US3868451A - Adenosine-5{40 -esters in treating angina pectoris - Google Patents

Adenosine-5{40 -esters in treating angina pectoris Download PDF

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US3868451A
US3868451A US356530A US35653073A US3868451A US 3868451 A US3868451 A US 3868451A US 356530 A US356530 A US 356530A US 35653073 A US35653073 A US 35653073A US 3868451 A US3868451 A US 3868451A
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adenosine
acetate
angina pectoris
coronary
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Herman Hal Stein
Thomas Dillard Darby
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • Angina pectoris is a coronary syndrome characterized by a special type of paroxysmal sensation of pressing or strangling pain usually located behind the sternum or in the precordial region. The pain often radiates to the back of the left arm but may often radiate elsewhere. The attacks can vary greatly in severity and frequency.
  • angina pain rises from an imbalance in the heart between the supply of and the demand for oxygen.
  • the pain is usually brought about by episodes of extremeemotional stress, exposure to cold, excitement or any other stressful situation.
  • any sudden increase in cardiac work any decrease in coronary blood flow or, any interference with oxygenation of the blood may cause an attack.
  • anginal attacks can occur while the patient is sleeping. Therefore, anginal pain is not necessarily due to'a decrease of blood flow but rather to an insufficiency of the flow in relation to the metabolic requirements or oxygen demands of the heart.
  • nitroglycerin is probably the most widely used agent in managing acute attacks of angina, however, there has been a long standing need for a prophylactic agent which when ad; ministered to patients with a history of, or who are susceptible to attacks of angina pectoris, will prevent or reduce the severity of future attacks.
  • adenosine-5 '-esters to be orally active, long acting anti-anginal agents.
  • the esters act as sparing agents, that is, not like adenosine itself, the compounds useful in the practice of this invention, increase the myocardial efficiency, reduce the amount of oxygen required by the heart, and reduce the actual cardiac wdrk.
  • Such activity is wholly unexpected, since the parent compound, adenosine is not orally active, is very rapidly metabolized and does not increase coronary sinus p and thus is not suitable as a therapeutic agent.
  • adenosine and adenosine-5'-acetate lowered blood pressure in mice and had some effect as vasodilators, they reported adenosine 5'-a cetates blood pressure lowering effect to be only one-sixth to onethirtieth that of adenosine itself, and further reported that adenosine-5 '-acetate was times weaker as a coronary dilator in isolated, profused guinea pig heart. Since adenosine is not orally active, and is so rapidly metabolized that it, is useless as a therapeutic agent, one
  • R is C -C alkyl.
  • -C C refers to both straight and branched chain alkyl groups such as methyl, ethyl, n-propyl and iso-propyl.
  • the compounds of this invention can be prepared according to the method described by Brown et al., J. Chem. Soc. 1950, 3299 (1956).
  • adenosine-5 acetate is an excellent orally-active anti-anginal agent when administered to animals in dosages of from-0.5 to 100 mg./kg. preferably 15-30 mg./kg. of body weight daily.
  • adenosine-5'-acetate is administered daily in divided doses as a prophylactic agent to prevent anginal attacks.
  • administration of adenosine- 5'-acetate will be instituted at the onset of an anginal attack and at intervals to prevent further attacks.
  • Adenosine-5'-acetate has been found to increase coronary sinus partial pressure of oxygen (p0 when administered to mammals in dosages of from 0.5 to 100 v mg./kg. of body weight daily either orally or by intravenous, intraportal and intraduodenal routes.
  • p0 coronary sinus partial pressure of oxygen
  • adenosine-5-acetate is the preferred compound
  • the corresponding propionate, butyrate and valerate will also increase coronary sinus pO when administered to mammals in dosages of from 5,to mg./kg. of body weight daily.
  • the above compounds also exhibit oral activity.
  • the anti-anginal activity of the compounds useful in the practice of this invention were established according to the method described by Schoepke et al., Pharmacologist 8:204, (1966).
  • dogs are treated first with 5 mg./kg. of morphine administered subcutaneously and then they are anesthetized with 250 mg./kg. of barbital, administered intravenously.
  • the femoral artery is cannulated for blood pressure measurements.
  • Lead ll of the electrocardiogram is recorded and the R-wave is used to trigger a tachygraph for heart rate determinations.
  • the animals are placed on artificial respiration using room air and a positive pressure respirator.
  • the right chest of each dog is opened and a cannula is placed in the coronary sinus from an incision in the right arterial appendage.
  • a Beckman micro-electrode for measuring p0 is placed in the blood obtained from the coronary sinus.
  • the drug is suspended in 50% propylene glycol and water for intravenous, intraportal and intraduodenal administration. Filled capsules are used for oral administration.
  • the results obtained with adenosine-5-acetate with various dosage levels of administration are summarized in the following tables.
  • Adenosine-5-acetate was evaluated as an antianginal agent following the above Schoepke et al method over a dosage range of from 0.5 to 30 mg./kg. of body weight. As can be seen from Table l, adenosine-5-acetate greatly increases the coronary sinus p02.
  • EXAMPLE 2' Adenosine-5'-acetate was administered orally to unanesthetized, closed-chest dogs having an indwelling catheter in the coronary sinus to determine the effect on coronary sinus p
  • the average effect on coronary sinus p0 is summarized in Tables 2a and 2b.
  • EXAMPLE 3 Three anesthetized dogs, prepared according to the method of Schoepke etal. received 5 mg./kg. of adenosine-5-acetate intravenously, and the effect ofthe drug on various hemodynamic parameters were recorded. As can be seen from Table 3, 5 mg./kg. of adenosine- 5'-acetate decreases the left ventricular work by an average of 45%. The work decrease is considered by physicians to be therapeutically beneficial in the treatment of angina pectoris. It should be noted that adenosine, on the other hand, is reported to increase cardiac work (G. Rowe et al., Am. Heart J., 64, 228, 1962).
  • Adenosinc-S '-acetatc l 83 active Adenosine I I2 60+ inactive Adenosinc-S '-aectate 2 (ml 60 active Adcnosine 2 0 0 inactive
  • the present invention includes within its scope pharmaceutical compositions comprising adenosine- 5-acetate in association with a pharmaceutically acceptable carrier or diluent.
  • Adenosine-5-acetate exhibits both oral and parenteral activity and can be formulated in dosage forms for oral, sublingual, parenteral or rectal administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. ln such solid dosage forms, the active compound is admixed with at least one inert diluent such as sucrose; lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixers containing inert diluents commonly used in the art, such as water. Beside inert diluents, such compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
  • Preparations according to this invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions.
  • non-aqueous vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile, injectable medium immediately before use.
  • compositions for rectal administration are suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
  • the dosage of active ingredient in the composition of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of treatment.
  • adenosine-5'-acetate is administered in dosage levels of from 0.5 to 30 mg./kg. of body weight daily to patients in need of coronary oxygen increase or who are susceptible to attacks of angina pectoris.
  • LD in mice of I000 mg./kg. because of the low toxicity of the adenosine-5-acetate (LD in mice of I000 mg./kg.) dosages of up to mg./kg. or more can be administered if desired.
  • the method of increasing the supply of coronary sinus oxygen in a mammalian patient in need of said coronary oxygen increase comprising orally administering to said patient a therapeutically effective amount of a compound of the formula ITIHz OH OH wherein R is C -C alkyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A method of preventing and/or decreasing the severity of attacks of angina pectoris by administering adenosine-5''-ester to a patient suffering from or having a history of such attacks.

Description

United States Patent [191 Stein et al.
[451 Feb. 25, 1975 ADENOSINE-5'-ESTERS IN TREATING ANGINA PECTORlS [75] Inventors: Herman Hal Stein, Skokie, lll.;
Thomas Dillard Darby, Milford Court, Ky.
[73] Assignee: Abbott Laboratories, North Chicago, Ill.
[22] Filed: May 2, 1973 [21] Appl. No.: 356,530
Related U.S. Application Data [63] Continuation of Ser. No. 129,606, March 30, 1971, abandoned, and a continuation-in-part of Ser. No. 28,916, April I5, 1970, abandoned.
[52] U.S. Cl. 424/180, 424/253 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/253, 180
[56] References Cited OTHER PUBLICATIONS Giertz et al., Arch. Exper. Path. u. Pharmakol., Bd. 229, pp. 26-33, (1956).
Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Robert L. Niblack; Joyce R. Krei; Vincent A. Mallare 4 Claims, NoDrawings 1 ADE QS1 r5.'- $IEB IN .IBEATINQANG NA PEC TORIS CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation of Ser. No. 129,606, filed Mar. 30, 1971 and a continuation-inpart of Ser. No. 28,916 filed Apr. 15, 1970, both are now abandoned.
DETAILED DESCRIPTION OF THE INVENTION Angina pectoris is a coronary syndrome characterized by a special type of paroxysmal sensation of pressing or strangling pain usually located behind the sternum or in the precordial region. The pain often radiates to the back of the left arm but may often radiate elsewhere. The attacks can vary greatly in severity and frequency.
Generally speaking, angina] pain rises from an imbalance in the heart between the supply of and the demand for oxygen. The pain is usually brought about by episodes of extremeemotional stress, exposure to cold, excitement or any other stressful situation. In summation, any sudden increase in cardiac work, any decrease in coronary blood flow or, any interference with oxygenation of the blood may cause an attack. However, anginal attacks can occur while the patient is sleeping. Therefore, anginal pain is not necessarily due to'a decrease of blood flow but rather to an insufficiency of the flow in relation to the metabolic requirements or oxygen demands of the heart.
There are several available drugs useful in the management of angina pectoris attacks. Most of the therapeutic agents, such as nitroglycerin and related nitrites are coronary dilators which do not effect the underlying coronary artery pathology or myocardial cardiac damage. Accordingly, currently available therapy is symptomatic rather than curative. Nitroglycerin is probably the most widely used agent in managing acute attacks of angina, however, there has been a long standing need for a prophylactic agent which when ad; ministered to patients with a history of, or who are susceptible to attacks of angina pectoris, will prevent or reduce the severity of future attacks.
We have found certain adenosine-5 '-esters to be orally active, long acting anti-anginal agents. The esters act as sparing agents, that is, not like adenosine itself, the compounds useful in the practice of this invention, increase the myocardial efficiency, reduce the amount of oxygen required by the heart, and reduce the actual cardiac wdrk. Such activity is wholly unexpected, since the parent compound, adenosine is not orally active, is very rapidly metabolized and does not increase coronary sinus p and thus is not suitable as a therapeutic agent.
Geitz et al. first reported adenosine-5-acetate as a new ester of adenosine having analgesic and antipyretic activity, Arch. Exper. Path u.'Pharmak0l., Bd. 229, pp. 26-33 (1956). While Gietz el al. observed that both adenosine and adenosine-5'-acetate lowered blood pressure in mice and had some effect as vasodilators, they reported adenosine 5'-a cetates blood pressure lowering effect to be only one-sixth to onethirtieth that of adenosine itself, and further reported that adenosine-5 '-acetate was times weaker as a coronary dilator in isolated, profused guinea pig heart. Since adenosine is not orally active, and is so rapidly metabolized that it, is useless as a therapeutic agent, one
OH OH wherein R is C -C alkyl. The term -C C as used herein refers to both straight and branched chain alkyl groups such as methyl, ethyl, n-propyl and iso-propyl.
The compounds of this invention can be prepared according to the method described by Brown et al., J. Chem. Soc. 1950, 3299 (1956).
We have found that adenosine-5 acetate is an excellent orally-active anti-anginal agent when administered to animals in dosages of from-0.5 to 100 mg./kg. preferably 15-30 mg./kg. of body weight daily. Generally speaking, adenosine-5'-acetate is administered daily in divided doses as a prophylactic agent to prevent anginal attacks. Normally, administration of adenosine- 5'-acetate will be instituted at the onset of an anginal attack and at intervals to prevent further attacks.
Adenosine-5'-acetate has been found to increase coronary sinus partial pressure of oxygen (p0 when administered to mammals in dosages of from 0.5 to 100 v mg./kg. of body weight daily either orally or by intravenous, intraportal and intraduodenal routes. However, it is preferred to administer the compound orally in a suitable dosage form such as tablets, pills, filled capsules and the like.
While adenosine-5-acetate is the preferred compound, we have also found that the corresponding propionate, butyrate and valerate will also increase coronary sinus pO when administered to mammals in dosages of from 5,to mg./kg. of body weight daily. The above compounds also exhibit oral activity.
The anti-anginal activity of the compounds useful in the practice of this invention were established according to the method described by Schoepke et al., Pharmacologist 8:204, (1966). Generally speaking, using the Schoepke method, dogs are treated first with 5 mg./kg. of morphine administered subcutaneously and then they are anesthetized with 250 mg./kg. of barbital, administered intravenously. The femoral artery is cannulated for blood pressure measurements. Lead ll of the electrocardiogram is recorded and the R-wave is used to trigger a tachygraph for heart rate determinations. The animals are placed on artificial respiration using room air and a positive pressure respirator. The right chest of each dog is opened and a cannula is placed in the coronary sinus from an incision in the right arterial appendage. A Beckman micro-electrode for measuring p0 is placed in the blood obtained from the coronary sinus. The drug is suspended in 50% propylene glycol and water for intravenous, intraportal and intraduodenal administration. Filled capsules are used for oral administration. The results obtained with adenosine-5-acetate with various dosage levels of administration are summarized in the following tables.
EXAMPLE I Adenosine-5-acetate was evaluated as an antianginal agent following the above Schoepke et al method over a dosage range of from 0.5 to 30 mg./kg. of body weight. As can be seen from Table l, adenosine-5-acetate greatly increases the coronary sinus p02.
TABLE 1 EFFECT OF ADENOSINE-5'-ACETATE ON No EKG changes were observed. Blood pressure and heart rate effects were small and variable, although both tended to decrease in response tovthe drug.
EXAMPLE 2' Adenosine-5'-acetate was administered orally to unanesthetized, closed-chest dogs having an indwelling catheter in the coronary sinus to determine the effect on coronary sinus p The average effect on coronary sinus p0 is summarized in Tables 2a and 2b.
TABLE 2a EFFECT OF ADENOSINE--ACETATE ON PEAK CORONARY smus Po2 BY ORAL ADMINISTRATION IN UNANESTHETIZED DOGS Dose Peak pO Time to Increase Increase in mg/kg (mm Hg) Peak (hrs) in pO p0 (mm Hg) Controls l5 TABLE 2!) EFFECT OF ADENOSINE 5'ACETATE ON CORONARY SINUS p0 BY ORAL ADMINISTRATION IN UNANESTHETIZED DOGS Dose Number of Onset Duration mg/kg Experiments (hrs) (hrs) Gelatin 3 Capsule alone 4 TABLE 217 Continued EFFECT OF ADENOSINE 5'-ACETATE ON CORONARY SINUS p0 BY ORAL ADMINISTRATION IN UNANESTHETIZED DOGS Dose Number of Onset Duration mg/kg Experiments (hrs) (hrs) It can be seen from Tables 2a and 2b that in unanesthetized dogs, adenosine-5'-acetate is orally active and that the effect is dose-respondent over the test range of l530 mg./kg.
EXAMPLE 3 Three anesthetized dogs, prepared according to the method of Schoepke etal. received 5 mg./kg. of adenosine-5-acetate intravenously, and the effect ofthe drug on various hemodynamic parameters were recorded. As can be seen from Table 3, 5 mg./kg. of adenosine- 5'-acetate decreases the left ventricular work by an average of 45%. The work decrease is considered by physicians to be therapeutically beneficial in the treatment of angina pectoris. It should be noted that adenosine, on the other hand, is reported to increase cardiac work (G. Rowe et al., Am. Heart J., 64, 228, 1962).
TABLE 3 EFFECT OF ADENOSINE-5'-ACETATE (5 mg/kg I.V.) ON HEMODYNAMIC PARAMETERS (rt-3) IN ANESTHETIZED DOGS Aortic pressure -20 Heart rate +20 Cardiac output '-25 (after transient increase) ITI' +60 (Index of Contractility) Resistance 35 (then a gradual increase) Left ventricular work 45 Stroke volume 30 EXAMPLE 4 Adenosine-5-acetate and adenosine were evaluated in a cross-over study to compare the effect of both substances on coronary sinus p0 As can be seen from Table 4, adenosine does not significantly effect coronary sinus p0 TABLE 4 CROSSOVER STUDY WITH ADENOSINE-5'-ACETATE AND ADENOSINE p0 Overall Drug Dog change Duration activity (15 mg/kg. i.d.) No. min. rating Adenosinc-S '-acetatc l 83 active Adenosine I I2 60+ inactive Adenosinc-S '-aectate 2 (ml 60 active Adcnosine 2 0 0 inactive The present invention includes within its scope pharmaceutical compositions comprising adenosine- 5-acetate in association with a pharmaceutically acceptable carrier or diluent. Adenosine-5-acetate exhibits both oral and parenteral activity and can be formulated in dosage forms for oral, sublingual, parenteral or rectal administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. ln such solid dosage forms, the active compound is admixed with at least one inert diluent such as sucrose; lactose or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixers containing inert diluents commonly used in the art, such as water. Beside inert diluents, such compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of non-aqueous vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile, injectable medium immediately before use.
Compositions for rectal administration are suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
The dosage of active ingredient in the composition of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of treatment. Generally, adenosine-5'-acetate is administered in dosage levels of from 0.5 to 30 mg./kg. of body weight daily to patients in need of coronary oxygen increase or who are susceptible to attacks of angina pectoris. However, because of the low toxicity of the adenosine-5-acetate (LD in mice of I000 mg./kg.) dosages of up to mg./kg. or more can be administered if desired.
We claim:
1. The method of increasing the supply of coronary sinus oxygen in a mammalian patient in need of said coronary oxygen increase comprising orally administering to said patient a therapeutically effective amount of a compound of the formula ITIHz OH OH wherein R is C -C alkyl.
2. The method of claim 1 wherein the compound is adenosine-5'-acetate.
3. The method of claim 2 wherein from about 0.5 to about 100 mg./kg. of adenosine-5'-acetate is administered to said patient.
4. The method of claim 3 wherein adenosine- 5-acetate is administered orally to said patient.

Claims (4)

1. THE METHOD OF INCREASING THE SUPPLY OF CORONARY SINUS OXYGEN IN A MAMMALIAN PATIENT IN NEED OF SAID CORONARY OXYGEN INCREASE COMPRISING ORALLY ADMINISTERING TO SAID PATIENT A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA
2. The method of claim 1 wherein the compound is adenosine-5''-acetate.
3. The method of claim 2 wherein from about 0.5 to about 100 mg./kg. of adenosine-5''-acetate is administered to said patient.
4. The method of claim 3 wherein adenosine-5''-acetate is administered orally to said patient.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0071926A1 (en) * 1981-08-10 1983-02-16 Fujisawa Pharmaceutical Co., Ltd. New ribofuranuronic acid derivatives, processes for preparation thereof and pharmaceutical compositions thereof
WO1988002258A1 (en) * 1986-10-06 1988-04-07 The University Of Virginia Alumni Patents Foundati Use of an adenosine, hypoxanthine and ribose-containing solution for improved protection of the heart during surgery
WO1994013687A1 (en) * 1992-12-08 1994-06-23 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US5470838A (en) * 1987-10-28 1995-11-28 Pro-Neuron, Inc. Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine
US5573772A (en) * 1993-03-15 1996-11-12 Gensia, Inc. Methods for protecting tissues and organs from ischemic damage
US5583117A (en) * 1987-10-28 1996-12-10 Pro-Neuron, Inc. Acylated uridine and cytidine for elevating tissue uridine and cytidine
US5691320A (en) * 1987-10-28 1997-11-25 Pro-Neuron, Inc. Acylated pyrimidine nucleosides for treatment of systemic inflammation and inflammatory hepatitis
US6297222B1 (en) * 1987-10-28 2001-10-02 Pro-Neuron, Inc. Acyl deoxyribonucleoside derivatives and uses thereof
US6329350B1 (en) 1987-10-28 2001-12-11 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US20030212036A1 (en) * 1994-07-01 2003-11-13 Pro Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory heptitis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Giertz el al., Arch. Exper. Path u. Pharmakol., Bd. 229, pp. 26-33 (1956). *

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0071926A1 (en) * 1981-08-10 1983-02-16 Fujisawa Pharmaceutical Co., Ltd. New ribofuranuronic acid derivatives, processes for preparation thereof and pharmaceutical compositions thereof
US4479942A (en) * 1981-08-10 1984-10-30 Fujisawa Pharmaceutical Co., Ltd. Tetrahydrofurnancarboxylic acid derivatives, processes for preparation thereof and pharmaceutical compositions thereof
WO1988002258A1 (en) * 1986-10-06 1988-04-07 The University Of Virginia Alumni Patents Foundati Use of an adenosine, hypoxanthine and ribose-containing solution for improved protection of the heart during surgery
US4880783A (en) * 1986-10-06 1989-11-14 University Of Virginia Alumnia Patents Foundation Use of adenosine, hypoxanthine and ribose-containing solution for improved protection of the heart during surgery
US6258795B1 (en) 1987-10-28 2001-07-10 Pro-Neuron, Inc. Acylated uridine and cytidine and uses thereof
US6316426B1 (en) 1987-10-28 2001-11-13 Pro-Neuron, Inc. Acylated uridine and cytidine and uses thereof
US7173017B1 (en) 1987-10-28 2007-02-06 Wellstat Therapeutics Corporation Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US5583117A (en) * 1987-10-28 1996-12-10 Pro-Neuron, Inc. Acylated uridine and cytidine for elevating tissue uridine and cytidine
US5691320A (en) * 1987-10-28 1997-11-25 Pro-Neuron, Inc. Acylated pyrimidine nucleosides for treatment of systemic inflammation and inflammatory hepatitis
US6232298B1 (en) 1987-10-28 2001-05-15 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US7105498B2 (en) 1987-10-28 2006-09-12 Wellstat Therapeutics Corporation Acylated uridine and cytidine and uses thereof
US6274563B1 (en) 1987-10-28 2001-08-14 Pro-Neuron, Inc. Acylated uridine and cytidine and uses thereof
US6297222B1 (en) * 1987-10-28 2001-10-02 Pro-Neuron, Inc. Acyl deoxyribonucleoside derivatives and uses thereof
US5470838A (en) * 1987-10-28 1995-11-28 Pro-Neuron, Inc. Method of delivering exogenous uridine or cytidine using acylated uridine or cytidine
US6329350B1 (en) 1987-10-28 2001-12-11 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US20020035086A1 (en) * 1987-10-28 2002-03-21 Pro Neuron, Inc. Acylated uridine and cytidine and uses thereof
US20040220134A1 (en) * 1987-10-28 2004-11-04 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US20040033981A1 (en) * 1987-10-28 2004-02-19 Pro-Neuron Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
CN1089239C (en) * 1992-12-08 2002-08-21 普罗神经细胞有限公司 Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
WO1994013687A1 (en) * 1992-12-08 1994-06-23 Pro-Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis
US5573772A (en) * 1993-03-15 1996-11-12 Gensia, Inc. Methods for protecting tissues and organs from ischemic damage
US20030212036A1 (en) * 1994-07-01 2003-11-13 Pro Neuron, Inc. Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory heptitis
US7709459B2 (en) 1994-07-01 2010-05-04 Wellstat Therapeutics Corporation Pyrimidine nucleotide precursors for treatment of systemic inflammation and inflammatory hepatitis

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