoms. A secondary problem is that many schools have enforced absenteeism if a child has any nits (lice eggs) in their hair. Such a xe2x80x9cno-nitxe2x80x9d policy has negative social implications for the child and parents. Head lice is becoming a sensitive social issue.
Although head lice are not generally considered to be vectors for systemic human infection, the evidence strongly supports the possibility that head lice could be vectors. For example, rickettsiae and spirochetes are known to be obtainable from the blood of the host (head lice are blood suckers like mosquitoes); these organisms multiply in the gut of the head lice, and are also found in high numbers in their feces. Viruses, like the AIDS virus, also can be found in the gut and feces of head lice, but these organisms do not multiply in the gut of the louse; thus, the number of viruses in the feces would not be high. However, any organism in the blood of the host would be found in the feces of the louse, and thereby, could be potentially transmitted when the louse finds a new host, i.e., a new human being to infest.
Various over-the-counter and prescription topical treatments for head lice are currently available. These treatments are no longer as effective as in previous years in killing adult head lice and nits. In fact, an article in the September, 1999 issue of Archives of Pediatrics and Adolescent Medicine reported that only 90% of adult head lice are killed by the two main products currently used in head lice therapy, Nix and Rid. It is clear that resistance or tolerance of head lice to insecticides has increased in recent years. The reduced effectiveness of current treatments raises the possibility that people may resort to the use of dangerous agents such as kerosene to treat head lice, or may resort to the use more toxic insecticides that could damage the scalp. Thus, it would be desirable to provide a more effective treatment for head lice and other parasitic skin diseases that avoids the need to use such drastic measures, particularly since the majority of head lice patients are children.
Various polymers are presently being used in medicine. TopiCare by Penederm and Berteck Laboratory is a polyolprepolymer included in xe2x80x9cAvitaxe2x80x9d, a topical skin cream with vitamin A. Ortho Division of Johnson and Johnson produces xe2x80x9cRetin A Microxe2x80x9d, a skin product containing vitamin A in a microsponge polymer made by Advanced Polymer Systems. Additionally, Chitogenics makes a polymer called N,O-carboxymethylchitosan (NOCC), a glycosaminoglycan synthesized from the natural polysaccharide, chitin. NOCC and other polymers have been proven to be of value in drug delivery, preventing post-surgical adhesions, wound management, and arthoscopic surgical aids. In Japan, polymers are used as flocculents in the clarification of waste water and beverages, in food processing, and in moisturizers that adhere well to skin and hair. In particular, chitosan polymers are used in many skin creams and hair care products in Japan. However, it has never been suggested to use a polymer delivery system in improved treatments for parasitic skin diseases.
This invention relates to a formulation for the treatment of a parasitic skin disease. In a preferred embodiment, the formulation is effective for the treatment of head lice. The formulation includes a parasiticide to kill the parasite. The formulation also includes a polymer effective to increase retention of the formulation on the skin, and to reduce absorption of the formulation into the skin. The formulation also includes a vehicle for the polymer and the parasiticide.
In another embodiment for the treatment of head lice, the formulation includes an insecticide and a polymer such as a beta-sheet breaker peptide which is effective to increase absorption of the insecticide into the head lice and/or the eggs of the head lice.
Various objects and advantages of this invention will become apparent to those skilled in the art from the following detailed description of the preferred embodiments.
The present invention relates to the use of a polymer delivery system in treatments for parasitic skin diseases, to provide improved therapeutics and to reduce potential hazards of the treatments. The parasitic skin diseases to be treated include any diseases in which parasites infest the surface of the skin, especially on those skin areas covered by hair, such as the scalp and pubic area. Such diseases include, for example, infestations with lice, especially head lice and pubic lice, and mites (e.g., scabies, chiggers, Demodex mites, and the like).
The polymer delivery system is effective to increase retention of the formulation on the outside surface of the skin, and to reduce absorption of the formulation into the skin. In a treatment for head lice, the polymer increases the retention of the treatment on the hair and the outside surface of the scalp, and reduces the absorption of the treatment into the skin. As a result, the polymer delivery system provides one or more of the following advantages. The polymer delivery system can allow the use of higher concentrations of parasiticide on the skin without risk of increased toxicity. The polymer delivery system can also allow parasiticides to stay on the skin for longer time periods without risk of increased toxicity. Additionally, the polymer delivery system can allow the use of parasiticides that are sometimes considered too toxic to be used, because the parasiticides are not significantly absorbed into the skin and are therefore measurably less toxic. There is a great demand for such a treatment in therapies for parasitic skin diseases.
Given the increasing resistance of head lice to various insecticides, the polymer delivery system will allow over-the-counter and prescription topical products to add efficacy by keeping the insecticide on the hair and skin surface for a longer period of time, while reducing absorption of the insecticide into the skin and thereby reducing the risk of toxicity. This is applicable because head lice normally shut down absorption by closing off their spiracles (respiratory channels). These channels are the method by which head lice obtain oxygen as they have no lungs. Head lice can shut down these spiracles for over an hour without ill effects, but by allowing insecticide products more time of exposure to the head lice, the formulations of the invention will allow more penetration when the head lice reopen their spiracles. More prolonged application by means of the polymer delivery system should also result in better penetration into the nit which is lipophilic with several membranes to penetrate before getting to the developing egg. Typically, the formulation is retained on the scalp for either about 10 minutes or overnight (e.g., about 7-9 hours), depending on the particular patient.
In the case of over-the-counter head lice products containing pyrethrum extract, the polymer deliver system increases efficacy by at least partially overcoming resistance of the head lice to the insecticide, while reducing absorption of the insecticide into the skin to reduce potential toxicity. In the case of prescription head lice products such as malathion (Ovide by Medicis, which is presently sold in a 78% alcohol base), the insecticide could be formulated in a polymer base initially, or the existing product could be incorporated into a final polymer formulation. This would not only increase the efficacy of the product, but would also decrease its flammability (which is definitely a concern with this particular product in this childhood disease).
In addition to the above-mentioned advantages, the polymer will aid in louse and nit removal when the formulation is used to treat head lice. The polymer also decreases the egg laying ability of the louse, by decreasing the attachment of the eggs.
The parasiticides useful in the treatments include any materials effective for killing the parasites, such as various insecticides. Some insecticides that may be used include, but are not limited to, permethrin, pyrethrin (in higher concentrations than presently allowed), gamma benzene hexachloride, malathion, ivermectin, moxidectin, other macrocyclic lactones such as compound F28249, doramectin, pyrantel pamoate, fenbendaxole, oxibendazole, benzimidazole, thiabendazole, abamectin, avermectin, carboxyl, DDT (chlorophenothene), cromiton, benzylbenzoate, temephos, coumaphos, diazinon, sumithrine, fluorescein, pyrantel embonate, carbophenothiion, chlorfenvinphos, crotoxyphos, fenitrothioin, derris, bromocyclen, diflubenzuron, organophosphates, organochlorines, nicotine, hexachlorocyclohexanes, crotoxyphos (plus dichlorvos), stirofos, tetrachlorvinphos, adioxathion, phosmet, bromocyclen, famphur, fenthion, methoxychlor, totoqhene, trichlorfon, cypermethrin, bioallethrin, cyano substituted pyrethroid, phenothrin, pirimiphos methyl, carbaryl, propoxur, temepho, pralidoxine, parathion, and natural insecticidal oils such as coconut oil, anise, ylang ylang, garlic, and lavender. The amount of insecticide in the formulation is usually within a range of from about 0.25% to about 10% by weight of the formulation.
The polymer delivery system can be any polymer, or combination of polymers, capable of better retaining the treatment on the surface of the skin and reducing absorption into the skin. The polymer(s) of the polymer delivery system can be water soluble, or non-water soluble, and can come in various lengths to accommodate one""s needs. Some polymers can change from a solution state to solid state dependent upon temperature. Thus, a polymer could be in solid form at room temperature, but in a solution state when heated a few degrees more. The amount of polymer in the formulation is usually within a range of from about 0.5% to about 20% by weight of the formulation.
Preferred polymers for use in the polymer delivery system include, but are not limited to, microsponge polymers, polytrap polymers, N,O-carboxymethyl-chitosan (xe2x80x9cNOCCxe2x80x9d), polyolprepolymers, chitosan polymers, and beta-sheet breaker peptides. Microsponge polymers consist of polymeric beads having a network of pores. One such microsponge polymer is available commercially from Advanced Polymer Systems, Redwood City, Calif. The microsponge polymer is described in more detail in U.S. Pat. No. 4,690,825 to Won, issued Sep. 1, 1987, and in U.S. Pat. No. 5,145,675 to Won, issued Sep. 8, 1992 (both of which are incorporated by reference herein).
Polytrap polymers are highly cross-linked polymethacrylate copolymers. Such a polymer is manufactured by Dow Corning Corporation, Midland, Mich., and sold under the trademark Polytrap. It is powder having particles capable of absorbing high levels of lipophilic liquids and some hydrophilic liquids. The powder structure consists of a lattice of unit particles less than one micron that are fused into agglomerates of 20 to 100 microns, and the agglomerates are loosely clustered into macro-particles or aggregates of about 200 to about 1200 micron size. Advanced Polymer Systems also sells a Polytrap System which can be used in the invention.
NOCC is a chitosan derivative having carboxymethyl substituents on some of both the amino and primary hydroxyl sites of the glucosamine units of the chitosan structure. One such polymer is available commercially from Chitogenics, Inc., Halifax, Nova Scotia, Canada. This polymer is described in detail in U.S. Pat. No. 4,619,995 to Hayes, issued Oct. 28, 1986, U.S. Pat. No. 5,679,658 to Elson, issued Oct. 21, 1997, and U.S. Pat. No. 5,888,988 to Elson, issued Mar. 30, 1999 (all of which are incorporated by reference herein).
Polyolprepolymer is a mixture of liquid hydroxyl terminated polymers and polyethylene glycol. One such polymer, Polyolprepolymer-2, is available commercially from Bamet Products, Inc., Englewood Cliffs, N.J.
Chitosan is deacetylated chitin, or poly-N-acetyl-D-glucosamine. It is available commercially from many sources, such as Protan Laboratories Inc., Redmond, Wash. As used herein, xe2x80x9cchitosanxe2x80x9d includes chitosan, inorganic or organic salts of chitosan, and any chemically modified forms of chitosan or chitosan derivatives. This polymer is described in detail in U.S. Pat. No. 5,141,964 to Noel, issued Aug. 25, 1992, and U.S. Pat. No. 5,744,166 to Illum, issued Apr. 28, 1998 (both of which are incorporated by reference herein).
Certain polypeptides such as beta-sheet breaker peptides are another type of polymer that is preferred for use in the invention. The beta-sheet breaker peptides would be used to loosen the nit sheath and any other louse parts affected by the polymer, instead of increasing retention of the formulation on the skin or reducing absorption of the formulation into the skin. This beta-sheet breaker peptides may increase absorption of insecticides into the egg or louse.
It should be understood that the above-mentioned polymer examples are not intended to be limiting, and that numerous other types of polymers can be used in the formulations of the invention.
The formulations also include a vehicle or carrier for the polymer and the parasiticide. Typically, the carrier is water. The polymer and the parasiticide are usually dispersed in the carrier. The carrier can also include an alcohol such as isopropyl alcohol, propylene glycol and/or polyethylene glycol.
The formulations may also include other categories of materials to improve the effectiveness of the formulations. For example, the formulations may include one or more of the following agents:
an agent that would affect the bacterial symbiotes which live in the guts of the head lice.
an agent that affects the beta-sheathing of the nit sheath. The beta-sheathing is the type of protein binding that makes the nit sheath solidify on exposure to air.
a chitinolytic agent. Chitin is the external skeleton of the louse, and such an agent may have various effects such as affecting their joints so that they cannot squat to lay eggs, or may affect their ability to keep moisture in their bodies.
an agent that affects the respiratory system of the head lice (such as irritating their spiracles or increasing the CO2 so that they are not properly oxygenated).
an agent that affects the muscle tone of the head lice (so that they would not be able to cling to hair very well).
an antimetabolite, or agent that affects the nutrition of the head lice. These will affect their survival if given for prolonged intervals in a hair gel.
an agent that is hormonal. Such an agent would mostly affect the instars, the developing adults.
an agent that affects the sensory perception of the head lice. These insects are very smell sensitive and this could affect their behavior considerably.
an agent that dries out the head lice. These insects dry out easily when off the human scalp. Indeed, that is what they die of when they fall off the scalp hair.
an agent that affects oviposition (anything that deters the female from squatting and laying eggs).
The formulations may optionally include ingredients for enhancing the consistency and feel of the formulations, for example, a fatty acid such as oleic acid. Other optional ingredients include an antioxidant such as tocopherol, a preservative such as methylparaben or propylparaben, glycerine, and sorbitol.
The formulations can be prepared in any suitable manner, so long as the polymer and parasiticide are well mixed so that the polymer is effective to increase retention of the parasiticide on the skin and to reduce absorption of the parasiticide into the skin. Typically, the ingredients are mixed together until the ingredients are well dispersed throughout the formulation. In a preferred embodiment, the parasiticide is mixed initially with a polymer base so that it is incorporated into the base, and then the polymer base with incorporated parasiticide is mixed with the remaining ingredients of the formulation.

Polymer delivery system in treatments for parasitic skin diseases


A protective sleeve for plants or flowers composed of a pair of sheets of material which are joined together along their side edges to form a tapered tubular sleeve to house the plant. At least one of the sheets is formed of porous, spun bonded synthetic fibrous material to permit circulation of air within the sleeve and enable the plant to be watered directly through the sleeve. The sleeve, due to the use of the spun bonded fibrous sheet, has substantial strength so that the plant can be lifted and handled by grasping the upper end of the sleeve.

Floral or foliage growers normally ship potted plants to florists or wholesalers in protective sleeves in order to protect the plant during shipment and handling. In the past, the protective sleeves have been formed of sheets of Kraft paper or polyethylene film, which are formed in the shape of a tapered tubular sleeve. The upper edges of the sleeves are stapled or otherwise secured to a holder or wicket, and in use, one workman will hold the sleeve in an open position, while a second workman will drop the potted plant into the open sleeve. The sleeve containing the plant is then removed from the wicket.
The plastic film sleeves, as used in the past, are impervious and thus prevent the circulation of air through the sleeve. As the plastic film sleeves are normally applied in warm climates where the flowers are grown, the plastic film, being soft and pliable, will tend to collapse over the plant and cling together which further restricts circulation. Due to the impervious nature of the plastic film, condensation occurs within the sleeve, and the lack of circulation in combination with the condensation, can cause rapid deterioration of the plant. Attempts have been made to improve the circulation of the plastic film sleeves by forming the sleeves with a plurality of holes, but the holes do not appreciably aid the circulation and decrease the strength of the sleeve.
As a further disadvantage of the plastic sleeve, it is not possible to water the plant directly in the sleeve due to the impervious nature of the plastic film. To water the plant, the upper end of the sleeve must be spread apart and water introduced directly onto the top of the plant.
The Kraft paper sleeves, as used in the past, have certain advantages over the plastic film in that the Kraft paper will stand upright but the paper sleeve restricts air circulation. Moreover, the Kraft paper sleeve lacks strength, particularly if the paper is wet, either due to outside water or condensation. As a further disadvantage, the plant cannot be watered when contained within a paper sleeve.


Two mechanically identical cranes whose luffing jibs have the same maximum and minimum out-reach and which have their own slewing machinery, are mounted via respective supporting structures on a common foundation, at the same level for rotation about the same axis by bearings and an axle which provide a compact journalling of the supporting structures upon the foundation.

Twin-type slewing cranes are used for handling loads on board ship, the individual cranes which together make up the twin cranes being either used singly to load and unload individual holds, or in combination for moving heavy freight.
Ordinary twin slewing cranes have a large mass (weight) and are expensive as well, since each single crane is constructed and arranged in such a way as to allow an individual slewing motion. Each crane is thus rotatably arranged on a common platform which itself can be rotated round a foundation firmly anchored in the hull of the ship. Such cranes have three slewing rims, three gear rings, three slewing mechanisms and, in addition, a large common platform. This type of construction makes for complex and expensive assembly procedures and leads to high costs of transport, assembly, inspection and maintenance.
Another type of twin slewing cranes using only a single gear ring and a slewing rim is sometimes met with. This rim, or bearing, however, is constructed so as to provide a double pivoting link, that is, two bearing functions are combined so that the middle race of the bearing is attached both to the foundation of the crane and to the gear ring, while the outer race of the bearing is connected by a collar arm to one crane, and the inner race is connected, by another collar arm, to the other crane. This type of bearing is very special, and since it produces a slewing rim of very large diameter it is extremely expensive and difficult to repair or replace if it is damaged. In addition to this, the positions of the collar arms in relation to the bearing require different mechanical constructions in each crane while at the same time the slewing mechanisms in each crane must be mounted differently, in one the driving motor is mounted upwards, in the other it is mounted downwards. Disadvantages are complications of construction and assembly of the mechanism and the fact that, e.g. the driving motors must be differently designed to allow drainage of condensing water.