WO2000041686A1 - Traitement de l'hypertension avec des composes inhibant la destruction des enkephalines ou des endorphines - Google Patents

Traitement de l'hypertension avec des composes inhibant la destruction des enkephalines ou des endorphines Download PDF

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WO2000041686A1
WO2000041686A1 PCT/US2000/000722 US0000722W WO0041686A1 WO 2000041686 A1 WO2000041686 A1 WO 2000041686A1 US 0000722 W US0000722 W US 0000722W WO 0041686 A1 WO0041686 A1 WO 0041686A1
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phenylalanine
ribose
blood pressure
administering
hypertensive
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Seymour Ehrenpreis
Kenneth Blum
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Seymour Ehrenpreis
Kenneth Blum
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Priority to AU25027/00A priority patent/AU2502700A/en
Priority to EP00903252A priority patent/EP1158972A4/fr
Publication of WO2000041686A1 publication Critical patent/WO2000041686A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61K31/70—Carbohydrates; Sugars; 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
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to hypertension or high blood pressure. More specifically, this invention relates to treatment of animals and humans with a substance that inhibits and/or delays the inherent breakdown of a class of substances called enkephalins and/or endorphins that are created and exist within animals. These substances, the enkephalins and endorphins, can lower blood pressure; however, they are rapidly destroyed by endogenous enzymes and ordinarily do not play a major role in controlling blood pressure. However, by protecting the enkephalins and/or endorphins from destruction through the use of enzyme inhibitors, these substances are caused to accumulate, resulting in the- lowering of blood pressure.
  • the amino acid D-phenylalanine (DPA) or the D,L racemic mixture is such an enzyme inhibitor and is representative of a new class of compounds or drugs which can lower elevated blood pressure by raising body levels of enkephalins and/or endorphins.
  • DPA amino acid D-phenylalanine
  • D,L racemic mixture is such an enzyme inhibitor and is representative of a new class of compounds or drugs which can lower elevated blood pressure by raising body levels of enkephalins and/or endorphins.
  • DISCUSSION There are a number of classes of drugs which are currently in use to treat hypertension. These consist of the following: drugs which modify the adrenergic part of the autonomic nervous system; drugs which dilate blood vessels: diuretics, drugs that inhibit angiotensin converting enzyme (ACE inhibitors); drugs that block calcium channels; and drugs that block angiotensin receptors.
  • ACE inhibitors angiotensin converting enzyme
  • drugs that block calcium channels drugs that block angiotensin receptors
  • the enkephalins and endorphins are peptides which are present in the central nervous system and many other tissues including the blood. Although their main function appears to be control of the pain response, they have many other actions including lowering of blood pressure in some animal species when they are injected into the blood stream.
  • enkephalinases or endorphinases enzymes that are found everywhere in the body and rapidly destroy any endorphins or enkephalins which are given exogenously or produced endogenously.
  • D,L-phenylalanine would be used for therapeutic purposes because of the considerably lower cost of the racemic mixture as compared with pure D-phenylalanine. It is understood that, as previously described, only D-phenylalanine is the amino acid form which actually inhibits the destruction of the enkephalins. D-phenylalanine and D,L-phenylalanine are long known compounds and listed in the Merck Index.
  • D,L-phenylalanine was administered in quantity of 50 or 100 mg per day for 15 days, and D-phenylalanine was administered in quantity of 100 mg per day for 15 days.
  • Deprenon A commercial drug, sold under the Trademark “Deprenon”, is available for treatment of depression, by oral ingestion of 3-4 capsules per day. Deprenon's specifications state that each capsule contains: D-phenylalanine - 50 mg
  • D-phenylalanine and D,L-phenylalanine also possess analgesic activity by virtue of the accumulated enkephalins and/or endorphins within the central nervous system.
  • D,L-phenylalanine is currently being sold over the counter in the United States and England as DLPA. For-this purpose, it is administered in divided oral doses of 1-2 grams per day for up to several weeks.
  • Other inhibitors of enkephalin degradation include D-leucine, bestatin, thiorphan, bacitracin, puromycin, and captopril. These compounds also produce analgesia, as shown primarily in animals, but have not been tested for their effects on blood pressure in animals or man.
  • a method of choice for evaluating anti-hypertensive drugs before administration to humans is to determine their effectiveness in lowering blood pressure in the spontaneously hypertensive rat (SHR).
  • SHR spontaneously hypertensive rat
  • This genetic variant at adulthood, develops very high blood pressure - systolic in the range of 180 - 220 mm Hg, diastolic 150 - 170 mm Hg.
  • a substance which successfully lowers blood pressure in the SHR without causing appreciable side effects would be considered as a good candidate for hypertensive therapy in humans.
  • D-ribose is a naturally occurring pentose monosaccharide containing a functional aldehyde group and an alcohol group. D-ribose is used by the body in the synthesis of nucleotides and metabolic intermediates such as D-ribose-5-phosphate (R-5-P). R-5-P is an important intermediate of the pentose phosphate pathway (PPP) of glucose metabolism (also known as the hexose monophosphate shunt or the phosphogluconate pathway).
  • PPP pentose phosphate pathway
  • glucose metabolism also known as the hexose monophosphate shunt or the phosphogluconate pathway.
  • the PPP results in the formation of NADPH and pentose-based molecules in animal cells. This pathway is especially pronminent in tissues actively carrying out the biosynthesis of fatty acids and steroids from small precursors where reducing power (NADPH) is needed.
  • NADPH reducing power
  • the pathway is also active in human and animal erythrocytes.
  • the NADPH produced is required for preventing the unsaturated fatty acids in the cell membrane from undergoing abnormal reactions with oxygen and for keeping the iron atoms of hemoglobin in their normal ferrous valence state.
  • Pentose molecules generated by way of the PPP are necessary for the synthesis of nucleic acids, glycogen and glucose.
  • nucleic acids for example, requires 5- phosphoribosyl-1-pyrophosphate (PRPP) which is derived from ribose.
  • PRPP 5- phosphoribosyl-1-pyrophosphate
  • ribose is utilized by many different tissues in animals and in man, including the heart and skeletal muscle.
  • FIG. 1A shows the adenine nucleotide de novo synthetic pathway: Ribose-5- phosphate and PRPP are early precursors in this pathway. The interrelationship between the de novo pathway and the degradative and salvage pathways has been demonstrated.
  • FIG. IB shows adenine nucleotide synthetic pathways: Pathways 2 and 3 are considered the most active. The two entrance sites of phosphoribosyl pyrophosphate (PRPP) into the salvage pathways is demonstrated.
  • PRPP phosphoribosyl pyrophosphate
  • FIG. IC shows adenine nucleotide degradation pathways: Degradation of AMP to the diffusable metabolites, adenosine. inosine and hypoxanthine is enhanced during ischemia.
  • FIG. ID shows blood pressure lowering activity of D-phenylalanine in spontaneously hypertensive rat (tail cuff method).
  • FIG. IE shows blood pressure lowering activity of D-phenylalanine in spontaneously hypertensive rat (cannulation method).
  • FIG. 2 shows a dose response to D-phenylalanine for blood pressure lowering in SHR (tail cuff method).
  • FIG. 3 shows the synergistic effect on blood pressure lowering in SHR by D- phenylalanine and propranolol.
  • FIG. 3A shows the effect of DPA on blood pressure in normotensive rats (cannulation method).
  • FIG. 3B shows blockage of anti-hypertensive DPA effects by naltrexone.
  • FIG. 3C shows reversal of DPA hypotension by naltrexone.
  • FIG. 4 shows hypotensive effects of DPA in humans.
  • FIG. 5A shows effects of DPA on blood pressure in SHR.
  • FIG. 5B shows effects of thiorphan and actinonin on blood pressure in SHR.
  • FIG. 6 shows pharmacokinetics of DPA given orally to a human subject.
  • D-phenylalanine was tested for its anti-hypertensive action in the spontaneously hypertensive rat in the laboratory of a major Japanese pharmaceutical company. They confirmed completely the inventors' observation that DPA at
  • Data shows the pharmacokinetics of DPA given orally to a human subject at a dose of 2 grams dissolved in 250 ml of water. Phenylalanine of course if present in the blood and the amount present before DPA administration was subtracted from that obtained at each data point. As can be seen, the elimination half life is about 6 h although a significant amount is still present in serum 10 h. after administration.
  • An important aspect of the present invention is a method for anti-hypertensive therapy in a human.
  • This method comprises administering an effective amount of a substance that inhibits the destruction of enkephalins or endorphins.
  • a preferred inhibitor of endorphinase or enkephalinase is D-phenylalanine, and a preferred mode of administration is oral by tablet or as a dietary component.
  • D-phenylalanine may be administered as the D-isomer or as part of the D,L-racemic mixture.
  • Such D- phenylalanine is preferably administered in an amount of about 2 to 4 grams daily.
  • the inhibitor may be accompanied by other anti-hypertensive agents such as propranolol or another ⁇ blocker.
  • the present invention envisions the use as an anti-hypertensive agent of: D- phenylalanine; D-leucine or D,L-leucine, a combination of D-phenylalanine and D- leucine; bestatin; thiorphan; captopril; and/or puromycin. These substances may be used individually or in combination.
  • the D-phenylalanine is used in combination with a separate anti-hypertensive agent.
  • One separate anti- hypertensive agent is a diuretic or blood vessel dilator.
  • Dietary supplements comprising an inhibitor of endorphin or enkephalin destruction are another preferred aspect of the present invention.
  • These inhibitors of enkephalin or endorphin destruction in one aspect are preferably combined with D- ribose.
  • These inhibitors of endorphin or enkephalin destruction are often inhibitors of the appropriate hydrolytic enzymes destroying these substances, i.e. endorphinases or enkephalinases.
  • Other inhibitors that may be used in combination with, or perhaps instead of, D-phenylalanine are hydrocinnamic acid and D,L-leucine.
  • the anti-hypertensive effects of inhibitors of endorphin or enkephalin destruction may also involve administration of at least one of ferrulic acid, pharmaline, huperzine, at least one of a chromium salt such as, e.g., chromium picolinate, chromium nicotinate, and chromium polynicotinate, Co-enzyme Q, Pycogenol or Hawthorn or Hawthorn extract.
  • a chromium salt such as, e.g., chromium picolinate, chromium nicotinate, and chromium polynicotinate, Co-enzyme Q, Pycogenol or Hawthorn or Hawthorn extract.
  • the present invention provides a treatment of hypertension comprising administering an enkephalinase or endorphinase inhibitor in combination with a diuretic, sympatholytic, direct vasodilator, angiotensin-converting enzyme inhibitor, calcium channel blocker, angiotensin II receptor antagonist, a T- type calcium antagonist such as nisoldipene, losartin, moxonidine or fenoldopam.
  • a method for the treatment of hypertension involving administering an enkephalinase and/or endorphinase inhibitor in combination with a stimulator of increased norepinephrine.
  • angiotensin II antagonists such as clonidine, and adrenergic receptor blockers.
  • the method of inhibiting hypertension comprising administration of an enkephalinase or endorphinase inhibitor may also be combined with the administration of an inhibitor of norepinephrine synthesis selected from a group consisting of methyl-p-tyrosine, carbidopa, diethyl, diethyldithiocarbonate, FAI63 and disulfiram or other inhibitors of dopamine- ⁇ -hydroxylase.
  • an inhibitor of norepinephrine synthesis selected from a group consisting of methyl-p-tyrosine, carbidopa, diethyl, diethyldithiocarbonate, FAI63 and disulfiram or other inhibitors of dopamine- ⁇ -hydroxylase.
  • the administration of enkephalinase or endorphinase inhibitors may also be combined effectively with the administration of a magnesium salt or a chromium
  • Rhodiola rhosea extract may be useful in combination with the endorphinase or enkephalinase inhibitors as a method of lowering hypertension.
  • One preferred Rhodiola extract is Salidrosid.
  • Huperzine, Hawthorn berry or Hawthorn berry extract may also be combined with the enkephalinase or endorphinase inhibitors for lowering hypertension.
  • An adrenergic- ⁇ -blocking agent may be effectively combined with the enkephalinase or endorphinase inhibitors or other substances described herein for an effective hypertension-lowering agent.
  • An important aspect of the present invention is a pharmaceutical composition for lowering blood pressure, comprising D or D,L-phenylalanine, a chromium salt, D- ribose, calcium chelate, L-taurine and L-glycine.
  • this composition also contains at least one of a brain cognitive enhancing amount of ferrulic acid, pharmaline and huperzine to increase focus, memory or attention.
  • a preferred pharmaceutical composition of the present invention is one comprising as a daily dose: D or D,L-phenylalanine, 1 mg to 10,000 mg; chromium salts (picolinate or nicotinate or other salts), 1 microgram to 30,000 micrograms; D- ribose, 100 mg to 10,000 mg; calcium chelate, 10 mg to 3,000 mg; L-taurine, 10 mg to 10,000 mg; and L-glycine, 10 mg to 10,000 mg.
  • One object of this invention is to provide a new method for reducing blood pressure in animals and man which is safer than currently available means of achieving this.
  • Another object of this invention is to provide a new method for producing a longer lasting reduction in blood pressure than is possible by means of currently available drugs.
  • One additional object of this invention is to provide a new method for enhancing the effectiveness of currently available anti-hypertensive drugs, thereby permitting lower doses of such drugs to be used and in this way reducing the incidence of side effects from such drugs.
  • the inventors have evaluated the effectiveness of D-phenylalanine in spontaneously hypertensive rats (SHR) by two methods: l) By measuring blood pressure directly via an indwelling cannula and 2) By measuring blood pressure by means of a tail cuff.
  • Method 1 The rats were anesthetized with ether and a midline neck incision was made and the right carotid artery was exposed. A cannula was inserted into the artery and a pressure transducer was attached to the cannula. Blood pressure readings were recorded by means of a polygraph, Baseline blood pressure was recorded after the rat had fully recovered from anesthesia (approximately one hour after cannulation) and ranged between 190 to 220 mm Hg. Drugs were administered via the carotid artery cannula. This method permits measurement of both systolic and diastolic pressure.
  • Method 2 The rat was placed in a warmed chamber (30°C) and the tail was placed in a cuff which was connected to a blood pressure monitoring device. Blood pressure (only systolic) was determined every minute, as well as heart rate. Injections of various solutions were made by the intraperitoneal route. This method permits blood pressure measurements to be made for several days.
  • Drug evaluation Two different procedures were used: cumulative and single dose. In the single dose studies, one dose of DPA (generally 400 mg/kg) was administered and the animal's blood pressure was followed for the next 6 h. In the cumulative procedure, 100 mg/kg DPA was administered as a bolus, and when the effect had leveled off an addition 100 mg/kg was given followed by 200 mg/kg of the compound. In studying the effect of a combination of drugs, DPA was given at a low dose together with a low dose of the second drug (propranolol) and the blood pressure followed for the next few hours. The doses chosen of each drug separately produced only a very small fall in blood pressure over this time period.
  • DPA was administered to normotensive rats and humans after which their blood pressure was determined.
  • Enkephalinase inhibitors include a variety of materials, including thiorphan, captoril and puromycin.
  • DPA lowered the systolic blood pressure an average of 36.8 mm Hg or 21.5 percent (P is less than .01).
  • DPA's effect on diastolic blood pressure was impressive as well.
  • the mean diastolic blood pressure was initially 184.8 mm Hg (plus or minus 5 mm Hg) and was reduced to 150.2 mm Hg (plus or minus 5 mm Hg) within six hours after infusion. This represents an average decrease in diastolic blood pressure of 34.6 mm Hg or 23 percent.
  • D-phenylalanine was able to lower systolic blood pressure of the SHR very close to that of normal rats about 150 mm Hg (Table 1).
  • DPA was administered along 1 3 with propranolol, a highly significant potentiation of the hypotensive effect was observed as compared with the effect of each compound given separately (FIG. 3).
  • Diastolic BP 220 190 178 180 180 170 170
  • Diastolic BP 200 190 190 188 164 164 164
  • Systolic BP 200 190 190 182 174 174 160
  • naltrexone 1 mg/kg plus 1 mg/kg plus 3 mg/kg
  • D-phenylalanine was tested for its anti-hypertensive action in the spontaneously hypertensive rat in the laboratory of a major Japanese pharmaceutical company. They confirmed completely the inventors' observation that DPA at 400 mg/kg gives a significant lowering of blood pressure with a time-course very similar to what the inventors found. Three rats were used (see FIG. 5A). Also tested were two other inhibitors of enkephalin degradation, thiorphan and actinonin. Neither of these were effective in lowering blood pressure even though used at very high doses (see FIG. 5B). In the case of thiorphan this could be explained by lack of penetration into the central nervous system which appears to be the site of action of DPA.
  • Data of FIG. 6 show the pharmacokinetics of DPA given orally to a human subject at a dose of 2 grams dissolved in 250 ml of water. Phenylalanine of course if present in the blood and the amount present before DPA administration was subtracted from that obtained at each data point. As can be seen, the elimination half life is about 6 h although a significant amount is still present in serum 10 h. after administration.
  • D-phenylalanine, or D,L-phenylalanine as an anti-hypertensive agent has the following important features, many of which constitute advantages over other blood pressure lowering drugs currently in use at this time:
  • Blood pressure lowering is not accompanied by an increase in heart rate, unlike what may occur when conventional anti-hypertensive drugs are given. 4. D-phenylalanine potentiates the. blood pressure lowering effectiveness of a ⁇ blocker such as propranolol permitting lower doses of the latter to be used. This may also occur with other classes of anti-hypertensive drugs.
  • a ⁇ blocker such as propranolol permitting lower doses of the latter to be used. This may also occur with other classes of anti-hypertensive drugs.
  • D-phenylalanine is essentially devoid of side effects, unlike all other anti-hypertensive drugs which have many severe side effects.
  • D-RlBOSE Ribose plays a vital role in myocardial metabolism, largely through its participation (as PRPP) in the synthesis of ATP and adenine nucleotides. Ribose bypasses the limiting and critical step in the PPP, the glucose-6-phosphate dehydrogenase (G-6-PDH) reaction, thereby elevating PRPP levels. Elevated PRPP levels can lead to increased myocardial adenine nucleotide biosynthesis which can accelerate replenishment of depleted cardiac adenine nucleotide pooIS5. This was demonstrated by Zimmer and Gerlach (1978). They studied the effects of certain penitols and pentoses, including ribose. on the heart of adult female rats.
  • PRPP glucose-6-phosphate dehydrogenase
  • Pentoses and penitols intravenously injected in a single dose of 100 mg/kg, increased the available pool of PRPP and of the rate of adenine nucleotide biosynthesis of the heart.
  • the stimulatory effect of isoproterenol on myocardial adenine nucleotide biosynthesis could be further potentiated by ribose and xylitol, but not glucose.
  • the isoproterenol- induced decrease of cardiac adenine nucleotide concentrations could be almost completely prevented by repeated administrations of ribose.
  • pentoses and penitols in combination with beta-receptor stimulation markedly and quite specifically enhanced adenine nucleotide biosynthesis in the rat heart.
  • G-6-PDH is similar in such species as rats, guinea pigs, dogs, and humans (Zimmer et al, 1983).
  • the effects of ribose on myocardium are discussed in more detail in the section entitled "Ribose Effects on the Myocardium”.
  • Pentoses and penitols intravenously injected in a single dose of 100 mg/kg, induced a considerable enhancement of the available PRPP pool and the rate of nucleotide biosynthesis in the heart but not the liver or kidney 1 1.
  • De novo synthesis of adenine nucleotides not detectable in skeletal muscle of normal rats became measurable after application of ribose.
  • Tullson and Terjung (1991) found that ribose perfusion of endurance-trained rat skeletal muscle increased adenine nucleotide biosynthesis by 3.7 to 4.5 times.
  • Ribose (as R-5-P) also plays a role in erythrocyte metabolism. In porcine erythrocytes. for example, it was found that ribose was used in the formation of lactate (via R-5-P) and maintained ATP levels in these cells. Dawson et al. (1981) found that ribose (15 mM) alone provided marginally increased 2,3-diphosphoglycerate (2,3- DPG) maintenance in human blood over control preservative (0.25 CPD-adenine), but ribose with phosphate (10 mM) maintained 2,3-DPG levels above 70% of normal for five weeks of storage and two weeks longer than the control.
  • ATP levels were maintained at normal or above for six weeks with phosphate plus ribose or inosine (15 mM). 2,3-DPG maintenance has previously been shown to be impaired by phosphate, unless inosine is also present. The ribose and inosine effects on 2,3-DPG maintenance are not additive. Phosphate also has an enhancement effect on ATP maintenance in the presence of either ribose or inosine.
  • ATP and creatine phosphate (CP) are depleted in the myocardium following brief ischemia in the isolated, perfused heart (Swain et al, 1982).
  • the lowering of ATP during ischemia is caused by anoxic inhibition of oxidative phosphorylation; excess ADP which accumulates as a result of catabolized oxypurines.
  • Pasque et al. (1982) described this process in detail, as follows:
  • Myocardial AMP and ADP levels initially rise during ischemia as the balance between high energy ATP bond utilization and the mitochondrial ability to rephosphorylate AMP and ADP is disturbed. With prolongation of the ischemic period, however, these levels gradually fall, presumably secondary to the degradation of ADP to AMP, which is, in turn, metabolized to adenosine. Upon reaching the vascular endothelium, adenosine is further degraded to inosine and hypoxanthine. Myocardial levels of inosine and hypoxanthine rise significantly as ischemia is prolonged.
  • the cellular AMP and ADP that have not been degraded during ischemia are rephosphorylated as the oxygenated reperfusion rejuvenates the mitochondrial machinery and restores the ATP/ADP ratio.
  • Available adenosine, inosine and hypoxanthine are converted to AMP by the normally rapid salvage pathways.
  • the levels of these diffusable salvage metabolites are quite low, however, because of the washout which occurs during reperfusion. Therefore, the salvage pathways are inadequately fueled and, even in combination with the de novo pathways, are limited in their ability to rapidly replete AMP levels:
  • nucleotide pools depletion of nucleotide pools occurs during ischemia and, with reperfusion, nucleotide content (and cardiac function) is restored only slowly. Delayed repletion does not appear to be caused by a defect in mitochondrial synthesis of ATP because CP content is restored rapidly (Swain et al, 1982).
  • the slow repletion of nucleotides, particularly the adenine nucleotides may be secondary to loss of nucleotide precursors during reperfusion and may result in widespread alterations in myocardial metabolism. The loss of precursors forces the myocardium to rely on de novo synthesis of adenine nucleotides.
  • a postischemic decrement in ATP levels may persist for several days following episodes of myocardial ischemia because the de novo pathways are relatively slow in the myocardium (Mahoney, 1990).
  • ANW and ADP is preserved in myocardial mitochondria subjected to moderate periods of ischemia.
  • the well-documented rapid repletion of CP levels to normal and often supernormal levels upon reperfusion suggests that the machinery is available and functional under these conditions. It is reasonable to conclude that the predominant factor in the inability of the myocardium to completely replete ATP levels during reperfusion following moderate periods of oxygen deprivation is lack of available AMP and ADP for rephosphorylation to ATP.
  • Interventions into the adenine nucleotide degradation and synthetic pathways that elevate postischemic ANM levels may be of importance in achieving improved postischemic myocardial recovery.
  • the second point of intervention would be enhanced replenishment of ANW through the acceleration of salvage and de novo synthetic pathways.
  • the salvage pathways require less energy than the de novo synthetic reactions and are normally responsible for the majority of the adenine nucleotide synthesis in the heart. However, they are dependent upon the presence of adenosine, inosine and hypoxanthine. On initiation of reperfusion, these metabolites are washed out in large volumes and the salvage pathways rapidly become dependent upon the fixed uptake of the limited supply of purine precursors from the liver.
  • De novo adenine nucleotide synthesis is particularly responsible for the replacement of the relatively small volume of dephosphorylated adenine nucleotide degradation products which are continually lost during normal cardiac activity. It shares this responsibility with the salvage pathway incorporation of 'new' purine precursors supplied by the liver. ...Under normal conditions the de novo synthetic pathway is suppressed when purine metabolites are available for fueling the salvage pathways. Following ischemia, suppression of the de novo pathway is released, but this pathway is slow relative to the volume of the postischemic adenine nucleotide deficit. ... Manipulation of the various rate-limiting steps of de novo synthesis under postischemic conditions could reasonably be expected to further enhance this acceleration.
  • a biochemical limitation on adenine nucleotide repletion by de novo synthesis is the availability of a primary pentose phosphate pathway substrate, PRPP.
  • PRPP pentose phosphate pathway substrate
  • Zimmer (1982) and Zimmer and Ibel (1983) provided evidence that PRPP availability limits adenine nucleotide synthesis by the de novo and salvage pathways.
  • the direct conversion of adenine to AMP also requires availability of PRPP.
  • Zimmer (1983) stated how synthesis of myocardial adenine nucleotides could be stimulated by increasing the availability of PRPP, as follows.
  • adenosine inosine and adenine
  • PRPP 5-phosphoribosyl- 1-pyrophosphate
  • the second approach is aimed at enhancing the biosynthesis of adenine nucleotides with ribose.
  • PRPP supplies the ribose-phosphate to all adenine nucleotides, and its availability is rate limiting in both salvage and de novo adenine nucleotide synthetic pathways ( Figures 2 and 3). PRPP availability is in turn limited by the activity of the hexose monophosphate shunt [pentose phosphate pathway] which supplies the ribose-
  • Ribose would be converted into ribose-5 -phosphate, thus entering the pathway at a point past the rate-limiting G-6-P DH/6-P DGH enzymatic steps and thereby increase PRPP synthesis and in turn de novo adenine nucleotide synthesis.
  • Studies have shown in fact that infusion of ribose into rats accelerates cardiac adenine nucleotide synthesis, presumably by increasing PRPP levels (Zimmer and Gerlach, 1978; Zimmer et al, 1980).
  • Ribose has been shown to lead to further stimulation of cardiac nucleotide biosynthesis and promoting the recovery of depressed myocardial ATP levels during recovery from intermittent asphyxic periods, from temporary regional ischemia, and in the non-ische ic myocardium (Pasque et al, 1982; Zimmer, 1980; Ibel and Zimmer, 1986; Zimmer, 1983; Mauser et al, 1985; Zimmer and Ibel, 1984; Clay et al, 1988; Mahoney et al, 1989; St. Cyr et al, 1989).
  • ribose ATP and adenine nucleotide (AN) levels in male and female (mongrel) dog hearts subjected to brief periods of ischemia was studied by Sami and Bittar (1987).
  • ribose 200 mg/kg/h was infused for 24 h; in five dogs, saline was infused instead.
  • the dogs were then anesthetized, ventilated and the heart exposed through left thoracotomy.
  • the LAD was dissected and a snare occluder placed around it. Contractility in the LAD bed was measured with a pair of ultrasonic crystals and a left ventricular catheter.
  • the LAD was briefly occluded for 15 min followed by release of the snare and reperfusion for 60 min.
  • ATP and AN levels were measured before and at the end of occlusion, and during recovery (5. 10, 30, 40, and 60 min). Contractility measurements were done similarly. The authors reported that recovery of contractility was significantly improved in the ribose group versus the saline group. ATP and AN levels were also higher in the ribose group before ischemia and during reperfusion. The data suggest that by enhancing the resynthesis of adenine nucleotides, and thus ATP. with ribose, contractility recovers at a higher rate after reversible ischemia.
  • Ventricular biopsies were obtained through an indwelling ventricular cannula prior to ischemia, at the end of ischemia and 4 and 24 h postischemia and analyzed for adenine nucleotides and creatine phosphate levels.
  • Radiolabeled microspheres were used to measure myocardial and renal blood flows and no significant difference was found between ribose-treated and control groups. In both groups, myocardial ATP levels fell by at least 50% at the end of ischemia. No significant ATP recovery occurred after 24 h in the control dogs, but in the ribose-treated animals ATP levels rebounded to 85% of baseline by 24 h.
  • Indicators of myocardial metabolism such as the cyclic AMP level, biosynthesis of adenine nucleotides and ATP content were also evaluated.
  • Ribose is converted to ribose-5-phosphate by ribokinase, which can then be utilized in three different ways: a) synthesis of glucose; b) glycolysis (formation of pyruvate); and c) synthesis of nucleotides.
  • ribose is the substrate for formation of PRPP.
  • PRPP is, in turn, the substrate for de novo synthesis of nucleotides, such as ATP, nucleotide coenzymes, and adenine and hypoxanthine utilization by the salvage pathway as depicted in FIG. 1A, FIG. IB, FIG. IC (taken from Pasque et al, 1982).
  • nucleotides are essential energy sources for basic metabolic reactions and play important roles in protein, glycogen and nucleic acid synthesis (ribonucleotides and deoxyribonucleotides), cyclic nucleotide metabolism and energy transfer reactions.
  • ATP levels were essentially normal. Without ribose, ATP content was still significantly depressed, although it had recovered to a certain extent.
  • the depression of LVSP and LV dP/dtmax was not altered by ribose infusion; however, there was a marked and significant attenuation of the elevation of LVEDP compared to that seen in animals treated with 0.9% NaCI. Since ATP levels were better preserved in non- ischemic regions of hearts from animals treated with ribose and this was accompanied by the attenuation of the elevated LVEDP, the investigators concluded that metabolic support of the noninfarcted areas results in improvement of global heart function.
  • glucose is commonly used as the sole energy source for the heart although other substrates such as ribose and xylitol have been used.
  • Mahoney et al. (1989) were interested in examining the role of pentose sugars and polyols in myocardial metabolism. They studied the ability of ribose to serve as the sole added carbon source in a rat isolated working heart model. Rat hearts were extirpated and configured as per the working heart model.
  • Ribose can also prevent the inhibition of cardiac AN biosynthesis by propranolol (Zimmer et al, 1984) .
  • Adult rats were treated with isoproterenol (25 mg/kg for 5 h) alone or in combination with propranolol (50 mg/kg for 5 h) while others were treated with propranolol (50 mg/kg for 5 h) alone or in combination with a solution of ribose (450 mg/kg/h).
  • the rate of cardiac adenine nucleotide biosynthesis was determined in each case.
  • Isoproterenol markedly stimulated cardiac adenine nucleotide biosynthesis that was completely abolished when propranolol was simultaneously administered. Propranolol alone inhibited adenine nucleotide biosynthesis considerably; this effect was prevented when ribose was infused.
  • ribose retains its stimulating metabolic effects on myocardium when administered in conjunction with the calcium antagonist verapamil and the (BI- specific adrenoceptor blocker metoprolol was studied (Zimmer et al, 1987).
  • LVEDP was elevated. Cardiac output and stroke volume index were depressed after two days. The ATP content in the non-ischemic region was lower than control, but recovered spontaneously toward the normal value within the first four days. Continuous i.v. administration of ribose (200 mg-/kg/hr; 5 mg/kg/h) which stimulates further adenine nucleotide biosynthesis attenuated the fall and promoted the restoration of ATP in the non-ischemic myocardium within four days after coronary artery ligation. The elevation of LVEDP was attenuated with ribose after two to four days.
  • Ribose decreased 14C-adenine nucleotide into the adenine nucleotides in kidney, lungs and liver.
  • prazosin 100 (pg/kg/h)
  • the rate and LV dP/dtmax were not changed, but LVSP (-20%), mean aortic pressure (-16%) and peripheral resistance (- 40%)) were decreased.
  • Cardiac output was enhanced (+40%).
  • Verapamil (2 mg/kg/h) and metoprolol (2 mg/kg/h) infused for 24 h decreased the pressure-rate and pressure- volume product of the left ventricle to the same extent (-40%)).
  • Verapamil had no influence on cardiac output, while metoprolol depressed it (-30%).
  • CdTe miniature cadmium-telluride radiation detection probes were inserted into the hearts of a total of 17 young pigs, one positioned against the endocardium of the anterior wall and the other against the endocardium of the posterior left ventricular wall.
  • the CdTe probes measured 20'TI activity continuously.
  • the ribose treatment group consisted of eight animals that received i.v. ribose, 3.3 mg/kg/min for 30 min.
  • the control group consisted of nine animals that received saline in place of ribose.
  • a subtotal LAD occlusion was performed reducing LAD flow to about 25% of baseline based on electromagnetic flow probe readings.
  • Microsphere injections were used to document the flow reduction. After 10 min of occlusion, LAD flow was restored gradually over a 5-10 min period. Thallium was injected during the 10 min of subocclusion. The percent difference in 20'TI activity between the ischemic anterior and non-ischemic posterior wall during ischemia was comparable. Twenty-five min after the subocclusion was released and intravenous infusion of ribose (3.3 mg/kg/min) or saline was started and continued for 30 min.
  • 20'Thallium redistribution was defined as the percent decrease in the pretreatment 20'TI defect at the end of the 30-min infusion and at 60 min.
  • the ribose- treated animals had significantly greater thallium redistribution at the end of the ribose infusion compared to saline infusion, 48% ⁇ 1% v. 20% ⁇ 4% (p ⁇ 0.05).
  • the ribose group had a 69.9% ⁇ 6% reduction in the initial 20'TI defect in the ischemic area compared to a 44% ⁇ 5% in the saline group. This difference was significant (p ⁇ 0.05).
  • the maximum percent difference in the 20'TI activity between ischemic and non-ischemic myocardium was the same in ribose- and saline-treated animals. The presence of ribose did not appear to alter the initial myocardial uptake of 20'Thallium.
  • Mean ( ⁇ SEM) pre-infusion plasma glucose was 148+20 mg/dl in the ribose group and 127+21 mg/dl in the saline group. At the end of the study these values were 137+18 mg/dl and 1 13+13 mg/dl for the ribose and saline groups, respectively. These falls of 1 1% and 14% were not statistically significant.
  • Ultrasonic crystals were implanted at the epicardial and endocardial surfaces of the ischemic and nonischemic myocardium.
  • the percent thickening in the ischemic myocardium in the ribose group may have improved to a greater extent than the saline group.
  • ribose 3.3 mg/kg/min
  • imaging was carried out at 4 h and 24 h. All patients in the saline group did not have 24-h images.
  • the mean patient age was 62 years and predominately male. Seventy- three percent had 2- or 3-vessel disease. Previous Q wave myocardial infarction(s) with an associated wall motion abnormality was present in 40%o. Antianginal medication was maintained at constant dosage throughout the study.
  • Myoadenylate deaminase is the rate-limiting enzyme in the purine nucleotide cycle that is biochemically linked to glycolysis and the citric acid cycle (Goebel and Bardosi, 1987). Deficient MAD activity has been reported in association with hypokalemic periodic paralysis, Duchenne's muscular dystrophy and other neuromuscular diseases as well as a primary disease associated with exertional myalgia. The following table from Goebel and Bardosi (1987) Summarizes the diseases in which MAD (MADD) deficiency has been described (noted references are from the reported study): Table 1 Myoadenylate Deaminase Deficiency in Association with Other Diseases
  • Duchenne's muscular dystrophy Zimmer and Ibel, 1984 Late onset muscular dystrophy Lee et al, 1988 Facioscapulohumoral dystrophy 44 Facial and limb girdle myopathy Sami and Bittr, 1987 Congenital myopathy Clay et o/., 1988 Infantile hypotonia 45
  • MAD irreversibly deaminates adenosine monophosphate (AMP) in the purine nucleotide cycle, which plays an important role in skeletal muscle metabolism during exercise.
  • AMP adenosine monophosphate
  • the invention involves the combination of certain inhibitors of "Endorphinase” or “Enkephalinase” or other related inhibitors of enzymes involved in the breakdown of natural opioid peptides.
  • Said inhibitors could be from a group of D-amino acids and their metabolites (i.e. D-phenylalanine, hydrocinnamic acid, D-leucine etc.) and other precursor amino acids, especially those which effect dopamine synthesis (i.e.
  • L- tyrosine as well as herbal-based natural substances (ferrulic acid, pharmaline, huperzine).
  • chromium salts picolinate, nicotinate and poly nicotinate etc.
  • Other important nutrients include co-enzyme Q and pycnogenol and Hawthorn.
  • D-phenylalanine, D-leucine or D,L-leucine or other D-amino acids with acetylsalicylic acid to prevent stroke has important prophalatic benefit.
  • the combination of D-amino acids or other similar inhibitors of opioid peptidyl degradation with the following known anti-hypertensive agents is also considered:
  • Mockers direct vasodilators angiotensin-converting enzyme inhibitors calcium channel Mockers angiotensin II receptor antagonists
  • An additional embodiment of this disclosure is the potential of combining the proposed formulae suggested with genotyping for certain known gene polymorphisms and identified alleles (i.e. human Chromosome 2 [D2S311], tissue pathway inhibitor, the vitronectin receptor alpha- subunit, the alpal chain typel 11 collagen, the alpha-2- chain of type V collagen, homeobox D cluster as well as a potential of more than 100 expressed sequence tags which have been recently expressed and have been mapped in the human genome localized and are potential candidates for familial primary pulmonary hypertension and other related hypertensive conditions.
  • gene polymorphisms and identified alleles i.e. human Chromosome 2 [D2S311], tissue pathway inhibitor, the vitronectin receptor alpha- subunit, the alpal chain typel 11 collagen, the alpha-2- chain of type V collagen, homeobox D cluster as well as a potential of more than 100 expressed sequence tags which have been recently expressed and have been mapped in the human genome localized and are potential candidates for familial primary pulmonary
  • Another gene which may have a potential role in hypertension may be localized to a micro-satellite polymorphism, D2 SI 788, mapped to chromosome
  • GNKR glucokinase regulatory protein
  • POMC pro-opiomelancortin
  • hypertension ranks as the fourth largest mortality risk factor in the world predicting 6% of all deaths.
  • Multiple risk factors for cardiovascular disease are often present in the hypertensive patient.
  • Recent guidelines ranging from those prepared by the World Health Organization/ International Society of Hypertension to those of the three European Societies of Cardiology, Atherosclerosis, and Hypertension, stress the importance of evaluating global risk, based on the presence of all cardiovascular risk factors in an individual or in a group of subjects. It has also been suggested that treatment should aim to correct all modifiable risk factors.
  • safety of drug treatment of hypertension can only be seen in relation to efficacy, which has now come to mean not just blood pressure reduction but improvements in hard end-points including mortality.
  • the physician can maximize the efficacy of the regimen and minimize the adverse effects the patient may experience.
  • Optimal therapy requires a knowledge of the pharmacologic properties of the six broad classes of anti-hypertensive drugs: diuretics, sympatholytics, direct vasodilators, angiotensin-converting enzyme inhibitors, calcium channel Mockers and angiotensin 11 receptor antagonists.
  • diuretics a wide range of drugs which do not worsen diabetes mellitus, do not cause dyslipidaemia, or induce potassium loss, while not provoking drowsiness, depression, or being associated with rebound hypertension when medication is stopped.
  • Single drug therapy for the treatment of hypertension has traditionally been a standard of practice. More recently combination therapy as first-line treatment has gained acceptance both by the medical practice community and the US Food and Drug Administration.
  • the advantages of combinations may be a synergistic or additive ant-hypertensive effect, metabolic improvement , or both.
  • the combination of a thiazide-type diuretic and a potassium-sparing diuretic has been quite useful in the past to prevent the need for potassium supplementation.
  • the combination of ⁇ -adrenoreceptor blockade and thiazide diuretic results in an additive anti-hypertensive effect that permits the effective use of very low thiazide doses.
  • each member of the combination has an additive hypertensive effect as well: however, the complimentary mechanisms are less obvious.
  • angiotensin converting enzyme inhibition has been useful in selected patients, but again the complimentary mechanisms are less obvious.
  • combinations of diuretics and beta- 1 -receptor blockers have been useful for achieving increased anti-hypertensive effect with decreased adverse drug effect.
  • the catecholamines dopamine (DA), norepinephrine and epinephrine (E) are all neuro transmitters.
  • Catecholamines possess two adjacent hydroxyl (OH) groups on a phenyl ring.
  • OH hydroxyl
  • L-tyrosine which is hydro xylated to L-3, 4-dihydroxyphenylalanine (L-dopa) by tyrosine hydroxylase.
  • L-tyrosine is actively take up into noradrenergic nerve terminals.
  • L-phenylalanine is a precursor of L-tyrosine (Blum and Kozlowski, 1990; Schwartz et al, 1992).
  • Tyrosine hydroxylase is located in the cytoplasm of noradrenergic neurons and is the rate-limiting enzyme in the synthesis of norepinephrine.
  • Extensive research has revealed that reduced pteridine cofactor, molecular oxygen and ferrous ions are all required for activity.
  • L-dopa is decarboxylated to DA by L-aromatic amino acid decarboxylase, an enzyme which requires pyridoxal phosphate (Vitamin B6) as a cofactor.
  • the dopamine (DA) is actively taken up into granular storage vesicles in which the DA is hydroxylated to form norepinephrine by the enzyme dopamine- ⁇ -hydroxylase.
  • norepinephrine is further converted to epinephrine (E) by the enzyme phenylethanolamine-N-methyltransferase.
  • Tyrosine hydroxylase activity is influenced by the following: "end product" inhibition, caused by increased concentration of norepinephrine within nerve terminals which decreases the rate of conversion of L-tyrosine into L-dopa; increased sympathetic activity from the CNS which increases the synthesis of norepinephrine; the angiotensin II mediated increases the rate of norepinephrine synthesis; and agonists (e.g., clonidine) and blockers (e.g., phentolamine) of adreno-receptors which change the rate of norepinephrine release by mechanisms involving adrenergic receptors located on the presynaptic terminal.
  • end product inhibition caused by increased concentration of norepinephrine within nerve terminals which decreases the rate of conversion of L-tyrosine into L-dopa
  • increased sympathetic activity from the CNS which increases the synthesis of norepinephrine
  • the angiotensin II mediated
  • Inhibitors of the enzymes of norepinephrine synthesis include: methyl-p-tyrosine (inhibits tyrosine hydroxylase); carbidopa (inhibits aromatic amino acid decarboxylase in tissues outside the CNS); and diethyldithiocarbonate, FAI63 and disulfiram (inhibitors of dopamine- ⁇ -hydroxylase).
  • Norepinephrine is stored within the nerve terminal in multiple storage complexes and more than one anatomical location.
  • One form of norepinephrine storage type is a granular complex found within vesicles in noradrenergic nerve terminals.
  • the granular complex consists of norepinephrine bound to ATP, several proteins collectively called chromogranins, includes dopamine- ⁇ -hydroxylase, Mg++, Zn++ and Cu++.
  • the uptake of DA and norepinephrine into storage vesicles is an active-transport process which requires ATP as an energy source and Mg++ to activate the ATPase enzyme which is Mg++ dependent.
  • This Mg++-dependent uptake process of norepinephrine and DA into storage vesicles is a separate and different process from the neuronal uptake process for norepinephrine across the nerve cell membrane, which is an Na.sup.+ /K.sup.+ -ATPase dependent.
  • the stability of the norepinephrine-ATP -protein- ion storage complex can be disrupted by some compounds which act as chelators of Mg++. This may be linked to the magnesium deficiency sometimes found in chronic cocaine abusers. In this regard, chronic administration of cocaine produces an increase in norepinephrine turnover.
  • norepinephrine from nerve terminals occurs by a process of exocytosis, which is calcium dependent, whereby a vesicular membrane fuses with the plasma membrane and the vesicular contents, consisting of norepinephrine, ATP, dopamine- ⁇ -hydroxylase and chromogranins, are released into the synaptic cleft.
  • exocytosis which is calcium dependent, whereby a vesicular membrane fuses with the plasma membrane and the vesicular contents, consisting of norepinephrine, ATP, dopamine- ⁇ -hydroxylase and chromogranins, are released into the synaptic cleft.
  • One mechanism known to control the availability of norepinephrine to postsynaptic receptors operates by means of presynaptic receptors located on the terminal from which norepinephrine is released.
  • norepinephrine in the synaptic cleft are terminated by removal from the synaptic cleft by an uptake system found on presynaptic nerve endings.
  • uptake I The actions of norepinephrine in the synaptic cleft are terminated by removal from the synaptic cleft by an uptake system found on presynaptic nerve endings.
  • uptake II There are two types of neuronal uptake of norepinephrine— uptake I and uptake II.
  • Uptake I is energy dependent, requiring ATP which is broken down by a sodium dependent ATPase. This is a high-affinity process, which means that it is efficient at the eliminating low concentrations of norepinephrine from the synaptic cleft.
  • the neuronal uptake system transports norepinephrine into the nerve terminal. Inside the nerve terminal most of the norepinephrine is taken up into storage vesicles. Inhibitors of this process include: cocaine, tri cyclic anti-depressants, amphetamine and tyramine.
  • Uptake II involves the accumulation of norepinephrine by nonneuronal tissues.
  • High plasma levels of norepinephrine derived from stimulation of the adrenal medulla, or intravenous injection of a catecholamine will be removed by uptake into non-nervous tissues such as liver, muscle and connective tissue.
  • the norepinephrine or any other catecholamine diffuses back into the circulation or, more commonly is destroyed intracellularly by the enzymes monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT).
  • MAO monoamine oxidase
  • COMP catechol-O-methyltransferase
  • MAO is found in all tissues which contain mitochondria, and is bound to their outer membranes. MAO is present in liver, brain, nerves, muscles and all actively metabolizing tissues. It oxidatively deaminates norepinephrine to 3,
  • MAO 4-dihydroxymandelic acid which can then by O-methylated (by COMT) to give rise to 3-methoxy-4-hydroxy-mandelic acid.
  • MAO describes a group of isoenzymes which possess different tissue distributions, substrate specificities, inhibitor characteristics and physical properties.
  • MAO A has a substrate preference for norepinephrine and 5HT, and is selectively inhibited by clorgyline.
  • MAO ⁇ has a substrate preference for dopamine and phenylethylamine, and is selectively inhibited by deprenyl (selegiline).
  • Other well known MAO inhibitors include iproniazid, niacinamide, pargyline, tranclypromine and phenelzine.
  • COMT is found in large quantity in liver cells. In the CNS, COMT acts on E and norepinephrine which have not been inactivated by neuronal re-uptake.
  • Pyrogallol an inhibitor works by blocking the COMT dependent transfer of a methyl group from S-adenosyl-L-methionine to the hydroxyl group at the 3' position of the catechol ring of norepinephrine, E and DA.
  • Dopamine is the precursor of norepinephrine and E, and plays a significant role in the CNS and at some ganglia in the autonomic nervous system.
  • L-dopa is actively taken up into DA neurons in the CNS where it is converted to DA. Following L-dopa therapy there is a significantly increase in the amount of DA synthesized and stored. By comparison with the dopaminergic system, there is relatively little increase in the synthesis of norepinephrine following L-dopa, treatment.
  • Dopamine is stored in storage granules where the catecholamine is complexed with chromogranins, divalent metal ions and ATP.
  • DA is believed to be released into the synaptic cleft by exocytosis. As with norepinephrine, this is a calcium dependent process and occurs in response to action potentials reaching nerve terminals or to drugs.
  • the following substances can increase DA release; cocaine, (+)-amphetamine, methylamphetamine, tyramine, amantadine, m-phenmetrazine, phentermine and nomifensine.
  • these compounds can also, to different degrees, inhibit neuronal re-uptake of DA.
  • DA neuronal re-uptake system which is a high affinity, energy-dependent active-transport process.
  • the system is similar to that already described for norepinephrine. Both MAO and COMT are responsible for the transformation of DA to 3,
  • DOPAC 4-dihydroxyphenylacetic acid
  • HVA homovanillic acid
  • Cocaine by virtue of blocking re-uptake of DA into presynaptic nerve terminals, prolongs the effect of release DA in the synaptic cleft. Elevation of brain tyrosine levels results in an increase in L-DOPA synthesis in the brain. L-DOPA in turn is metabolized to dopamine. The synthesis and release of dopamine is elevated following tyrosine administration. Without increasing catecholamine levels, dietary tyrosine increases turnover and release of dopamine and norepinephrine. Stress, cold or certain drugs, induce an increase in nerve firing to lower the levels of catecholamines in the nerve terminals.
  • L-Phenylalanine is an essential amino acid which is also a precursor for the synthesis of the neurotransmitters dopamine and norepinephrine. These neurotransmitters, as measured by their metabolites, HVA, DOPAC, and MHPH, are significantly altered during periods of intense exercise and physical endurance. L-phenylalanine may be used instead or in combination with L-tyrosine or L-dopa to restore dopamine reserves after depletion by cocaine abuse.
  • dopaminergic releasers may be supplemented at appropriate stages of treatment with dopaminergic releasers, blockers, agonists or antagonists, or agents affecting the reuptake or degradation of dopamine, norepinephrine or epinephrine.
  • opioid peptides e.g., enkephalins and endorphins
  • centrally administered opioid peptides endorphins and enkephalins
  • opioid peptides produce elevations in levels of catecholamines in blood plasma in animals and humans (Clouet, 1982).
  • blockade of presynaptic dopaminergic receptors results in an enhancement of ⁇ -endorphin release, showing a unique reciprocal relationship.
  • Compounds that may be used as precursors include L- tyrosine, L-phenyalanine, pharmaline.
  • Chromium Salts such as Picolinate, Nicotinate, etc. Dietary chromium is an essential nutrient whose value in human nutrition has been conclusively documented. Interest in chromium stems from the view that because chromium is an essential trace mineral and a cofactor to insulin, it could play a role in glucose, lipid, and amino acid metabolism by it's potentiating effects on insulin action. Supporting this argument is the observation that chromium deficiency results in impaired glucose tolerance, insulin resistance, elevated blood glucose levels, and symptoms of type 11 diabetes; in addition, adequate amounts of physiologically active forms of chromium can reduce insulin requirements in humans (Kaats et al, 1996).
  • Picolinate acid a naturally occurring metabolic derivative of tryptophan.
  • Picolinate acid appears to combine with trace metal ions in the intestines and blood, which facilitates the collection and use of essential trace metals (Evans and Bowman,
  • Chromium can potentially facilitate the maintenance or addition of fat-free mass (FFM). It has been suggested that if CrP can lower insulin resistance it can improve body composition, as insulin resistance or deficiency results in impaired entry of glucose and amino acids into muscle cells and increased catabolism of muscle protein as well as insulin deficiency's potential to accelerator lipid deposition (Kaates et al. , 1996). Other references indicate that insulin resistance may help stabilize body fat in the obese patient, albeit at an obese level, acting much like a "set point" to prevent further weight gain (Eckel, 1 92).
  • Chromium Picolinate (CrP) is the most heavily used, studied and promoted chromium compound, but in vitro work suggests that chromium nicotinate may be also viable in the area of weight loss and changes in body composition. In this regard, very recent work by the inventors suggest that the nicotinate salt may be even more important than the picolinate salt (Grant et al, 1997). These data are presented here as an example of the usefulness of Chromium Nicotinate as an addition to the basic composition of matter specified in the aspect of this work. Chromium Salts and Hypertension: Diabetes Link
  • Chromium salts are known to increase insulin sensitivity and reduce glucose intolerance and has been shown to reduce sucrose induced elevations of systolic blood pressure in SHR, the combination of D- or Dl-Phenylalanine and chromium will be most beneficial in diabetes mellitus patients showing associated hypertension. We also believe that this combination would be most beneficial in obese patients also presenting with hypertension. The combination exacts tow important benefits to these obese patients, the first being anti-glucose craving and the second being blood pressure lowing, which is important in cases of obesity and associated cardiovascular disease.
  • taurine or its synthetic derivatives such as S-2- methyltaurine (2-aminopropanesulphonic acid)
  • D- phenylalanine two important papers suggest a potential rationale, but it is unknown and therefore non-obvious that this inclusion would synergize with the blood-pressure lowing effect of our proposed composition in this invention.
  • SHRSP hypercholesterolemic
  • taurine hypercholesterolemic
  • taurine stimulates bile acid synthesis, which is closely related to the enhancement of cholesterol 7-alpha-hydroxylase activity, and thereby reduces serum cholesterol.
  • a decrease in the intestinyl acyl CoA cholesterol acyltransferase activity by taurine suggests that the inhibition of cholesterol absorption may also be related to the hypolipidemic effect of taurine.
  • SHRSP 's have hypercholesterolemic and fat deposits including cholesteryl esters in the walls in small and medium sized arteries, such as the mesenteric and cerebral arteries, when fed a HC diet for several weeks and these changes are never observed in normotensive rats (Yamori et al. Stroke, 7:120-125, 1976; Lowry et al. J. Biol.
  • vascular smoothmuscle cells from SHR and SHRSP have a higher cell prliferation and accumulate mor cholesterol than those from normotensive rats (Yamori et al. Heart Vesicles, 4:94-99, 1988; Maurakami et al. Life Sci. 56:509-520, 1995; Warrick et al. Clin Chem. 28:1379-1388, 1982).
  • Rhodiola rosea or Golden Root, is a perennial herbaceous plant of the Orpine (Crassulaceae) family, growing in the Polar Arctic and Alpine regions. In the altai mountains, in Eastern Siberia, Tien-sdhein and in the Far East, the cultivation of Rhodiola rosea has been successfully mastered. It is possible to reproduce it both from seeds and by a vegetative method (Polozhy et al, 1985; Saratikov and Krasnov, 1987).
  • Rhodiola possess stimulative and adaptogenic characteristics. It is thought that this compound improves the ability to perform physical work; reduce fatigue; shorten the recovery period after prolonged muscular workloads; and normalize cardiovascular activity.
  • Rhodiola prevent loss of micurgic phosphates in brain and muscles by optimization of the processes of oxidative phosphorylation, stabilizing the muscular activity of lipids; improving the indicators of metabolism
  • Rhodiola activation of aminacyl-t-RNA-synthetase in the skeletal muscles, increase of the RNA content, and increasing the blood supply to the muscles, especially to the brain (Saratikov et al, 1968; Saratikov, 1974). Rhodiola can increase attention span, memory; improve mental work and enhance performed work. The area of the brain involved in this activity is the thalamocortical and posterior hypothalamus (Marina et al, 1973). Various other action have been noted for Rhodiola and include; prevent development of hyper-and hypoglycemia, leukocytosis and leukopenia, erythrocytosis and erythropenia, hypoxia; reduce stress and bring about a cardio-protective action.
  • Rhodiola increases the anti-tumor resistance of the organism. It significantly inhibits the growth of experimental tumors, decrease the frequency of their metastases; prolongs the life expectancy of animals with recidivistic tumors, and decrease the outcome of spontaneous tumors (Dementyeva and Yaremenko, 1983). Their is some evidence that Rhodiola also reduces neurosis and fights exhaustion (Saratikov, 1977). S li os id (an extract of Rhodiola)
  • SAL Salidrosid
  • BBB Blood Brain Barrier
  • rhodosine which contains SAL, aglycone p-tyrosol and rosavin
  • DOPA dopamine
  • 5-HT 5-HT
  • SAL did not alter the levels of epinephrine
  • DOPA DOPA
  • the literature reveals a number of interactions with Rhodiola and neurotransmitter dynamics.
  • a decrease of dopamine in the n.accumbens may be due to preferential DA release in this area
  • an increase of 5-HT in the hypothalamus an increase of norepinephrine in the hippocampus
  • an agonistic activity of cholinergic receptors has been reported.
  • Certain mechanisms are accepted in neuroscience related to the differential roles of various neurotransmitters in terms cognition. Cholinergic mechanisms underlie the fixation of memory trace.
  • the noradrenergic system of the brain enhances positive reinforcement.
  • the serotonergic mechanisms are more involved in the process of the consolidation of memory.
  • Rhodiola extract in a single dose of 0.10 ml per rat essentially improves learning and retention after 24 h. Significant improvements of the long-term memory is also established in memory tests after 10 day treatment with the same dose of the extract.
  • Rhodiola extract had a favorable effect on the training processes using the "staircase" method with positive (food) reinforcement as well.
  • Rhodiola extract in the dose used (0.01 ml per rat) had no substantial effect on learning and memory, showing the inconsistency of this alcohol- aqueous extract.
  • Albino rats were used to study the effects of meclofenoxate and Rliodiola on the memory-impairing action of convulsant electroshock (Lazarova et al, 1986).
  • Huperzine is a compound belonging to a class know as acetylcholinesterase inhibitors. It has been shown to inhibit the enzyme that is responsible for the breakdown of acetylcholine, an important neurotransmitter, or brain chemical, which is believed to be critical in learning and memory.
  • Huperzine is a naturally occurring compound that was originally isolated from the club moss Huperzine Serrata. It has been used in Chinese folk medicine and more recently in limited clinical trials conducted in China as a treatment for age-related memory disorders. Results suggest that it improves learning and memory in certain patients. However, these suggested results have not been substantiated by clinical trials. This natural substance is contemplated for use with the composition of matter claimed in this patent to affect attentional processing.
  • the recommended dose to enhance memory is 150 ⁇ g daily (the therapeutic range is 1.50 to 1,500 meg daily).
  • the effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine.
  • Scopolamine (0.2 mg/kg) significantly impaired spatial memory in rats.
  • Huperzine A (0.1-0.4 mg/kg, by mouth [p.o.])
  • E2020 0.5-1.0 mg/kg, p.o.
  • tacrine 1.0-2.0 mg/kg, p.o.
  • huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, indicating it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease (Cheng et al, 1996).
  • Huperzine A a novel, potent, reversible, and selective acetylcholinesterase (AChE) inhibitor has been expected to be superior to other AChE inhibitors now for the treatment of memory deficits in patients with Alzheimer's disease.
  • AF64A (2 nmol per side, i.c.v.) caused significant impairment in rats' ability to perform the spatial working memory task. This behavioral impairment was associated with a significant decrease in the activity of choline acetyltransferase (ChAT) in the hippocampus.
  • ChAT choline acetyltransferase
  • Huperzine A (0.4-0.5 mg kg-1, i.p.) significantly ameliorated the AF64A-induced memory deficit.
  • HuperazonTM A major component of HuperazonTM is a proprietary extract of the club moss, Huperzia serrata used to treat Alzheimer's. Studies carried out in China indicated that the active substance in this extract Huperzine A. is a promising new treatment for Alzheimer's disease. Other studies indicate that Huperzine A is a superior acetylcholinesterase (AChE) inhibitor with excellent penetration into the CNS and a remarkable in vivo half-life. Two double-blind clinical trials carried out in China demonstrate that Huperzine A is both safe and effective for the long term treatment of
  • AChE acetylcholinesterase
  • Huperzine A has other neuroprotective functions: Huperzine A inhibits glutamate-induced cytotoxicity in cultures of rat neonatal hippocampal and cerebella neurons; Huperzine A promotes dendrite outgrowth of neuronal cultures.
  • Alzheimer's disease is characterized by abnormalities and degeneration of neurons which depend upon acetylcholine and acetylcholine esterase for normal activity and viability. These cells located in the basal forebrain are also implicated in other neurological diseases such as Parkinson's disease.
  • Huperzine A is a potent inhibitor of acetylcholine esterase, superior in activity to Cognex ® , the first drug licensed in the USA for Alzheimer's disease and E2020 which was licensed recently by Eisai Pharmaceuticals.
  • Huperzine A has been shown to protect neuronal cells in culture from death caused by the excitoamino acid glutamate. Because of the dual pharmacological action of Huperzine A, HuperazonTM provides a unique and important activity for the treatment of attention deficit and senile memory deficits. Toxicology and efficacy studies of Huperzine A show it to be non-toxic even when administered at 50-100 times the human therapeutic dose.
  • the extract is active for 6 h at a dose of 2 ⁇ g/kg with no remarkable side effects.
  • Huperzine A is highly specific for brain acetylcholine esterase (AChE) vs. AChE found elsewhere in the body. This selectivity is believed to be responsible for the relatively low toxicity of the extract.
  • Huperzine A has been shown to lack binding to receptors in the CNS that can cause side effects such as the muscarinic receptors Ml and M2.
  • compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
  • Circulatory System Symptoms Cardiovascular Disease, Circulation, High Blood Pressure, Low Blood
  • Hawthorn berries have been used since the 19th century to support the heart and normalize cardiovascular functions.
  • hawthorn berries are one of the most popular herbs used in Europe.
  • Hawthorn berries appear to work best when taken as a preventative herb, possibly helping reduce the risk of cardiovascular disease.
  • hawthorn berries With its high content of biofiavonoids, hawthorn berries best support the heart- The bioflavonoid substances help dilate and strengthen the walls of blood vessels, relax arteries, and improve circulation of blood to heart muscles. Hawthorn berries help normalize the heart, either by stimulating or depressing its activity. For this reason, hawthorn berries are used to lower high blood pressure and high cholesterol, as well as increase low blood pressure.
  • hawthorn berries When used to support weight loss programs, hawthorn berries reduce water retention expelling excess salt from the body. Hawthorn berries have also been known to reduce nervous tension, alleviate insomnia and aid digestion.
  • Hawthorn is a heart and circulatory tonic. It strengthens weak or damaged heart tissue by allowing oxygen to be better utilized by the heart muscle. It has been shown to be a valuable aid for feeble heart action, irregular pulse and preventing hardening of the arteries. Its anti-spasmodic properties assist in angina pectoris, it is valuable for palpitations, arteriosclerosis, high blood pressure, inflammation of the heart muscle, and valvular insufficiency.
  • Hawthorn Berries (Craraegus oxyacantha)
  • One important focus of the present invention is a method for effecting an anti- hypertensive therapy in animals which involves the step of administering to the animals a substance that inhibits the destruction of enkephalins or endorphins.
  • a substance is usually an inhibitor of enkephalinase or endorphinase a prototypical substance being D-phenylalanine.
  • D-phenylalanine may be administered orally or parenterally and is useful for the lowering of blood pressure in hypertensive humans. In many cases the racemic D,L- phenylalanine may be used for the same purpose.
  • One effective dosage of D-phenylalanine is administration at about 2 to 4 grams per patient daily.
  • Such administration may be accompanied by numerous substances, including an adrenergic beta blocker such as propranolol.
  • Analygous antihypertensive results are obtainable by the administration of D-leucine or D,L- leucine. This may be in combination with D- or D,L-phenylalanine.
  • drug: bestatin; thiorphan; captopril; or puromyein may be used as hypertensive agents, perhaps in combination with D- phenylalanine or D,L- phenylalanine administration.
  • the enkephlinase or endorphinase inhibitors are a component of a dietary supplement.
  • a dietary supplement might be complimented with other substances such as D-Ribose. It has been found that hydrocinnamic acid is also useful for inhibiting endorphinase or enkephalinase and controlling hypertension.
  • an endorphinase or enkephalinase inhibitor may be conducted with positive effects in combination with the administration of at least one of ferrulic acid, pharmaline-P, huperzine-H, a chromium salt selected from at least one of chromium picolinate, chromium nicotinate, and chromium polynicotinate.
  • Co-enzyme Co-enzyme, Q Pycogenol and Hawthorn or Hawthorn extract.
  • enkephalinase or endorphinase inhibitors may be in combination with a diuretic, a sympatholytic, a direct vasodilator, an angiotensin- converting enzyme inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a T-type calcium antagonist including, nisoldipene, losartin, moxonidine and fenoldopam.
  • an inhibitor of endorphinase or enkephalinase might be combined with a source of magnesium known to aid in the treatment of hypertension.
  • Such endorphinase or enkephalinase inhibitors might be in combination with other substances such as Rhodiola rhosea extract (pharmaline) or Salidrosid. Additionally, it may be in combination with Huperzine, Hawthorn berry or Hawthorn berry extract. Additionally, an adrenergic-beta-blocking agent may also be of value in combination with such endorphinase or enkephalinase inhibitors for the reduction of hypertension.

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Abstract

L'invention concerne une nouvelle catégorie d'agents efficaces contre l'hypertension: ces produits inhibent la destruction des substances endogènes, à savoir les enképhalines ou les endorphines. L'action hypotensive d'un inhibiteur de ces substances est considérablement améliorée si on combine le produit avec un bêtabloquant. Spécifiquement, la D-phénylalanine est un inhibiteur du type considéré, si on l'utilise seule, et cet inhibiteur donne d'excellents résultats quant à la réduction de la pression sanguine chez l'animal et l'homme. La combinaison de D-phénylalanine et de propranolol bêtabloquant améliore considérablement l'action hypotensive chez le rat spontanément hypertendu. La réduction de la pression sanguine par administration de D-phénylalanine, ou par administration de la combinaison susmentionnée, a un effet très durable chez le rat spontanément hypertendu et chez l'homme. Si la pression sanguine chez le rat et chez l'homme est normale, la D-phénylalanine produit un effet réduit ou bien est inopérante sur la pression sanguine. On prévient l'action hypotensive de ce produit en effectuant chez le rat spontanément hypotendu un prétraitement à base de naloxone et de naltrexone, ces deux substances étant des antagonistes spécifiques vis-à-vis des enképhalines ou des endorphines.
PCT/US2000/000722 1999-01-12 2000-01-12 Traitement de l'hypertension avec des composes inhibant la destruction des enkephalines ou des endorphines WO2000041686A1 (fr)

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CA002363847A CA2363847A1 (fr) 1999-01-12 2000-01-12 Traitement de l'hypertension avec des composes inhibant la destruction des enkephalines ou des endorphines
AU25027/00A AU2502700A (en) 1999-01-12 2000-01-12 Treatment of hypertension with compounds that inhibit the destruction of enkephalins or endorphins
EP00903252A EP1158972A4 (fr) 1999-01-12 2000-01-12 Traitement de l'hypertension avec des composes inhibant la destruction des enkephalines ou des endorphines

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WO2003094934A1 (fr) * 2002-05-14 2003-11-20 Nipro Corporation Médicament pour prévenir et traiter l'amyloïdose
WO2017165699A1 (fr) * 2016-03-23 2017-09-28 Bioadatp, Llc Composition et méthode ayant une influence sur l'enképhaline

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US5238932A (en) * 1992-05-20 1993-08-24 Merrell Dow Pharmaceuticals Inc. Mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
US5420271A (en) * 1992-08-24 1995-05-30 Merrell Dow Pharmaceuticals, Inc. 2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
US5425954A (en) * 1993-09-30 1995-06-20 Curafas Incorporated Topical amino acid - vitamin complex compositions for pharmaceutical and cosmetic use

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US5420271A (en) * 1992-08-24 1995-05-30 Merrell Dow Pharmaceuticals, Inc. 2-substituted indane-2-mercaptoacetylamide tricyclic derivatives useful as inhibitors of enkephalinase
US5425954A (en) * 1993-09-30 1995-06-20 Curafas Incorporated Topical amino acid - vitamin complex compositions for pharmaceutical and cosmetic use

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See also references of EP1158972A4 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003094934A1 (fr) * 2002-05-14 2003-11-20 Nipro Corporation Médicament pour prévenir et traiter l'amyloïdose
WO2017165699A1 (fr) * 2016-03-23 2017-09-28 Bioadatp, Llc Composition et méthode ayant une influence sur l'enképhaline
US9937146B2 (en) 2016-03-23 2018-04-10 Bioadatp, Llc Enkephalin-influencing composition and method
US10413523B2 (en) 2016-03-23 2019-09-17 Bioadatp, Llc Enkephalin-influencing composition and method

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AU2502700A (en) 2000-08-01
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CA2363847A1 (fr) 2000-07-20

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