WO2002017898A2 - Compositions et procedes visant a induire une vasorelaxation - Google Patents

Compositions et procedes visant a induire une vasorelaxation Download PDF

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Publication number
WO2002017898A2
WO2002017898A2 PCT/US2001/026983 US0126983W WO0217898A2 WO 2002017898 A2 WO2002017898 A2 WO 2002017898A2 US 0126983 W US0126983 W US 0126983W WO 0217898 A2 WO0217898 A2 WO 0217898A2
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arginine
composition
derivative
nitric oxide
antioxidant
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PCT/US2001/026983
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WO2002017898A3 (fr
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Meir S. Sacks
Knox Van Dyke
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Sacks Meir S
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Publication of WO2002017898A3 publication Critical patent/WO2002017898A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the present invention relates to compositions comprising an antioxidant and a nitric oxide (NO) donor or producer.
  • the compositions are useful in the treatment of diseases in which vasoconstriction occurs or is a symptom. Accordingly, methods for treating such diseases are also within the scope of the present invention.
  • Nitroglycerin and similar nitrate-type drugs in the treatment of cardiovascular disease is widespread.
  • Nitroglycerin and other clinical nitrates convert into nitric oxide (NO) in vivo.
  • NO nitric oxide
  • Nitric oxide is a key vasodilator for coronary and other vessels such as those in the kidney; NO induced vasodilation can, among other things, relieve the pain of angina caused by insufficient perfusion of coronary vessels of the heart.
  • Nitroglycerin is very fat soluble and can be given, for example, under the tongue, in a mouth spray or on a skin patch; it relieves the pain of angina very quickly because it gets into the blood stream and finds its way to the heart in seconds.
  • U.S. Patent No. 5,543,430 reports a therapeutic mixture comprising L-arginine and a nitrate. Methods of using the mixture to treat a disease condition in a subject by vasodilation (vasorelaxation) are also disclosed.
  • U.S. Patent No. 5,767,160 discloses similar mixtures and methods, using a biological equivalent of arginine instead of L-arginine itself. Use of L-arginine and/or its biological equivalents in these applications, however, has significant drawbacks. L-arginine has side effects, as do other nitrates, that can lead to major toxicity. It causes release of growth hormone which can lead to acromegaly, and is known to produce hyperkalemia in renal failure patients.
  • Peroxynitrite a strong oxidizer, which, among other things, causes tissue damage and damage to membrane lipids and DNA of cells.
  • Peroxynitrite has 1000 times the oxidative activity as concentration-equivalent amounts of hydrogen peroxide, and is therefore a potent oxidizer capable of causing significant damage in vivo.
  • the present invention relates to compositions comprising one or more nitric oxide (NO) donors and one or more antioxidants.
  • NO donors include L-arginine, arginine derivatives, and nitrates.
  • the present compositions are useful in the generation and maintenance of NO levels in vivo. NO is believed to function in the same manner as endothelium-derived relaxing factor (EDRP), which is known to cause vasodilation (vasorelaxation) of the blood vessels.
  • EDRP endothelium-derived relaxing factor
  • the antioxidants according to the present invention deplete superoxide to minimize if not prevent formation of peroxynitrite, while destroying any peroxynitrite that does form. Thus, NO levels are raised or at least maintained, while peroxynitrite levels are decreased, if not eliminated.
  • arginine derivatives of the present invention produce more NO per mole of substrate than does L-arginine. Because these derivatives are more efficient precursors for NO production than L-arginine, in combination with supra or mega doses of antioxidant, they produce vasodilation without tachyphylaxisis and without producing the tissue damaged caused by peroxynitrite. This is significant because it allows for the avoidance or minimization of the toxicity associated with the use of L-arginine or nitrates, alone or in combination.
  • compositions can further comprise tetrahydrobiopterin (BF ⁇ , and/or hydralazine, both of which inhibit the formation of superoxide.
  • superoxide can react with NO to form toxic peroxynitrite.
  • the present invention further relates to methods of inducing vasorelaxation in a patient comprising administering to the patient one or more NO donors and one or more antioxidants, such as by administration of the compositions of the present invention.
  • the present methods overcome the tachyphylaxis and the production of peroxynitrite that often accompanies multiple administration of NO donors such as nitrates and L-arginine. This is in contrast to various art reported methods, in which NO is generated in sufficient quantity to alleviate tachyphylaxis but superoxide and the peroxynitrite that results are left to cause damage to tissues, membranes and DNA.
  • Various illnesses, such as angina pectoris in which vasorelaxation is desired can be treated correctly according to the present methods without short or long-term toxicity.
  • compositions that induce vasorelaxation while minimizing the level of peroxynitrite.
  • Another aspect of the present invention is to provide such compositions for the study and treatment of diseases and disorders in which vasoconstriction or loss of vasodilation is a symptom.
  • Figure 1 shows the transporter-mediated uptake of FITC-labeled arginine and peptides by alveolar macrophages (AM), determined according to the methods of Example 1, wherein the peptides are actively pumped into the cell.
  • AM alveolar macrophages
  • Figure 2 shows the effects of anti-pepT t antibodies on NO production, determined according to the methods of Example 3.
  • FIG. 3 shows the effects of membrane transporter inhibitors on NO production, determined according to the methods of Example 4.
  • compositions comprising one or more nitric oxide (“NO") donors.
  • NO donor(s) or “NO producer(s)” is used herein to refer to arginine derivatives, L-arginine, and nitrates.
  • arginine derivatives used according to the present invention are superior sources of NO when compared to L-arginine itself.
  • L-arginine is a common substrate for two major enzymes—arginase and nitric oxide synthase ("NOS").
  • Arginase converts L-arginine to
  • L-ornithine and NOS converts L-arginine into citrulline and nitric oxide.
  • the present arginine derivatives avoid or at least minimize this competition.
  • many of the present arginine derivatives are not suitable substrates for arginase, but are suitable substrates for NOS; thus NO is generated while L-ornithine is not.
  • Arginine derivative is used herein to refer collectively to the following compounds: N -hydroxy-L-arginine ("hydroxylated L-arginine”); esters of N -hydroxy-L- arginine; amides of N G -hydroxy-L-arginine; di-, tri- or tetra peptides wherein the first amino acid at the amino terminal end is L-arginme, N -hydroxy-L-arginine, L-homoarginine, N - hydroxy-L-homoarginine or esters or amides of any of these amino acids; esters of L- arginine; amides of L-arginine; L-homoarginine, N -hydroxy-L-homoarginine or esters or amides of these amino acids; and D-arginine, hydroxylated D-arginine, or esters or amides of these amino acids.
  • N G -hydroxy-L-arginine is the direct intermediate in the production of NO. More specifically, L-arginine is metabolized by NOS to an oxidized intermediate known as N G -hydroxy-L-arginine. N G -hydroxy-L-arginine reacts with microsomal NOS and inducible NOS to produce NO far better than L-arginine alone. N G -hydroxy-L-arginine is the key substrate for the various NO synthases, but is not a substrate for arginase, therefore allowing for much greater NO production than L-arginine. The equilibrium constant (Km) for this amino acid is three times greater than L-arginine (6.6 ⁇ Molar compared to 2.3 ⁇ Molar).
  • the maximum velocity at saturation (Vmax) with N-hydroxy-L-arginine as a substrate is 9.9 ⁇ M x min "1 x Mg "1 , as compared to that L-arginine, which is 54 ⁇ M x min "1 x Mg "1 .
  • Vmax The maximum velocity at saturation
  • N-hydroxy-L-arginine causes vasodilation (vasorelaxation) in a concentration dependent manner similar to L-arginine.
  • the relaxation is inhibited by addition of inhibitors of NO biosynthesis.
  • amino terminal amino acid is L- arginine, hydroxylated L-arginine, L-homoarginine, N-hydroxy-L-homoarginine or ester or amide derivatives of any of these acids.
  • the remaining acid or acids in the peptide are selected from any of the above acids (namely L-arginine or the listed derivatives), or any of the other 19 naturally occurring amino acids or derivatives thereof.
  • at least the amino terminal amino acid is L-arginine or a derivative thereof more than one of the amino acids can also be L-arginine or one of its derivatives.
  • Derivatives of L-arginine in the present invention refers to hydroxylated L-arginine, L-homoarginine, hydroxylated L- homoarginine, and esters or amides of L-arginine, N G -hydroxy-L-arginine, L-homoarginine and N-hydroxy-L-homoarginine.
  • Especially preferred peptides include arginine-lysine, arginine-glycine, and arginine-lysine-aspartic acid.
  • L-arginine derivatives can be used in any of the current peptides in place of L-aginine; thus, for ease of reference "arginine-containing peptides" refers collectively to di-, tri- or tetra- peptides having at least one L-arginine or derivative of L-arginine. It is believed that peptides comprising hydroxylated L-arginine are even greater NO substrates than peptides comprising unhydroxylated L-arginine, although the inventors do not wish to be bound by this.
  • the arginine containing peptides may not produce L-arginine but can react directly with NO synthases.
  • peptides as compared to free amino acids, are taken into cells by a specialized transporter known as the proton-coupled oliogopeptide transporter. Selectivity of peptides exceeds selectivity of transport of individual amino acids.
  • the present arginine-containing peptides are transported into cells without degradation and once internalized in a cell are superior substrates for NO synthases than is L-arginine itself.
  • L-homoarginine and N-hydroxy-L-homoarginine are also within "arginine derivative" as that term is used herein. These compounds can alone represent the arginine derivative in the present compositions and methods, or can be within the peptides discussed above. L-homoarginine and N-hydroxy-L-homoarginine contain one extra methyl group (- CH 2 -) in the carbon chain of arginine. The advantage that the homoisomers of L-arginine have is that they are as good or nearly as good as L-arginine in reacting with NO synthases, but are not substrates of arginase.
  • ester derivatives of the carboxyl end of L-arginine are ester derivatives of the carboxyl end of L-arginine, hydroxylated L-arginine, homoarginine, hydroxylated homoarginine, and the L-arginine or L-arginine derivatives in the arginine- containing peptides.
  • a reaction can occur at the carboxyl end of the amino acid with, for example, acid chlorides or anhydrides to form an ester at the carboxyl end.
  • COOH has been esterified. This allows transfer across cell membranes to occur more easily.
  • N-acetyl derivatives such as L-arginine-acetate, are preferred.
  • Other derivatives include the amide derivatives of L-arginine, hydroxylated L- arginine, homoarginine, hydroxylated homoarginine, and the L-arginine or L-arginine derivatives in the arginine-containing peptides.
  • derivitization can also be effected at the amino terminal of the present amino acids.
  • the final type of "arginine derivative” used in the present invention is D- arginine.
  • D dexextrorotatory
  • L levorotatory
  • the natural amino acids in the body are in the "L” form.
  • the "D” form is not the preferred substrate for the NO synthases, it still reacts to produce NO in sufficient quantities to elicit a therapeutic benefit.
  • Hydroxylated D-arginine and esters or amide derivatives of D-arginine and hydroxylated D-arginine are within the present invention.
  • the arginine derivatives of the present invention are preferred substrates for the NO synthases (I, II and III).
  • L-arginine as noted above, is a naturally occurring amino acid. It is widely commercially available, such as from Sigma Chemical.
  • nitrate any substance that produces nitric oxide in solution can be used as the "nitrate" in the present composition, if desired.
  • Nitroglycerin is widely commercially available in a variety of forms including oral, parenteral and dermal. Suitable nitroglycerin is listed in the Drug Handbook 6 th Ed. Other suitable compounds include sodium nitroprusside and nitrate esters.
  • the present compositions comprise, as the nitric oxide of donor, a combination of an arginine derivative and a nitrate.
  • the preferable arginine derivatives are hydroxylated L-arginine and di-, tri- or tetra-peptides having L-arginine or hydroxylated L- arginine at the amino terminal.
  • the preferred nitrate is nitroglycerin.
  • compositions also comprise an antioxidant. Any antioxidant that will deplete superoxide levels and/or break down peroxynitrite is within the scope of the present invention.
  • the antioxidant should be in amounts sufficient to minimize peroxynitrite levels; such levels can be readily ascertained using cellular assays known to those skilled in the art.
  • the antioxidant will be used in what is regarded as a supratherapeutic amount, that is, amounts two times or greater the RDA value for antioxidants having an RDA value.
  • a preferred antioxidant is ascorbic acid, also known as L-ascorbate or Vitamin C, or its derivatives, such as ester C (the calcium salt of Vitamin C), dehydro-L-ascorbate C (an oxidized derivative of Vitamin C), ester C of dehydro-L-ascorbate (an oxidized derivative of ester C) and lipidated derivatives such as ascorbic acid palmitate; these compounds are collectively referred to herein as Vitamin C derivatives or L-ascorbate derivatives. Vitamin C and its derivatives function as antioxidants, converting superoxide molecule to hydrogen peroxide and oxygen. Superoxide, as noted above, combines with NO to form peroxynitrite causing vascular and DNA damage.
  • antioxidants such as Vitamin C or its derivatives
  • tachyphylaxis and damage from peroxynitrite which occurs with use of any of the medical nitrates or L-arginine.
  • other antioxidants, or combinations of antioxidants are within the scope of the present invention.
  • the present compositions comprise enough nitric oxide donor or donors to effect a desired level of vasorelaxation in a patient; the composition can therefore have varying concentrations.
  • Administration of the current nitric oxide donor or donors should be in accordance with established practices in the art.
  • Drug Handbook, 6 th Edition provides dosages for various forms of nitroglycerin; one skilled in the art could therefore determine the appropriate amount of nitric oxide donor or donors to administer to a patient to achieve the desired level of NO in that patient.
  • the present compositions can therefore be formulated to contain an appropriate amount of nitric oxide donor or donors.
  • Antioxidants should typically be present so as to result in administration of at least about 150 milligrams per day, and preferably range between 500 milligrams per day and 10,000 milligrams per day.
  • the composition can further comprise tetrahydrobiopterin (BEU).
  • BEU tetrahydrobiopterin
  • BH is a cofactor in the biosynthesis of nitric oxide with NO synthases that converts L-arginine and hydroxyarginine to nitric oxide and citrulline.
  • Tetrahydrobiopterin if not present in proper amounts, causes the blood vessels to secrete excessive superoxide. If enough tetrahydrobiopterin is added, however, the reaction favors NO production.
  • a range of doses from between about 10 and 500 milligrams of BF ⁇ may be added to the current compositions per dose of NO donor.
  • compositions also optionally comprise hydralazine.
  • Hydralazine inhibits the vascular enzyme nicotinamide adenine dinucleotide phosphate (NADP or NADPH) oxidase released upon vasodilation; NADP and NADPH oxidase produce superoxide anions, which in turn combine with NO to produce peroxynitrite. Inhibition of this reaction is therefore beneficial in maintaining levels and minimizing peroxynitrite levels.
  • NADP or NADPH nicotinamide adenine dinucleotide phosphate
  • Hydralazine if used, should be in an amount sufficient to inhibit NADP oxidase. Typically, this amount will be between about 25 mg and 100 mg, per dose of NO donor.
  • a preferred composition is one comprising an arginine derivative in conjunction with nitroglycerin as the NO donor, and vitamin C, its derivatives, or combinations thereof as the antioxidant.
  • the present invention is further directed to a method of treating a patient for an illness comprising administering to the patient an effective amount of NO donor and an antioxidant.
  • the present methods have been found to reduce the tachyphylaxis associated with introduction of nitroglycerin or other nitrates. More specifically, as discussed above, repeated dosage of nitrates results in reduced response to the drug.
  • the present methods overcome this phenomenon.
  • the NO donor provides a substrate for NO production, providing an agonist of NOS that stimulates conversion of the substrate into NO.
  • the increased NO levels lead to vasorelaxation.
  • the antioxidant minimizes, if not eliminates, peroxynitrite.
  • Treating is intended to encompass both therapeutic and prophylactic treatment of any of the illnesses discussed below; for ease of reference “therapeutic benefit” is therefore used collectively to refer to a benefit that is either therapeutic or prophylactic.
  • a number of therapeutic benefits can be achieved according to the present methods. For example, induction of vasorelaxation leads to blood pressure reduction as well as the pain associated with vasoconstriction.
  • the antioxidant prevents or at least minimizes production of the toxic oxidant peroxynitrite. Reduction of the tachyphylaxis associated with nitrate tolerance is another therapeutic benefit, as is stimulation of NOS and minimization of superoxide production.
  • the present methods are particularly useful for the treatment of: chronic stable angina; unstable angina; acute myocardial infarction; hibernating myocardium; stunned myocardium; limitation of ventricular remodeling in post myocardial infarction and subsequent risk of congestive heart failure; prophylaxis of recurrent myocardial infarction; prevention of sudden death following myocardial infarction; vasospastic angina; congestive heart failure-systolic; congestive heart failure-diastolic; microvascular angina; silent ischemia; reduction of ventricular ectopic activity; any or all of the states of ischemia myocardium associated with hypertensive heart disease and impaired coronary vasodilator reserve; control of blood pressure in the treatment of hypertensive crisis, perioperative hypertension, preaclampsia or aclampsia; uncomplicated essential hypertension and secondary hypertension; regression of left ventricular hypertrophy; prevention and or regression of epicardial coronary athe
  • TAA stroke pulmonary hypertension
  • Patient is used herein to refer to members of the animal kingdom including but not limited to humans. Patients particularly suitable for treatment according to the - re present methods include those who need NO, such as those who suffer from an illness in which vasoconstriction is a symptom. Typically, such patients will suffer from high blood pressure, that is a blood pressure of 95-180 mmHg in the systolic range and 55-115 mmHg in the diastolic range. "Effective amount” is used herein to refer to that amount of the present compositions needed to bring about the desired effect in a patient. Most typically, an effective amount will be the amount that results in raising the NO concentration in vivo above basal levels, while minimizing peroxynitrite formation.
  • an effective amount can be that amount needed to induce vasorelaxation while minimizing levels of peroxynitrite; whether a suitable level of vasorelaxation has been achieved can be determined, for example, by monitoring the blood pressure of the patient.
  • An effective amount can also be that amount of the present compounds needed to reduce blood pressure in a patient, or that amount needed to treat tolerance to nitrates or other NOS agonists, while minimizing levels of peroxynitrite.
  • the effective amount will vary depending on various factors including the patient to be treated, the illness being treated, the severity of the illness, the patient' s reaction to the treatment, and the like.
  • An effective amount may be at least about 0.4 mg of NO donor per dose (with 5 doses per day being typical).
  • An effective amount of antioxidant is that amount that will reduce levels of peroxynitrite, typically is at least about 150 mg per day. Any level of vasorelaxation and reduction of peroxynitrite levels is within the scope of the present invention and may be achieved using less than the "typical" amounts listed herein. Similarly, the amount needed to cause the desired level of vasorelaxation in a particular patient may be much higher than the typical effective amount needed to elicit any response.
  • the term "illness" is used herein to refer to any disease condition that would benefit from the presence of additional NO and/or the induction of vasorelaxation. Examples include, but are not limited to, hypertension, other diseases characterized by high blood pressure, hypertensive heart disease, coronary heart disease including stable, unstable, and microvascular angina, myocardial infarction, hibernating and stunned myocardium, cardiovascular disease including heart failure, stroke and peripheral vascular diseases, renovascular ischemia or hypertension, and congestive heart failure. Any of the conditions listed above in the discussion of therapeutic benefits are also within the scope of the current definition of illness. As noted above, the present method comprises administering to a patient a NO donor and an antioxidant.
  • the components of the present compositions are contained in a pharmaceutically acceptable carrier.
  • “Pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Use of any of these media or agents is contemplated with the compositions of the present invention, absent compatibility problems with the active compound. Vehicles or carriers standardly used in the pharmaceutical arts for the administration of nitrates, amino acids, and their derivatives and antioxidants can be adapted for use in the present methods by one skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the patient to be treated, each unit containing a pre-determined quantity of the active ingredients or "effective amount" calculated to produce the desired therapeutic effectin association with the pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the characteristics of the active ingredients (i.e., the NO donor and antioxidant), the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such active ingredients for the treatment of sensitivity in individuals.
  • fluoroscein isothiocyanate (FITC) labeled lysine (Lys)* and lysine peptides B ala-lys, L-arg-lys, gly-sar-lys were used for cellular uptake studies.
  • L-arg-lys, L-arg-gly and L-arg-gly-asp were used as arginine containing peptides for transport and utilization studies. Lysine was used as a competitive inhibitor for CAT-2B (peptide transporter) mediated arginine or lysine uptake. Cephalexin and cephadrine were non-peptide substrates for the peptide transporter (PepT-1). Antiserums AntiPepT-1, and AntiP455-469 were obtained commercially and used to assess the role of the peptide transport in alveolar macrophage production of nitric oxide (NO).
  • NO nitric oxide
  • AM were isolated using non calcium containing physiological buffer. Cell counts were done with a Coulter counter and sizer.
  • AM were incubated with FITC-substrate for two hours at 37° C. AM were washed and centrifuged three times and finally resuspended in fresh medium. The cell suspension was sonicated for several minutes and fluorescence measured with excitation at 495 nm and emission at 5154 nm. Aveolar macrophages (AM) were cultured with 10% fetal bovine serum with or without substrate (200 micromolar) and or inhibitor (1 micromolar) at 37° C for two hours. AM conditioned medium was collected and NO measured by accumulated nitrite via the Griess reaction. The concentrations of substrate or inhibitor did not exert toxic effects as assessed by lactate dehydrogenase measurements.
  • This example demonstrates the presence of a peptide transporter in alveolar macrophages (AM) for small (2-4) peptide uptake.
  • the example also demonstrates how arginine-containing peptides are utilized by AM in NO production, and the effect of lysophosphatidylchloine (LPC) on the transport and utilization of arginine alone versus arginine-containing peptides by AM.
  • 10 ⁇ M of FITC, FITC-labeled lysine, and peptides either with or without 100 ⁇ M of lysine and cephradine were incubated with LPS-stimulated AM (106 cells) at 37° C for two hours.
  • the peptides used were arg-lys, B ala-lys, and gly- sar-lys.
  • Figure 1 demonstrates the presence of a peptide transporter in the plasma membrane of AM.
  • Small peptides here di- and tri- peptides, were internalized by AM without degradation.
  • the presence of a peptide transporter in the plasma membrane of AM is different from the cationic amino acid transporter that mediates the uptake of arginine and lysine alone.
  • EXAMPLE 2 This example compares the utilization of L-arginine with arginine-containing peptides by LPS-stimulated AM in production of NO. 200 ⁇ M of arginine and argine-containing peptides were incubated with PS- stimulated AM for 24 hours. NO production was determined by measuring the accumulation of nitrite using the Greiss assay.
  • This example demonstrates the effects of anti-pepTl antibodies on NO production by LPS-stimulated AM.
  • 200 ⁇ M of L-arginine and arginine-containing peptides either with or without antiserums were incubated at 37° C with LPS-stimulated AM for 24 hours.
  • the arginine-containing peptides were arg-lys, arg-gly, and arg-gly-asp.
  • This example demonstrates the effects of membrane transporter inhibitors on NO production by LPS-stimulated AM.
  • 200 ⁇ M of arg-containing peptides either with or without inhibitors (1 ⁇ M Lys and cephs, 5 ⁇ M LPC) were incubated with LPS-stimulated AM for 24 hours.
  • the arginine-containing peptides were arg-lys, arg-gly, and arg-gly-asp.
  • the amino acid lysine competes with the amino acid arginine for the amino acid transport, but it does not compete with arginine peptide transport.
  • the antibiotics cephalexin and cephadrine which use the peptide transporter to enter the cell, compete with the arginine peptides but do not compete with arginine transport, which uses the single amino acid transporter. This shows that the transport of peptides is different than that of single amino acids.
  • An 86 year old man with angina pectoris was taking approximately 0.4 milligrams of nitroglycerin five times a day, as prescribed by his doctor.
  • the man began taking approximately 1,000 milligrams of L-arginine per day and between 3,000 and 5,000 milligrams of L-ascorbic acid per day.
  • the patient experienced a reduction in blood pressure, and a concurrent reduction in the severity and incidents of angina attack.

Abstract

Composition renfermant un ou plusieurs donneurs de monoxyde d'azote et un antioxydant. Le donneur de monoxyde d'azote décrit dans cette invention constitue un substrat utile pour la génération de monoxyde d'azote ; couplées à l'antioxydant, les compositions de l'invention servent à augmenter les taux de monoxyde d'azote chez un patient tout en limitant la production de pernitrites. Il en résulte une vasorelaxation ou vasodilatation n'entraînant pas de lésions tissulaires et cellulaires associées à d'autres procédés de génération de NO. L'invention concerne aussi des traitements de maladies ayant pour symptôme ou impliquant une vasoconstriction. Ces traitements comprennent l'étape consistant à administrer au patient à traiter un donneur de NO, de façon simultanée ou consécutive à un antioxydant, selon une quantité efficace pour induire le degré voulu de vasorelaxation.
PCT/US2001/026983 2000-09-01 2001-08-29 Compositions et procedes visant a induire une vasorelaxation WO2002017898A2 (fr)

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WO2005004884A2 (fr) * 2003-07-09 2005-01-20 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Traitement d'etats cardio-vasculaires specifiques au moyen de nitrite
JP2006206521A (ja) * 2005-01-28 2006-08-10 Univ Of Tokyo 一酸化窒素供与体としてのｎ−ニトロソアミン化合物
WO2008080194A1 (fr) * 2006-12-29 2008-07-10 The University Of Queensland Compositions analgésiques et leurs utilisations
US7846400B2 (en) 2007-10-30 2010-12-07 The Invention Science Fund I, Llc Substrates for nitric oxide releasing devices
US7862598B2 (en) 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
WO2011011092A1 (fr) * 2009-07-22 2011-01-27 University Of Massachusetts Procédés et compositions pour réduire le stress oxydatif
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
US7975699B2 (en) 2007-10-30 2011-07-12 The Invention Science Fund I, Llc Condoms configured to facilitate release of nitric oxide
US8221690B2 (en) 2007-10-30 2012-07-17 The Invention Science Fund I, Llc Systems and devices that utilize photolyzable nitric oxide donors
US8557300B2 (en) 2005-05-19 2013-10-15 University Of Cincinnati Methods for treating bacterial respiratory tract infections in an individual using acidified nitrite
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WO2005004884A2 (fr) * 2003-07-09 2005-01-20 The Government Of The United States Of America As Represented By The Secretary, Department Of Health And Human Services Traitement d'etats cardio-vasculaires specifiques au moyen de nitrite
US9993481B2 (en) 2003-11-17 2018-06-12 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
US9433624B2 (en) 2003-11-17 2016-09-06 Biomarin Pharmaceutical Inc. Methods and compositions for the treatment of metabolic disorders
JP2006206521A (ja) * 2005-01-28 2006-08-10 Univ Of Tokyo 一酸化窒素供与体としてのｎ−ニトロソアミン化合物
US8557300B2 (en) 2005-05-19 2013-10-15 University Of Cincinnati Methods for treating bacterial respiratory tract infections in an individual using acidified nitrite
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US9994534B2 (en) 2006-12-29 2018-06-12 The University Of Queensland Pain-relieving compositions and uses therefor
WO2008080194A1 (fr) * 2006-12-29 2008-07-10 The University Of Queensland Compositions analgésiques et leurs utilisations
US7897399B2 (en) 2007-10-30 2011-03-01 The Invention Science Fund I, Llc Nitric oxide sensors and systems
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US8877508B2 (en) 2007-10-30 2014-11-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US8980332B2 (en) 2007-10-30 2015-03-17 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US10080823B2 (en) 2007-10-30 2018-09-25 Gearbox Llc Substrates for nitric oxide releasing devices
US8349262B2 (en) 2007-10-30 2013-01-08 The Invention Science Fund I, Llc Nitric oxide permeable housings
US8642093B2 (en) 2007-10-30 2014-02-04 The Invention Science Fund I, Llc Methods and systems for use of photolyzable nitric oxide donors
US7862598B2 (en) 2007-10-30 2011-01-04 The Invention Science Fund I, Llc Devices and systems that deliver nitric oxide
US7846400B2 (en) 2007-10-30 2010-12-07 The Invention Science Fund I, Llc Substrates for nitric oxide releasing devices
US9579321B2 (en) 2009-07-22 2017-02-28 University Of Massachusetts Methods and compositions to reduce oxidative stress
WO2011011092A1 (fr) * 2009-07-22 2011-01-27 University Of Massachusetts Procédés et compositions pour réduire le stress oxydatif
US9089573B2 (en) 2009-07-22 2015-07-28 University Of Massachusetts Methods and compositions to reduce oxidative stress
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