A medical device for providing retrograde venous perfusion to the cerebral vasculature for treatment of global or focal cerebral ischemia is disclosed. The device includes a catheter having an infusion port at its distal end, venous drainage port(s), and an expandable occluder disposed between the infusion port and drainage port(s). The catheter is adapted for insertion in the superior vena cava or the internal jugular vein. The catheter is attached proximally to a pump and an oxygenator with or without a cooling system. Alternatively, the device comprises two catheters, each having a lumen communicating with a distal infusion port and an occluder mounted proximal to the port. The catheters are adapted for insertion in the internal jugular veins distal to jugular venous valves. Methods of using the devices to provide retrograde venous perfusion and isolated cerebral hypothermia are disclosed.

The present invention generally relates to devices and methods useful in maintaining cerebral perfusion during global or focal cerebral ischemia. More specifically, the devices and methods provide effective retrograde perfusion to the cerebral circulation through the superior vena cava or the internal jugular veins. Retrograde venous perfusion may be used with hypothermia to provide isolated cerebral cooling. The devices and methods are also useful in improving perfusion to other peripheral organs besides the brain.
Cerebral ischemia refers to cessation or reduction of blood flow to the cerebral tissues. Cerebral ischmia can be characterized as either global or hemispherical. Hemispherical or focal ischemia refers to cessation or reduction of blood flow within the cerebral vasculature resulting from a partial or complete occlusion in the intracranial or extracranial cerebral arteries. Global ischemia refers to cessation or reduction of blood flow within the cerebral vasculature resulting from systemic circulatory failure from various causes, including aortic surgery, cardiac arrest, shock, and trauma. Circulatory arrest is often required in performing surgeries on the aorta, e.g., aneurysm repair, aortic dissection, endarterectomy of aortic atheroma, and aortic stenting. Blood flow through the aorta is often interrupted due to opening of the aorta for these surgical procedures. Cessation of systemic circulation therefore places a patient at great risk, particularly in the cerebral vasculature where ischemia can rapidly lead to irreversible neurologic damage.
Various techniques have been proposed to improve cerebral perfusion in a patient suffering from either global or focal ischemia. For example, conventional cardiopulmonary bypass is used during cardiovascular surgeries to maintain perfusion to peripheral organs during cardiac arrest. However, cardiopulmonary bypass is generally not useful when the aorta fails to remain intact during aortic surgeries. Retrograde aortic perfusion (RAP) has been proposed to improve cerebral perfusion by clamping the ascending aorta and perfusing the aorta in a retrograde direction through a peripheral arterial access, typically the femoral artery. Disadvantages associated with retrograde aortic perfusion include significant cerebral embolization from dislodgment of atheromatous material in the descending aorta and the aortic arch. Moreover, RAP is not useful for aortic procedures distal or proximal to a limited surgical region of the aorta.
Another technique for protecting the brain during global or focal ischemia is provided by hypothermic circulatory arrest (HCA). HCA is achieved by inducing marked systemic hypothermia prior to cessation or reduction of systemic circulation. There are several disadvantages associated the HCA. For example, during cardiac arrest from cardiac arrhythmia or aortic surgeries, the systemic circulation remains stopped, thereby placing the patient at significant risk of ischemia despite utilizing hypothermia. Moreover, HCA has been associated with systemic coagulopathy, typically disseminated intravascular coagulopathy. Therefore, aortic surgery performed with HCA is associated with relatively high mortality (approximately 20 percent).
Another proposed technique for cerebral perfusion is referred to as selective antegrade cerebral perfusion (SCP). SCP is achieved by introducing a catheter through the aorta into a carotid artery to perfuse the cerebral vasculature. However, cerebral embolization can occur from introduction of the catheter which can dislodge atheromatous material, often present at the take-off from the aorta. Cerebral embolization can also occur from dislodgment of atheromatous material by clamping or snaring of the carotid artery. Air embolization can also occur from insertion of the catheter in the aorta or the carotid artery.
Another technique for improving cerebral perfusion is provided by retrograde cerebral venous perfusion (RCP), which is achieved by clamping the inferior vena cava and introducing oxygenated blood through a catheter inserted in the superior vena cava. Flow is established in a retrograde direction up the vena cava into the brachial and jugular veins. However, there are several disadvantages associated with using the RCP. For example, a majority (approximately 80%) of the oxygenated blood will run off into the arms and/or the heart and lungs, with as little as 20% of the blood entering the brain. Secondly, valves in the jugular veins may obstruct blood flow into the intracranial venous system. The blood can flow outwardly through the extensive collateral circulation without perfusing the brain. The amount of blood returned to the aorta from the carotid arteries represents no more than approximately 5% of the blood initially introduced to the superior vena cava. Thirdly, such retrograde perfusion often results in an increase in cerebral pressure which further inhibits blood inflow. Arterial efflux to the cerebral vasculature is found by the inventor to disappear after 20 minutes. Therefore, during RCP, the venous flow rates and pressures required to achieve and maintain significant arterial efflux are highly variable.
For these reasons, it would be desirable to provide improved devices and methods for protecting the brain and cerebral vasculature of patients suffering from global or focal ischemia, without the risk of cerebral embolization or systemic side effects.
The present invention provides devices and methods for improving cerebral perfusion in patients suffering from focal or global ischemia. More specifically, the devices and methods provide oxygenated blood flow to the brain using retrograde venous perfusion, which can be used in conjunction with hypothermia. In one embodiment, the medical device comprises a catheter which includes an elongate tubular member having a proximal end, a distal end, and first and second lumens. The first lumen communicates with the proximal end and an infusion port at the distal end of the catheter. The second lumen communicates with the proximal end of the catheter and a drainage port proximal to the infusion port. In certain embodiments, the second lumen communicates with a plurality of drainage ports. An expandable occluder, which may be an elastomeric balloon in certain embodiments, is mounted on a distal region of the catheter between the infusion port and the drainage port. A manometer is mounted on the catheter distal to the occluder for measuring blood pressure distal to the occluder. The proximal end of the catheter is adapted for attachment to an oxygenator machine and/or a pump.
In another embodiment, the device comprises first and second catheters. Each of the two catheters has a lumen communicating with a proximal end and an infusion port at a distal end. An expandable occluder is mounted on a distal region of each of the catheters proximal to the infusion port. A manometer is mounted distal to each occluder. The first catheter and the second catheter are joined for a substantial length and are separated at their distal ends. In certain embodiments, the catheters are separated at their proximal ends. The proximal ends of the catheters are adapted for attachment to an oxygenator machine and/or a pump.
In still another embodiment, the device having two catheters described above may include a third lumen communicating with the proximal end of the catheter and a drainage port at its distal end. The drainage port is located proximal to the occluders. In certain embodiments, the third lumen communicates with 2, 3, 4, 5, 6, 7, or any other number of drainage ports. The proximal end of the catheter is adapted for attachment to a pump and/or an oxygenator.
In a first method of using the devices, the distal end of the catheter is inserted through a peripheral vein, e.g., the femoral vein, into the vena cava. The distal region of the catheter and the occluder are positioned in the superior vena cava (SVC), and the occluder is expanded to isolate blood flow in the SVC. Deoxygenated blood is withdrawn from the drainage port(s) and passed through the second lumen and the proximal end of the catheter, which is connected to an oxygenator. The oxygenated blood or medium is then infused into the first lumen and through the infusion port of the catheter to perfuse the cerebral tissues through the SVC in a retrograde fashion, thereby obviating the need for IVC clamping and backflow of oxygenated blood into the right atrium and the lungs which occurs with existing methods for retrograde cerebral venous perfusion (RCP). Infusion of oxygenated blood may be facilitated by a pump connected to the oxygenator and the proximal end of the first lumen. The infusion rate of oxygenated blood can be varied according to the venous pressure recorded by the manometer, which is mounted distal to the occluder.
In still another embodiment, retrograde venous perfusion can be achieved by inserting the distal end of the catheter in the right or the left internal jugular vein. The occluder is expanded to occlude the internal jugular vein. Deoxygenated blood is withdrawn from the vena cava, oxygenated by an oxygenator, and returned to the internal jugular vein to perfuse the cerebral tissues in a retrograde direction through the lumen and infusion port of the catheter. By positioning the catheter in the internal jugular vein to minimize backflow of oxygenated blood to the arm instead of the SVC, and by positioning the occluder distal to the jugular venous valves to minimize obstruction of blood flow to the intracranial venous system, the infusion rate of oxygenated blood can be reduced. The jugular venous pressure (JVP) is often obtained indirectly by measurement of the pulmonary artery pressure from a Swan-Ganz catheter, which is commonly inserted in patients having aortic surgery or hemodynamic instability. The pulmonary artery pressure, however, often fails to reflect the JVP due to the presence of jugular vein valves. The manometer, which is mounted distal to the occluder in the internal jugular vein, will provide a more accurate measurement of the JVP.
In another method, deoxygenated blood withdrawn from the drainage port is passed through an oxygenator and a cooling system. The cooled oxygenated blood or medium is then infused through the first lumen and the distal port of the catheter to provide isolated hypothermic and retrograde venous perfusion to the brain. In this way, complication associated with systemic hypothermic perfusion, e.g., disseminated intravascular coagulopathy, is avoided.
In another method, after venous blood withdrawn from the SVC is passed through an oxygenator, the oxygenated blood is passed through a pump which connects with the proximal end of the first catheter and a proximal end of a second catheter. The second catheter has a lumen communicating with a distal end inserted through the femoral artery and positioned within the femoral artery, the iliac artery, or the descending aorta. In this way, oxygenated blood is delivered to the brain and the lower extremities and/or other vital organs, such as the kidneys. During aortic surgeries, the space available for instrumentation on the aorta, e.g., insertion of cannula for cardiopulmonary bypass, is often limited. The methods described above provide perfusion to the peripheral organs during cardiac arrest without the need for instrumentation on the aorta, and therefore provide a superior alternative to conventional cardiopulmonary bypass.
In still another embodiment, retrograde venous perfusion can be achieved by inserting the distal ends of the first and second catheters in the respective right and the left internal jugular veins. The occluders, which are mounted on the distal regions of the catheters and proximal to the infusion ports, are expanded to occlude the internal jugular veins. Deoxygenated blood can be withdrawn from the vena cava or a peripheral vein, e.g., the femoral vein or the subclavian vein, and oxygenated. Oxygenated blood is then delivered retrograde to the cerebral tissues through the infusion ports of the catheters positioned in the internal jugular veins. Optionally, the oxygenated blood can be cooled before infusing into the jugular veins to provide isolated hypothermic perfusion to the cerebral tissues.
It will be understood that there are several advantages in using the devices and methods disclosed herein for protecting the brain and cerebral vasculature of patients suffering from global or focal ischemia. For example, compared with known techniques for retrograde cerebral venous perfusion (RCP), the retrograde venous perfusion of the invention (1) minimizes backflow of blood to the heart and/or the arms, thereby allowing lower infusion rates to be used, (2) eliminates the need for IVC clamping, thereby minimizing damage to the IVC, (3) positions the catheters distal to the jugular venous valves, thereby minimizing obstruction of blood flow by the valves, (4) provides isolated cerebral hypothermic perfusion, (5) provides an accurate measurement of the jugular venous pressure, and (6) provides perfusion to the brain, the lower extremities, and other vital organs during cardiac arrest. In addition, significant cerebral embolization associated with retrograde aortic perfusion (RAP) and selective antegrade cerebral perfusion (SCP) is avoided using the venous retrograde perfusion disclosed herein.

Retrograde venous perfusion with isolation of cerebral circulation


The present invention provides non-peptide organic compounds that have a structure analogous to or reminiscent of the TMOF structure and have pesticidal activity. Thus the present invention concerns pesticidal compounds that inhibit digestion in pests by terminating or otherwise blocking synthesis of digestive enzymes by activating a TMOF receptor (collectively referred to herein as xe2x80x9cpesticidal compoundsxe2x80x9d). The pesticidal compounds and other compounds of the present invention are usefully employed in the control of pests, particularly insect pests such as mosquitoes, which ingest blood.

The present invention concerns functionalized alkenes, along with alkane and alkyne analogs thereof, that have pesticidal activity, along with methods of use thereof.
Many blood-ingesting pests are known to feed on humans and animals, and many pests are vectors for pathogenic microorganisms that threaten human and animal health, including commercially important livestock, pets and other animals. Various species of mosquitoes, for example, transmit diseases caused by viruses, and many are vectors for disease-causing nematodes and protozoa. Mosquitoes of the genus Anopheles transmit Plasmodium, the protozoan which causes malaria, a devastating disease which results in approximately 1 million deaths annually. The mosquito species Aedes aegypti transmits an arbovirus that causes yellow fever in humans. Other arboviruses transmitted by Aedes species include the causative agents of dengue fever, eastern and western encephalitis, Venezuelan equine encephalitis, St. Louis encephalitis, chikungunya, oroponehe and bunyarnidera. The genus Culex, which includes the common house mosquito C. pipiens, is implicated in the transmission of various forms of encephalitis and filarial worms. The common house mosquito also transmits Wuchereria banuffi and Brugia malayi, which cause various forms of lymphatic filariasis, including elephantiasis. Trypanasomas cruzi, the causative agent of Chagas"" disease, is transmitted by various species of blood-ingesting Triatominae bugs. The tsetse fly (Glossina spp.) transmits African trypanosomal diseases of humans and cattle. Many other diseases are transmitted by various blood-ingesting pest species. The order Diptera contains a large number of blood-ingesting and disease-bearing insects, including, for example, mosquitoes, black flies, no-see-ums (punkies), horse flies, deer flies and tsetse flies.
Various pesticides have been employed in efforts to control or eradicate populations of disease-bearing pests, such as disease-bearing blood-ingesting pests. For example, DDT, a chlorinated hydrocarbon, has been used in attempts to eradicate malaria-bearing mosquitoes throughout the world. Other examples of chlorinated hydrocarbons are BHC, lindane, chlorobenzilate, methoxychlor, and the cyclodienes (e.g., aldrin, dieldrin, chlordane, heptachlor, and endrin). The long-term stability of many of these pesticides and their tendency to bioaccumulate render them particularly dangerous to many non-pest organisms.
Another common class of pesticides is the organophosphates, which is perhaps the largest and most versatile class of pesticides. Organophosphates include, for example, parathion, Malathion, diazinon, naled, methyl parathion, and dichlorvos. Organophosphates are generally much more toxic than the chlorinated hydrocarbons. Their pesticidal effect results from their ability to inhibit the enzyme cholinesterase, an essential enzyme in the functioning of the insect nervous system. However, they also have toxic effects on many animals, including humans.
The carbamates, a relatively new group of pesticides, include such compounds as carbamyl, methomyl, and carbofuran. These compounds are rapidly detoxified and eliminated from animal tissues. Their toxicity is thought to involve a mechanism similar to the mechanism of the organophosphates; consequently, they exhibit similar shortcomings, including animal toxicity.
A major problem in pest control results from the capability of many species to develop pesticide resistance. Resistance results from the selection of naturally-occurring mutants possessing biochemical, physiological or behavioristic factors that enable the pests to tolerate the pesticide. Species of Anopheles mosquitoes, for example, have been known to develop resistance to DDT and dieldrin. DDT substitutes, such as Malathion(trademark), propoxur and fenitrothion are available; however, the cost of these substitutes is much greater than the cost of DDT.
There is clearly a longstanding need in the art for pesticidal compounds that are pest-specific, that reduce or eliminate direct and/or indirect threats to human health posed by presently available pesticides, that are environmentally compatible in the sense that they are biodegradable, are not toxic to non-pest organisms, and have reduced or no tendency to bioaccummulate.
Many pests, including for example blood-imbibing pests, must consume and digest a proteinaceous meal to acquire sufficient essential amino acids for growth, development and the production of mature eggs. Adult pests, such as adult mosquitoes, need these essential amino acids for the production of vitellogenins by the fat body. These vitellogenins are precursors to yolk proteins which are critical components of oogenesis. Many pests, such as house flies and mosquitoes, produce oostatic hormones that inhibit egg development by inhibiting digestion of the protein meal and thereby limiting the availability of the essential amino acids necessary for egg development.
Serine esterases such as trypsin and trypsin-like enzymes (collectively referred to herein as xe2x80x9cTTLExe2x80x9d) are important components of the digestion of proteins by insects. In the mosquito, Aedes aegypti, an early trypsin that is found in the midgut of newly emerged females is replaced, following the blood meal, by a late trypsin. A female mosquito typically weighs about 2 mg and produces 4 to 6 ug of trypsin within several hours after ingesting a blood meal. Continuous boisynthesis at this rate would exhaust the available metabolic energy of a female mosquito; as a result, the mosquito would be unable to produce mature eggs, or even to find an oviposition site. To conserve metabolic energy, the mosquito regulates TTLE biosynthesis with a peptide hormone named Trypsin Modulating Oostatic Factor (TMOF). Mosquitoes produce TMOF in the follicular epithelium of the ovary 12-35 hours after a blood meal; TMOF is then released into the hemolymph where it binds to a specific receptor on the midgut epithelial cells, signaling the termination of TTLE biosynthesis. This regulatory mechanism is not unique for mosquitoes; flesh flies, fleas, sand flies, house flies, dog flies and other insect pests which need protein as part of their diet have similar regulatory mechanisms.
In 1985, Borovsky purified an oostatic hormone 7,000-fold and disclosed that injection of a hormone preparation into the body cavity of blood imbibed mosquitoes caused inhibition of egg development and sterility (Borovsky, D. [1985] Arch. Insect Biochem. Physiol. 2:333-349). Following these observations, Borovsky (Borovsky, D. [1988] Arch. Ins. Biochem. Physiol. 7:187-210) reported that injection or passage of a peptide hormone preparation into mosquitoes inhibited the TTLE biosynthesis in the epithelial cells of the gut. This inhibition caused inefficient digestion of the blood meal and a reduction in the availability of essential amino acids translocated by the hemolymph, resulting in arrested egg development in the treated insect. Borovsky observed that this inhibition of egg development does not occur when the oostatic hormone peptides are inside the lumen of the gut or other parts of the digestive system (Borovsky, D. [1988], supra).
Following the 1985 report, the isolated hormone, (a ten amino acid peptide) and two TMOF analogues were disclosed in U.S. Pat. Nos. 5,011,909 and 5,130,253, and in a 1990 publication (Borovsky et al. [1990] FASEB J. 4:3015-3020). Additionally, U.S. Pat. No. 5,358,934 discloses truncated forms of the full length TMOF which have prolines removed from the carboxy terminus, including the peptides YDPAP, YDPAPP, YDPAPPP, and YDPAPPPP.
D. Borovsky and R. Linderman, U.S. patent application Ser. No. 09/295,996, filed Apr. 21, 1999, now U.S. Pat. No. 6,413,530, discloses additional novel peptides and the use thereof to control insect pests.
TMOF analogs that have been identified to date are primarily peptide analogs. In order to provide a greater diversity of new pesticidal compounds, it would be desirable to possess compounds that are TMOF analogues, yet are not peptides.
The present invention is based on the discovery of non-peptide organic compounds that have a structure analogous to or reminiscent of the TMOF structure and have pesticidal activity. Thus the present invention concerns pesticidal compounds that inhibit digestion in pests by terminating or otherwise blocking synthesis of digestive enzymes by activating a TMOF receptor (collectively referred to herein as xe2x80x9cpesticidal compoundsxe2x80x9d). The pesticidal compounds and other compounds of the present invention are usefully employed in the control of pests, particularly insect pests such as mosquitoes, which ingest blood.
Thus, a first aspect of the present invention is a method of controlling a pest such as an insect pest, comprising administering to said pest a pesticidally effective amount of a non-peptide TMOF analog (that is, an organic compound that has TMOF activity). This definition is specifically intended to exclude the peptide TMOF agonists or analogs disclosed in, inter alia, U.S. Pat. Nos. 5,011,909; 5,130,253; and 5,358,934, the disclosures of which are incorporated by reference herein in their entirety.
Particular pesticidal compounds/non-peptide TMOF analogs of the present invention have the formula I below:
wherein:
X is selected from the group consisting of xe2x80x94CHCHxe2x80x94, xe2x80x94CH2CH2xe2x80x94, and xe2x80x94CCxe2x80x94;
Z is selected from the group consisting of xe2x80x94OH, xe2x80x94NH2 and xe2x80x94OR6 wherein R6 is loweralkyl;
mxe2x89xa70 and nxe2x89xa71 and together total an integer from 1, 2, 3 or 4 to 6, 8, 10 or 12;
the ring bearing substituents R1, R2, R3, R4 and R5 is a phenyl ring or a cyclohexyl ring;
R1, R2, R3, R4, and R5 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, halo, loweralkyl, loweralkoxy and phenyl; subject to the proviso that:
when the ring is a phenyl ring, a pair of R1 and R2, R2 and R3, or R3 and R4 on the phenyl ring may together represent xe2x80x94CR7xe2x95x90CR8xe2x80x94CR9xe2x95x90CR10xe2x80x94, to form with the phenyl ring illustrated above a naphthyl ring system, wherein R7, R8, R9, and R10 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, halo, loweralkyl, and loweralkoxy.
A second aspect of the present invention is a method of initiating a TMOF receptor-mediated biological response. The method comprises contacting to a TMOF receptor in vivo or in vitro for a time and in an amount sufficient to initiate a TMOF receptor-mediated biological response a compound of Formula I as described herein. The biological response may be any suitable biological response mediated by the TMOF receptor, including but not limited to inhibition of biosynthesis of a digestive enzyme such as trypsin.
As noted above, the pesticidal compounds of the present invention have advantageous biological activity against pests. The novel compounds of the invention are particularly active against blood-sucking insects, particularly against species of mosquitoes such as Aedes aegypti that are common vectors of arthropod-borne viral diseases, such as arboviruses. Other biting pests such as flies, fleas, ticks, and lice can also be controlled using compounds and methods of the subject invention. These pests utilize TTLE as their primary blood-digesting enzymes.
The subject compounds can also be used to control pests of agricultural crops, for example by applying the compounds to the agricultural crops. These pests include, for example, coleopterans (beetles), lepidopterans (caterpillars), and mites. The compounds of the subject invention can also be used to control household pests including, but not limited to, ants and cockroaches.
Another aspect of the subject invention pertains to a method for controlling pests, particularly insect pests, comprising administering to said pest a pesticidally effective amount of a pesticidal compound of the subject invention.
The subject invention provides pest control compositions comprising pesticidal compounds and a suitable pesticidal carrier. The pest control compositions are formulated for application to the target pests or their situs.
The methods and materials of the subject invention provide a novel approach to controlling insects and insect-transmitted diseases. The compounds of the subject invention have advantageous activity and increased resistance to proteolysis over previously disclosed compounds.
While the present invention is in part explained with reference to TMOF activity, it will be appreciated that this statement of underlying activity is provided for explanation, and that applicants do not intend to be bound by any particular theory of the invention. For example, the compounds of the invention may also be used as pest or insect repellants, and the compounds of the invention may control pests or insects by mechanisms in addition to, or different from, TMOF activity.
The present invention is explained in greater detail below.
As used herein, the term xe2x80x9cpesticidally effectivexe2x80x9d is used to indicate an amount or concentration of a pesticidal compound which is sufficient to reduce the number of pests in a geographical locus as compared to a corresponding geographical locus in the absence of the amount or concentration of the pesticidal compound.
The term xe2x80x9cpesticidalxe2x80x9d is not intended to refer only to the ability to kill pests, such as insect pests, but also includes the ability to interfere with a pest""s life cycle in any way that results in an overall reduction in the pest population. For example, the term xe2x80x9cpesticidalxe2x80x9d includes inhibition of a pest from progressing from one form to a more mature form, e.g., transition between various larval instars or transition from larva to pupa or pupa to adult. Further, the term xe2x80x9cpesticidalxe2x80x9d is intended to encompass anti-pest activity during all phases of a pest""s life cycle; thus, for example, the term includes larvacidal, ovicidal, and adulticidal activity.
The term xe2x80x9cloweralkylxe2x80x9d as used herein means C1 to C4 alkyl, preferably methyl, ethyl or propyl.
The term xe2x80x9cloweralkoxyxe2x80x9d as used herein means C1 to C4 alkoxy, preferably methoxy, ethoxy, or propoxy.
The term xe2x80x9chaloxe2x80x9d as used herein means halogen, preferably fluoro, chloro, bromo or iodo, most preferably fluoro.
1. Pesticidal Compounds.
Compounds useful in the present invention have the general formula I below:
wherein:
X is selected from the group consisting of xe2x80x94CHCHxe2x80x94, xe2x80x94CH2CH2xe2x80x94, and xe2x80x94CCxe2x80x94;
Z is selected from the group consisting of xe2x80x94OH, xe2x80x94NH2 and xe2x80x94OR6 wherein R6 is loweralkyl;
mxe2x89xa70 and nxe2x89xa71 and together total an integer from 1 to 12; and
R1, R2, R3, R4, and R5 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, halo, loweralkyl, loweralkoxy and phenyl; subject to the proviso that:
a pair of R1 and R2, R2 and R3, R3 and R4, or R4 and R5 on the phenyl ring may together represent xe2x80x94CR7xe2x95x90CR8xe2x80x94CR9xe2x95x90CR10xe2x80x94, to form with the phenyl ring illustrated above a naphthyl ring system, wherein R7, R8, R9, and R10 are each independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, halo, loweralkyl, and loweralkoxy.
In one preferred group of compounds of formula I above, n and m are each at least 1 and together total an integer from 2, 3 or 4 to 6, 8, 10 or 12.
In another preferred group of compounds of formula I above, the ring is a phenyl ring.
In another preferred group of compounds of formula I above, the ring is a cyclohexyl ring.
In another preferred group of compounds of formula I above, m is 0.
In another preferred group of compounds of formula I above, at least one of R1, R2, R3, R4 or R5 is phenyl.
Another preferred group of compounds of formula I above have the general formula II as given below:
wherein Z, n, m, R1, R2, R3, R4, and R5 are as described above. In compounds of formula II, the phenyl ring and the carbonyl carbon may be either cis (Z) or trans (E) with respect to one another. The trans configuration is preferred.
Specific examples of compounds as described above include:
E-7-phenylhept-4-enoic acid, which has the structure:
E-7-(4-methoxyphenyl)hept-4-enoic acid, which has the structure:
Methyl E-7-phenylhept-4-enoate, which has the structure:
E-7-phenylhept-4-enoic acid amide, which has the structure:
Z-7-phenylhept-4-enoic acid, which has the structure:
E-7-(2,4-difluorophenyl)hept-4-enoic acid, which has the structure:
E-10-phenyldec-6-enoic acid, which has the structure:
and E-10-(4-methoxyphenyl)dec-4-enoic acid, which has the structure:
Additional examples of acids of the present invention include:
E-7-(4-hydroxyphenyl)hept-4-enoic acid;
E-7-(2,4-dibromophenyl)hept-4-enoic acid;
E-7-(4-methylphenyl)hept-4-enoic acid;
E-7-(2,4-diethylphenyl)hept-4-enoic acid;
E-7-(2-ethoxyphenyl)hept-4-enoic acid;
E-7-(2,4,-dipropoxyphenyl)hept-4-enoic acid: and
E-10-(2,4-difluorophenyl)dec-4-enoic acid.
Additional examples of amides of the present invention include:
E-7-(2,4-difluorophenyl)hept-4-enoic acid amide;
E-7-(4-methoxyphenyl)hept-4-enoic acid amide;
E-10-phenyldec-6-enoic acid amide;
E-7-(2,4-difluorophenyl)dec-6-enoic acid amide;
E-7-(4-methoxyphenyl)dec-6-enoic acid amide; and
Z-7-phenylhept-4-enoic acid amide.
Additional examples of esters of the present invention include:
Methyl E-7-(2,4-difluorophenyl)hept-4-enoate;
Methyl E-7-(4-methoxyphenyl)hept-4-enoate;
Methyl E-10-phenyldec-6-enoate;
Methyl E-7-(2,4-difluorophenyl)dec-6-enoate;
Methyl E-7-(4-methoxyphenyl)dec-6-enoate;
Methyl Z-7-phenylhept-4-enoate;
Ethyl E-7-(2,4-difluorophenyl)hept-4-enoate;
Ethyl E-7-(4-methoxyphenyl)hept-4-enoate;
Ethyl E-10-phenyldec-6-enoate;
Propyl E-7-(2,4-difluorophenyl)dec-6-enoate;
Propyl E-7-(4-methoxyphenyl)dec-6-enoate;
Propyl Z-7-phenylhept-4-enoate;
Ethyl E-7-phenylhept-4-enoate;
Propyl E-7-phenylhept-4-enoate;
Butyl E-7-phenylhept 4-enoate;
Ethyl E-10-phenyldec-6-enoate;
Propyl E-10-phenyldec-6-enoate; and
Butyl E-10-phenyldec-6-enoate.
Additional examples of compounds of the invention include the following:
Still additional examples of compounds of the invention are as follows:
In all of the specific alkene active compounds named or illustrated above, the double bond can be replaced with a single bond to produce an analogous series of active compounds that are alkanes.
In all of the specific alkene active compounds named or illustrated above, the double bond can be replaced with a triple bond to produce an analogous series of active compounds that are alkynes.
In all of the specific alkene, alkane and alkyne compounds named or illustrated above, the phenyl ring can be replaced with a naphthyl ring to produce an analogous series of active compounds based upon a naphthyl ring system.
Compounds of the present invention can be made by the techniques described in the Examples below, or variations thereof that will be apparent to those skilled in the art.
Compounds of the present invention can be made by the technique described in M. Ansell and J. Ducker, Reduced cyclic Compounds. Part XI. The Cyclisation of xcfx89-Arylalkenoic Acids, J. Chem. Soc. 206-212 (1961), or variations thereof that will be apparent to those skilled in the art.
A further aspect of the subject invention are addition salts, complexes, or prodrugs such as esters of the compounds described herein, especially the nontoxic pharmaceutically or agriculturally acceptable acid addition salts. The acid addition salts can be prepared using standard procedures in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, ethanedisulfonic or methanesulfonic acids. Esterification to form derivatives such as the methyl or ethyl esters, can also be performed using standard procedures. Tartarate salts can be prepared in accordance with standard procedures.
Also, derivation of the pesticidal compounds with long chain hydrocarbons will facilitate passage through the cuticle into the pest body cavity. Therefore, in a further embodiment, the subject invention provides compositions comprising the pesticidal compounds bound to lipids or other carriers.
2. Methods and Formulations for Control of Pests.
The subject invention concerns novel pest control compounds and methods for using such compounds. Specifically exemplified are novel pesticidal compounds, compositions comprising said pesticidal compounds and the use of such pesticidal compounds and compositions in controlling pests, particularly insect pests such as mosquitoes
Preferably, the subject compounds have an LD50 against mosquito larvae of less than 3.0 xcexcmole/ml. More preferably, the compounds have an LD50 of less than 2.0 xcexcmole/ml, and, most preferably, the compounds have an LD50 of less than 1.0 xcexcmole/ml. As used herein, xe2x80x9cLD50xe2x80x9d refers to a lethal dose of a peptide able to cause 50% mortality of larvae maintained on a diet of 1 mg/ml autoclaved yeast supplemented with the pesticidal polypeptide.
Control of pests using the pest control compounds of the subject invention can be accomplished by a variety of methods known to those skilled in the art. The plant pests that can be controlled by the compounds of the subject invention include pests belonging to the orders Coleoptera, Lepidopterans, Hemiptera and Thysanoptera. These pests all belong to the phylum Arthropod. Other pests that can be controlled according to the subject invention include members of the orders Diptera, Siphonaptera, Hymenoptera and Phthiraptera. Other pests that can be controlled by the compounds of the subject invention include those in the family Arachnida, such as ticks, mites and spiders.
The use of the compounds of the subject invention to control pests can be accomplished readily by those skilled in the art having the benefit of the instant disclosure. For example, the compounds may be encapsulated, incorporated in a granular form, solubilized in water or other appropriate solvent, powdered, and included into any appropriate formulation for direct application to the pest or to a pest inhabited locus.
Formulated bait granules containing an attractant and the pesticidal compounds of the present invention can be applied to a pest-inhabited locus, such as to the soil. Formulated product can also be applied as a seed-coating or root treatment or total plant treatment at later stages of the crop cycle. Plant and soil treatments may be employed as wettable powders, granules or dusts, by mixing with various inert materials, such as inorganic minerals (phyllosilicates, carbonates, sulfates, phosphates, and the like) or botanical materials (powdered corncobs, rice hulls, walnut shells, and the like). The formulations may include spreader-sticker adjuvants, stabilizing agents, other pesticidal additives, or surfactants.
Liquid formulations may be aqueous-based or non-aqueous (i.e., organic solvents), or combinations thereof, and may be employed as foams, gels, suspensions, emulsions, microemulsions or emulsifiable concentrates or the like. The ingredients may include Theological agents, surfactants, emulsifiers, dispersants or polymers.
As would be appreciated by a person skilled in the art, the pesticidal concentration will vary widely depending upon the nature of the particular formulation, particularly whether it is a concentrate or to be used directly. The pesticidal compound will be present in the composition by at least about 0.0001% by weight and may be 99 or 100% by weight of the total composition. The pesticidal carrier may be from 0.1% to 99.9999% by weight of the total composition. The dry formulations will have from about 0.0001-95% by weight of the pesticide while the liquid formulations will generally be from about 0.0001-60% by weight of the solids in the liquid phase. These formulations will be administered at about 50 mg (liquid or dry) to 1 kg or more per hectare.
The formulations can be applied to the pest or the environment of the pest, e.g., soil and foliage, by spraying, dusting, sprinkling or the like.
The pest control compounds may also be provided in tablets, pellets, briquettes, bricks, blocks and the like which are formulated to float, maintain a specified depth or sink as desired. In one embodiment the formulations, according to the present invention, are formulated to float on the surface of an aqueous medium; in another embodiment they are formulated to maintain a depth of 0 to 2 feet in an aqueous medium; in yet another embodiment the formulations are formulated to sink in an aqueous environment.
The term xe2x80x9ccontrolxe2x80x9d is intended to include control by repelling insects, as discussed in greater detail below.
3. Repellant Methods and Compositions.
In insect repellant methods, the insect is administered the active agent by applying the active agent to a subject or substrate in an amount sufficient to repel insects.
Subjects to be treated with compounds of the present invention include both human and animal subjects (e.g., dogs, cats, horses, cattle). Subjects may be directly or indirectly treated, such as by applying the active compound to the skin of the subject, or by applying the active compound to an article worn by or otherwise protecting the subject.
Substrates to be treated with compounds of the present invention include, but are not limited to, floors, plants, containers, walls, pools or open bodies of water, etc.
Insects that may be repelled by the methods of the present invention include ticks, fleas, cockroaches, and biting flies, typically of the order diptera, and further including mosquitoes, horse flies, deer flies, black flies, gnats, no-see ums, chiggers, etc.
The term xe2x80x9cmosquitoxe2x80x9d as used herein concerns any type of mosquito (e.g., Anopheles, Aedes, and Culex), including but not limited to Tiger mosquitoes, Aedes aboriginis, Aedes Aegypti, Aedes, albopictus, Aedes cantator, Aedes sierrensis, Aedes sollicitans, Aedes squamiger, Aedes sticticus, Aedes vexans, Anopheles quadrimaculatus, Culex pipiens, and Culex quinquefaxciatus.
The term xe2x80x9ctickxe2x80x9d as used herein includes any type of tick, including but not limited to, deer ticks, the American dog tick (Dermacentor variabilis), Ornithodoros parkeri, O. moubata, and Dermacentor andersoni.
The term xe2x80x9ccockroachxe2x80x9d as used herein refers to any type of cockroach, including but not limited to the American cockroach (Periplaneta americana), German cockroach (Blattella germanica), oriental cockroach (Blatta orientalis), wood cockroach (Parcoblatta pennsylvanica), brownbanded cockroach (Supella longipalpa), and smokybrown cockroach (Periplaneta fuliginosa).
Other insect that can be treated by the repellant methods of the present invention include, but are not limited to: lice (Order Phthiraptera), such as head and body lice of humans, Pediculus humanus capitis and P. H. humanus; Fleas (Order Siphonaptera), such as cat and dog fleas, Ctenocephalides sp. human fleas, Echidnophaga, Pulex sp. Bees, wasps and ants (Order Hymenoptera) mites such as Sarcoptes scabei (human itch mite) the North American chigger or red bug, Trombicula sp. nematodes such as human parasitic nematodes, Silverfish (Order Thysanura), such as Lepisma saccharina, firebrat, Thermobia domestica; Termites (Order Isoptera) such as Reticulitermes flavipes, Incisitermes minor, Marginitermes hubbardi, and Cryptotermes brevis; Earwigs (Order Dermaptera); Psocids (Order Psocoptera) such as booklice; Beetles (Order Coleoptera), particularly wood eating beetles; Centipedes such as Lithobius, Geophilus, Scutigera and millipides such as Julus terrestris; Scorpions such as Centruroides sculpturatus and Mastigoproctus gianteus; etc.
Liquid repellant formulations may be aqueous-based or non-aqueous (i.e., organic solvents), or combinations thereof, and may be employed as foams, gels, suspensions, emulsions, microemulsions or emulsifiable concentrates or the like. The ingredients may include rheological agents, surfactants, emulsifiers, dispersants or polymers.
In one embodiment, a floor wax composition may include repellant compounds as described herein, in an amount effective to repel cockroaches that might otherwise feed upon the composition once applied to floors, or to simply repel cockroaches from floor surfaces to which they are applied.
As will be appreciated by a person skilled in the art, the repellant concentration will vary widely depending upon the nature of the particular formulation, particularly whether it is a concentrate or to be used directly. The repellant compound will be present in the composition in a concentration of at least about 0.0001% by weight and may be 10, 50, 99 or 100% by weight of the total composition. The repellant carrier may be from 0.1% to 99.9999% by weight of the total composition. The dry formulations will have from about 0.0001-95% by weight of the pesticide while the liquid formulations will generally have from about 0.0001-60% by weight of the solids in the liquid phase.
The formulations may be applied to the subject""s skin, or may be applied to garments, belts, collars, or other articles worn by the subject from whom insects are to be repelled. The formulation may be applied to netting or screening that protects a subject, particularly a sleeping subject. The formulations may be applied to non-animal substrates from which insects are to be repelled, such as plants. Application to subjects or substrates may be carried out by spraying, dusting, sprinkling or the like.
The compounds according to the present invention may be employed alone or in mixtures with one another and/or with such solid and/or liquid dispersible carrier vehicles as described herein or as otherwise known in the art, and/or with other known compatible active agents, including, for example, insecticides, acaricides, rodenticides, fungicides, bactericides, nematocides, herbicides, fertilizers, growth-regulating agents, etc., if desired, in the form of particular dosage preparations for specific application made therefrom, such as solutions, emulsions, suspensions, powders, pastes, and granules as described herein or as otherwise known in the art which are thus ready for use.
The repellant compounds may be administered with other insect control chemicals, for example, the compositions of the invention may employ various chemicals that affect insect behavior, such as insecticides, attractants and/or repellents, or as otherwise known in the art. The repellant compounds may also be administered with chemosterilants.
The repellant compounds are suitably applied by any method known in the art including, for example, spraying, pouring, dipping, in the form of concentrated liquids, solutions, suspensions, sprays, powders, pellets, briquettes, bricks and the like, formulated to deliver a repellant effective concentration of the repellant compound. The repellant formulations may be applied in a repellant effective amount to an area of pest infestation or an area susceptible to infestation, a body of water or container, a barn, a carpet, pet bedding, an animal, clothing, skin, and the like.
4. Computational Chemistry Methods.
Methods of identifying a non-peptide TMOF agonist from a peptide TMOF agonist are a further aspect of the present invention. Such methods typically comprise the steps of:
modeling in a computer (preferably with simulated annealing) a model peptide TMOF agonist selected from the group consisting of TMOF and peptide TMOF analogs;
determining in said computer spatial orientations for at least one key feature of said model peptide compound;
generating in said computer a putative non-peptide TMOF agonist structure, said structure including (i) said at least one key feature and (ii) spatial orientations for said at least one key feature corresponding to said spatial orientations for said at least one key feature of said model peptide compound; then
synthesizing said putative non-peptide TMOF agonist; and then
screening said putative non-peptide TMOF agonist to determine the presence of TMOF activity therein.
Peptide TMOF agonists or analogs that may be used as a basis for modeling of the instant invention include but are not limited to those disclosed in, inter alia, U.S. Pat. Nos. 5,011,909; 5,130,253; and 5,358,934, the disclosures of which are incorporated by reference herein in their entirety.
TMOF and other TMOF peptide agonists (preferably tripeptide fragments of TMOF) may be modeled by the INSIGHT(trademark) software (available through the North Carolina Super Computing Center for academic use) using a simulated annealing protocol as described by Lovas and Murphy (S. Lovas and R. Murphy, Molecular Modeling of Neuropeptides, in Neuropeptide Protocols, pp. 209-217 (Irvine, G. B.; Williams, C. H., Eds. Humana Press, NJ. 1997)) and Damewood (J. Damewood, Rev. Computational Chem. 9, 1-79 (1996). Peptide Mimetic Design with the Aid of Computational Chemistry). Composite structural data was then used to determine approximate spatial orientations for what were deemed to be key structural features, particularly as a phenyl ring and a carboxylate functional group. These data indicated a greater degree of flexibility in the N-terminus than in the C-terminus of the peptide structures. Non-peptide analogs were then subjected to energy minimization by molecular mechanics and distances between functional groups compared to the data obtained in the data set of the TMOF fragments. These data indicated a starting point for analog synthesis as exemplified by E-7-phenylhept-4-enoic acid. Actual compounds having structures corresponding to structures generated by the computational techniques are then synthesized in accordance with known techniques, and screened for activity in a bioassay such as described below. Thus, compounds produced by the method that have TMOF agonist activity and can be used in the methods described herein generally have the structure P-R-C, where P is a phenyl group, R is an alkane, alkene, or alkyne, and C is a carboxylate group, all of which may be substituted or unsubstituted.
The following examples are illustrative of the practice of the present invention and should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

Pesticidal activity of functionalized alkenes


A nutritional supplement is taught for treating chronic debilitating diseases such as HIV/AIDS to overcome conditions of oxidative stress, decreased lean muscle mass, decreased energy production (mitochondrial failure) and support immune function. It comprises orally administrable superoxide dismutase (SOD), preferably SOD/GLIADIN, in combination with other antioxidant/immune support components (Beta Glucans, Nucleotides, Fruit Polyphenols); High Immunoglobin Whey; (undenatured whey), Ornithine alpha ketoglutarate (OKG), Branched Chain Amino Acids and Glutamine to reduce loss of lean muscle mass; and Coenzyme Q 10, D-Ribose and L-Carnitine to provide energy support (decrease mitochondrial failure).

Unfortunately there appears to be a growing number of people suffering from chronic debilitating diseases characterized by muscle tissue wasting, decreased energy and oxidative stress and immune impairment.
Most dramatic of such disease is the major increase in HIV presently infecting over 50 million people. Currently approximately 22 million people have died from the consequences of HIV induced Acquired Immune Deficiency Syndrome (AIDS). HIV attacks the human immune system, weakening the body and reducing the patient""s ability to ward off opportunistic infections, ultimately rendering him/her defenseless against diseases that usually and under normal circumstances can be successfully treated. There is no cure for AIDS.
Over the years a sizable array of vaccines, antiretroviral drugs, such as AZT and other viral suppressive compounds, have been developed that seek toxe2x80x94if not defeat, at least control the rate at which HIV replicates and thereby slow the progression of the disease, or even arrest it. However, most of these drugs to be effective have to be taken in combination with complicated regimes that need to be followed meticulously and indefinitely. More importantly, the toxic nature of these drugs leads to further decreases in host defense, energy production and increases in oxidative stress furthering the development of the disease. These drugs are expensive and not affordable by many if not most HIV infected persons. Furthermore, even if available and affordable, there presently are no reliable data on the side effects of such long term therapy, or HIV""s capacity to mutate into drug resistant strains.
To those infected with AIDS and many other chronic debilitating diseases, wasting syndrome is a very real part of their every day life. Wasting is the term used for the loss of lean muscle mass due to the virus placing additional nutritional demands on the body. These stresses can diminish appetite causing the body to use protein and other nutrients from muscle stores that help the body function correctly. As a result of this, muscles become smaller, weaker and less flexible. Eventually when muscle loss becomes significant, the ability for the body to function normally and combat other common infection greatly diminishes.
In recent years, a considerable amount of information on the spectrum of clinical consequences of HIV infection has been accumulated. The most striking characteristics of this disease include severe malnutrition and wasting syndrome. Such malnutrition involves both changes in overall body composition as well as deficiencies of specific nutrients. As HIV infection progresses to AIDS, a significant result is under-nutrition producing the added effects of starvation, a potent immuno-suppressant. Nutritional support could thus help maintain health in the HIV+ patient by replacing lost nutrients, compensating for nutritional damage done by the retrovirus-induced immunodeficiency, and stimulating the remaining immune system and cells for better host defenses. The medical community generally agrees that there remains an urgent need for interventions, including inexpensive nutrient therapies, which serve as an adjunct to current medical treatment for persons with HIV/AIDS (PWAs).
It has been shown that the course of infection is influenced by different factors including age, genetics, environmental, opportunistic infections, therapy and nutritional status. Among these, there is considerable evidence to suggest important links between nutrients, oxidative stress and HIV infection. Alterations of nutrients and increased oxidative stress associated with inadequate antioxidant intake have been observed in HIV infected subjects. Such nutrient depletions may influence immunological function, viral replication, carcinogenesis, development of cardiomyopathy and resistance to infection.
Additionally adherence is also an extremely important issue for nutritional supplements. If the product is distasteful or unpleasant to consume its use will not be repeated.
Unfortunately, there currently is no nutritional supplement on the market that addresses these major issues and conditions, such as oxidative stress, decreased lean muscle mass and weight, and mitochondrial failure (decreased energy production), associated with HIV/AIDS and other chronic debilitating diseases.
The present nutritional support composition addresses the needs of those whose immune systems are compromised through HIV/AIDS and other chronic debilitating diseases through a multiprong approach designed to:
Decrease oxidation stress
Help restore lean muscle mass
Up-regulate/increase energy production (decrease mitochondria failure)
Support Immune System
Specifically the present composition comprises in combination:
1. Orally administrative superoxide dismutase (hereinafter referred to as SOD) in combination with a lipid or protein carrier derived from plants to serve as an antioxidant support.
Particularly preferred is the protein prolamine derived from cereals, and especially SOD/Gliadin.
The orally administrable SOD component may be supplemented by other antioxidant componentsxe2x80x94Beta Glucans, Nucleotides and Fruit Polyphenols.
2. A mitochondrial/energy support component selected from the group consisting of Coenzyme Q10, D-Ribose and L-Carnitine
3. A component for maintaining lean muscle mass comprising a member of the group Ornithine alpha ketoglutarate (OKG) and High Immunoglobulin Whey (undenatured whey), which may be supplemental by other components such as Branched Chain Amino Acids, Instantized Casein, and Glutamine.
In addition to the foregoing functions, SOD/Gliadin, Beta Glucans, Coenzyme Q10, Nucleotides, Glutamine and Undenatured Whey Protein also help to support immune function.
The present composition will not interfere with or react with current drug therapies for treating HIV/AIDS or cancer. It is easily miscible with water, milk or juices to completely dissolve. It is easily blendable with flavoring agents to overcome poor adherence plaguing other nutritional products. Flavors such as Dutch Chocolate, Wild Berry and Vanilla Honey Caramel have been produced.
While certain of the above components have been used therapeutically, the present invention distinguishes over such prior art by:
Providing a multicomponent system approach to treating chronic debilitating diseases, and
Providing the first orally bioavailable form of SOD in combination with other synergistic nutritional components
The primary agent is orally administrable superoxide dismutase (SOD) in combination with a lipid or protein carrier derived from plants. A detailed description of such an antioxidant will be found in U.S. Pat. No. 6,045,809 issued Apr. 4, 2000 whose specification is hereby incorporated by reference. Such SOD compositions have good bioavailability and are therefore therapeutically effective.
In one embodiment the proteins are selected form the group consisting of prolamines and polymer films based on prolamines. The prolamines are preferably of vegetable origin and can be obtained from different cereals, especially wheat, rye, barley, oats, rice, millet and maize. Particularly preferred is gliadin derived from wheat. SOD/Gliadin, which has recently become available commercially, is especially preferred in the instant composition.
In another embodiment, the plant lipids are preferably selected from the group consisting of ceramides, phospholipids tylacoids and diacylglycerols. Particularly desired are ceramides of vegetable origin derived from cereals, especially wheat.
SOD (Superoxide Dismutase)
In the past, SOD was a very popular supplement acting as a master cellular defense enzyme. Unfortunately, taking this supplement orally yielded little if any benefit since it is easily destroyed in the GI tract via digestive enzymes. Hence, the use of injectable SOD from bovine sources was the form of choice in most of the published studies. Today, after extensive research and development, SOD microencapsulated with Gliadin (SOD/Gliadin) has been shown to be absorbed intact orally as well as up-regulate other defense enzymes in the cell: Much of the research available on SOD and the immune system centers on HIV and antioxidants. Because the immune system has a more general function in the body, protecting us from disease and keeping us healthy in a myriad of ways, the clearest observations of the relationship between free radicals, SOD and immune system are found in studying HIV and AIDS. But research also makes associations between oxidative stress and the overall strength of the immune system. It has been found that SOD can offset the damage done by free radicals, prevent damage to the immune system, and consequently help delay or prevent the onset of degenerative diseases and immune-related conditions like HIV and AIDS.
Studies show that:
Adding SOD to infected white blood cells from patients with HIV showed that SOD slowed down the spread of HIV through the infected cells. The reducing effect of SOD on superoxide seems to affect not only the level of HIV in the white blood cells, but also the rate of transmission of the virus between cells.
SOD may slow the expression of HIV to AIDS by demonstrating that SOD reduced the levels of the virus core protein, an indicator of its presence in the cells.
SOD can enhance immunity. The presence of free radicals appears to contribute to the suppression of the immune system. As part of the immune response free radicals like superoxide are produced, but these free radicals can cause tissue and immune system damage. SOD can counter the effects of free radicals, thereby enhancing immune function.
Additional antioxidant support compounds (termed AASC for convenience) may also be present in the instant compositions. Such AASC compositions are selected from the group consisting of Beta Glucans and Fruit Polyphenols. The latter are polyphenolics from prune, apple, cherry, pomegranate and nectarine.
Beta Glucans
Our immune system is our primary natural defense against disease and aging. Beta Glucans are fuel for our immune system. Specifically, beta-1,3-D-glucans are unique ingredients derived from yeast cell walls and oats. Once activated by Beta-1,3-D-glucans, the immune system creates xe2x80x9can arsenal of defensexe2x80x9d against viral, bacterial, fungal, parasitic or neoplastic assailants. Unlike other immune enhancing supplements and pharmacological drugs, beta-1,3-D-glucans, trigger the immune response selectively where and pharmacological drugs, beta-1,3-D-glucans, trigger the immune response selectively where it starts-at the macrophage. Macrophages play an essential and pivotal role in the initiation and maintenance of the immune response.
Beta Glucans work by activating the macrophages, or immune cells, which trap and engulf foreign substances. Also, the activated cells start a cascade of events that cause the entire immune system to be alerted and mobilized, in an entirely naturally activated sequence. Beta Glucans also have powerful antioxidant attributes, with heightened free-radical scavenging activity to nutritionally enable the immune system to fight back against health invaders (pathogens) such as fungus, bacteria, viruses and parasites. While Beta Glucans can be derived from yeast and grain sources, activation of the immune response is best achieved from yeast cell wall and oat Beta Glucans.
Fruit Polyphenols
Polyphenolic Flavonoids (polyphenols) are compounds found in fruits, vegetables, tea, beans, and grains. Many of the flavonoid substances are known as xe2x80x9cbioflavonoidsxe2x80x9d. Polyphenolic flavonoids are very powerful antioxidants. Acting as antioxidants means that these flavonoids can help neutralize or inactivate free radicals before they damage the cells within the human body. Free radicals are natural by-products of daily metabolism and contribute to the aging process. Polyphenolic flavonoids have the following properties: immune-stimulating, anti-viral, anti-inflammatory, anti-mutagenic, cardio-protective, anti-allergic, and anti-carcinogenic. The anti-cancer activity of polyphenols has been correlated with the inhibition of colon, esophagus, lung, liver, breast and skin cancers.
Key ingredients for providing this result are Coenzyme Q10, D-Ribose and L-Carnitine.
Coenzyme Q10
Coenzyme Q10 is an essential component of cellular energy production and respiration by participation in the mitochondrial electron transport system, which supplies energy (ATP) for a variety of physiological functions. Virtually every cell of the human body contains coenzyme Q10. Muscle mitochondria lack adequate coenzyme Q10 in people several degenerative diseasesxe2x80x94from Alzheimer""s to HIV/AIDS.
Additionally, COQ10 plays an important role in the preserving a healthy functioning immune system and modulates immunity. Blood levels of Coenzyme Q10 are founds to be low in individuals with HIV infection or AIDS. It is known that HIV/AIDS individuals have a deficiency of COQ10 and the deficiency increased with the severity of the disease. Human studies have demonstrated that COQ10 increases IgG and T4-lymphocytes when administered orallyxe2x80x94clinically relevant for cancer, HIV/AIDS and other infectious diseases. Studies have shown that COQ10 has a positive influence on the host defense system. The T4/T8 ratios of lymphocytes are known to be low in patients with AIDS, ARC and malignancies. Oral administration of COQ10 revealed a positive increase in T4/T8 rations in HIV patients.
Individuals with HIV are characterized by both significant mitochondrial alterations and a dramatic tendency to undergo apoptosis. Coenzyme Q10 is an important antiapoptotic agent with promising potential for HIV therapy given the recent findings of apoptosis involvement toward AIDS progression of HIV infected individuals. Lastly, it has been shown that the antiviral nucleoside analogue zidovudine (AZT) depletes levels of mitochondrial DNA in muscle of patients on long-term therapy. Hence, COQ10 represents a critical therapeutic agent that may prevent neuronal mitochondrial dysfunction and apoptosis beneficial in the prevention of neurodegenerative processes in AIDS patients.
L-Carnitine
L-carnitine is an amino acid abundantly found in skeletal muscle. It functions primarily to regulate fat metabolism and also acts as a carrier of fatty acids into the mitochondria, where they are oxidized and converted into energy (ATP). Hence, it has the potential to improve mitochondrial function, fat metabolism, endurance and enhance the normal functioning of the heart. It has been established in the literature that serum Carnitine deficiency is common in patients with HIV/AIDS especially those on certain medications. AZT as used in the treatment of AIDS, causes mitochondrial myopathy. Additionally, since AZT is associated with mitochondrial destruction and impairment of mitochondrial DNA synthesis crucial to the pathogenesis of the disease, L-carnitine becomes a critical part of the nutritional support plan. The depletion of Carnitine which regulates the metabolism and function of peripheral nerves and mitochondrial DNA synthesis could contribute to the neurotoxicity of certain medications used to treat the disease as well as apoptosis and other significant symptoms. The depletion also is attributed to the clinical symptoms of myalgia and muscle weakness associated with the disease. Because Carnitine status is an important contributing factor to immune function in patients with AIDS, L-carnitine supplementation could have a role as a complimentary therapy for HIV infected individuals.
Ribose
Ribose is a carbohydrate, or sugar, used by all living cells and is an essential component in our body""s energy production. As a new nutraceutical Ribose helps the body naturally restore its energy level. It""s used by the body""s cells to form the primary source of all the body""s energyxe2x80x94ATP. ATP, the body""s primary energy-carrying molecule, is necessary for maintenance of cellular integrity and function. Ribose plays a key role in the generations and recovery of ATP. Since cells and organs need adequate energy in order to maintain integrity and function, it is essential that the supply of ATP be replenished soon after it is consumed. Ribose provides benefits by quickly restoring energy levels in heart and skeletal muscles. Numerous studies demonstrate the ability of ribose to increase ATP levels and total adenine nucleotide recovery promoting skeletal and cardiac muscle energy metabolism. Since ATP production is hampered via mitochondrial dysfunction typically seen in AIDS, Ribose offers powerful complimentary support to other nutrients addressing energy depletion.
In addition to the foregoing components, supplemented effect is obtained by the added presence of Glutamine and SOD/Gliadin (also present due to their antioxidant effect), as well as medium chain triglycerides.
The key component for affecting this result is Ornithine Alpha Ketoglutarate (OKG).
Ornithine Alpha-Ketoglutarate
The amino acids Ornithine and glutamine are combined to form Ornithine Alpha-Ketoglutarate (OKG). Ornithine Alpha-Ketoglutarate affects human metabolism through three primary mechanisms: as an anabolic agent (releasing Human Growth Hormone, HGH), as an anti-catabolic agent, and as an inducer of protein synthesis. All three mechanisms contribute to muscular development and enhanced recovery. OKG has been used to treat patients suffering from burns, surgery, malnutrition and other trauma. Although the precise mechanism""s unknown, OKG treatment decreases muscle protein catabolism (breakdown) and/or increases protein synthesis, in addition to promoting wound healing. OKG may promote the secretion of anabolic hormones such as insulin and growth hormone and increase amino acid metabolism (glutamine and arginine), which may help explain some of the clinical findings.
OKG supplements have been shown to improve protein retention, would repair, and immune function in hospitalized patients partly by increasing levels of anabolic (growth-promoting) hormones such growth hormone.
In addition to OKG, other agents for restoring lean muscle mass may be incorporated in the present compositions. Examples thereof are Undenatured Whey Protein, Instantized Casein and Branched Chain Amino Acids. The Nucleotides and Glutamine used for antioxidant support also contribute to restoring muscle mass.
Whey Protein
AIDS wasting is characterized by a loss of lean body mass including muscle and organ tissue, coupled with increased fat production. Loss of lean body mass can lead to muscle weakness, organ failure and sometimes death, making AIDS wasting a leading contributor to HIV related deaths. When it comes to nutritional support directed at maintain lean mass adequate calories and good quality protein are essential.
Whey protein concentrate has long been a favorite of body builders because it is the best protein for tissue repair and muscle building. The most commonly used criterion to measure quality of a protein in Biological Value (BV), which is the amount of nitrogen (body protein in grams) replaceable by 100 grams of protein in the adult diet. The higher its protein""s BV, the higher its nitrogen retention. Proteins with the highest BV are the most potent lean tissue sparing and growth promoting proteins.
Whey is a complete protein, which contains all the essential and non-essential amino acids, and boasts the highest branched chain amino acid content found in nature. Whey also has the highest BV of any available protein. It also appears to have a unique composition of immunomodulating fructions such as immunoglobulins. Using an advanced low temperature filtrations system our undenatured whey and our whey protein is superior in quality.
Branched Chain Amino Acids
In nature, there are three Branched Chain Amino Acids: L-lsoleucine, L-Leucine and L-Valine. Amino acids are the building blocks of protein. These three are among those considered xe2x80x9cessentialxe2x80x9d because they cannot be manufactured in the body and must be obtained through diet. They have been shown to provide safe nutritional support for individuals seeking optimal lean muscle mass. BCAA""s play a principle role in muscle recovery, muscle growth and energy maintenance and must be present in the muscle cells to promote protein synthesis. They help increase the bioavailability of complex carbohydrate intake and are absorbed by the muscle cells for anabolic muscle building activity. There is some encouraging evidence suggesting BCAA supplementation may have beneficial effects on fatigue prevention and enhancing recovery and adaptation. Why we need these special amino acids is simple: scientific evidence shows that branched-chain amino acids may help restore muscle mass following surgery, an injury, or trauma. They also help in people who have liver disease. A general deficiency of protein in the diet can cause a loss of stamina, lowered resistance to infection, slow healing of wounds, weakness, and depression.
Glutamine
Glutamine is the most abundant amino acid in the body. It is crucial for many aspects of healthy body function including maintenance of optimal antioxidant status, building and maintenance of muscle tissue, maintenance of optimal immune function, and repair and maintenance of intestinal tissue. L-Glutamine is highly correlated to muscle protein synthesis. It appears that during stress, whether inflicted on the body through heavy exercise, severe illness or a (viral) infection the body""s glutamine requirements increase considerably. With the short-term metabolic stress that is created by acute infections, the body can soon return to normal rates of glutamine use. The muscle glutamine levels are quickly restored and the muscles are not damaged. Unfortunately, with the continuous metabolic stress that results from the chronic infection of HIV disease, the demand for glutamine continues and the concentration of this amino acid in the muscles falls rather rapidly. This results in a decline in the synthesis of muscle tissue and, eventually, a wasting away of the muscles. This, of course, makes glutamine crucial for the prevention of internal decline and wasting. A growing body of evidence suggests that the body""s defense system requires increasing amounts of glutamine during stress to respond to health threatening events. In the long term low plasma and muscle glutamine levels may lead to net muscle protein loss and decreased resistance against infections. During an immune response when the immune cells have to increase in number and do their work of destroying pathogens, the rate at which glutamine is used increases dramatically. When the body""s supply of glutamine runs short, immune function is compromised. Glutamine also increases the activity of natural killer cells and improves the function of neutrophils. In addition, glutamine is critical for the immune function of the respiratory tract, the genitourinary tract, and the intestinal tract.
Nucleotides
Nucleotides are naturally occurring compounds that are involved in key metabolic processes including energy metabolism and enzymatic reactions. They are the building blocks of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Essentially, nucleotides are required by all cells, and are particularly important for cells with rapid turnover including mucosal cells, lymphocytes and macrophages. During stress states, a dietary source is required to promote optimal tissue growth and replication of T-cells. Dietary sources of preformed nucleotides seem to be important for optimal function of the cellular immune response. It has been reported that the absence of dietary nucleotides causes a significant decrease in many specific and non-specific immunologic responses. Nucleotide supplementation has been shown to improve immune function, promote the growth of healthy bacteria in the gut and suppress the growth of gram-negative bacteria in the large intestine. Research in humans and animals has shown that diets lacking dietary nucleotides result in increased susceptibility to infectious agents such as Candida albicans and Staphylococcus aureus, and may increase risk for gastrointestinal infections.
As problems continue to arise with antibiotic-resistant microorganisms, it will become more important for people to strengthen their immune defense system. Nucleotides represent a critical component in the arsenal.
In addition to the key components of the present invention, a conventional blend of vitamins and minerals can be incorporated. Other conventional ingredients to nutrient drinks may be added.
The range of components in the compositions of the present invention are set for in the Table A below:
All values are on a per daily basis. U stands for units of activity.

Nutrient therapy for immuno-compromised patients


A corrugated cardboard manufacturing machine (10) wherein at least one continuous supporting belt (11) for supporting/conveying a sheet of cardboard is moved along a predetermined path by actuating means (13); and where the supporting belt (11) is defined by a mat of multispiral fabric (1) preferably made of synthetic polymer fibers.

As is known, corrugated cardboard, of the type normally used for boxes or miscellaneous packaging, is produced on special corrugating machines: the sheets of cardboard are fed to the corrugating machine packed tightly between respective cylinder-operated supporting/conveying belts, and are subjected to the combined action of heating assemblies and pressure plates for gluing and shaping the various layers forming the corrugated cardboard.
On known machines, the belts supporting and conveying the cardboard sheets are made of felt, in particular acicular felt, or conventional fabric, which involves various drawbacks. Firstly, felt or conventional fabrics, mainly on account of not always being of even thickness, fail to provide for thin, top-quality finished products, and are therefore unsuitable for producing boxes or packages for select items such as perfume, ornaments, etc., unless the output speed of the machine is greatly reduced. Moreover, felt or conventional fabrics, which must be joined when fitted to the corrugating machine, show marked breaks in continuity at the joints, which further impair the quality of the finished product.
Felt or conventional fabrics are also relatively heavy and therefore difficult to assemble onto the machine; the weight, combined with a high friction coefficient, of such materials increases the energy consumption of the machine; and, finally, not being very permeable, felt or conventional fabrics not only impair dispersion of the steam issuing from the cardboard, but also call for coating the cardboard with a relatively large amount of glue.

Corrugated cardboard manufacturing machine