AU643487B2 - Use of optically pure s(-) atenolol for the treatment of cardiovascular disorders - Google Patents
Use of optically pure s(-) atenolol for the treatment of cardiovascular disordersInfo
- Publication number
- AU643487B2 AU643487B2 AU68933/91A AU6893391A AU643487B2 AU 643487 B2 AU643487 B2 AU 643487B2 AU 68933/91 A AU68933/91 A AU 68933/91A AU 6893391 A AU6893391 A AU 6893391A AU 643487 B2 AU643487 B2 AU 643487B2
- Authority
- AU
- Australia
- Prior art keywords
- atenolol
- beta
- medicament
- treatment
- cardiovascular disorders
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Use of optically pure (S)-atenolol for the treatment of cardiovascular disorders.
Description Background
Atenolol is a drug belonging to the general class of compounds known as beta-blockers.
Beta-blockers include beta1 - selective (cardio- selective) adrenoreceptor blocking agents, which are exemplified by such well-known commercial products such as Tenormin.
Atenolol is a potent cardiac regulator, which has both beta-blocking and ant ihyp ertens ive
activity. The beta- adrenoreceptor blocking activity of atenolol is characterized by a reduction in resting and exercize heart rate and cardiac output, a reduction in the systolic and diastolic blood pressure at rest and on exercise, inhibition of isopro terenol-induced tachycardia and reduction in reflex orthostatic tachycardia. A significant beta-blocking effect of atenolol is apparent within one hour following oral administration of a single dose. By blocking the positive chronotropic and inotropic effects of catecholamines and by
decreasing blood ressure, atenolol generally
reduces the oxygen requirements of the heart, at any given level of effort.
Atenolol is a racemic mixture. That is, it is a mixture of optical isomers, called enantiomers.
Enantiomers are organic compounds which differ only in that one isomer is a mirror image of the other and the mirror images cannot be superimposed. This phenomenon is known as chirality. Most biological molecules exist as enantiomers and exhibit
chirality. Although structurally identical,
enantiomers can have profoundly different effects in biological systems: one enantiomer is often biologically active while the other has little or no biological activity at all.
Summary of the Invention
The present invention relates to a method of treating cardiovascular disorders, including angina pectoris and hypertension, in an individual
comprising administering to the individual a beta- blocking or antihypertensive amount of the S (-) enantiomer of atenolol, which is substantially free of the R(+) enantiomer. The method is useful in treating cardiovascular disorders and in treating hypertension while reducing (decreasing or
eliminating) undesirable side effects. In these applications, it is important to have a beta- blocking and anti-hypertensive composition which reduces these side effects. A composition
containing the S (-) isomer of atenolol is
particularly useful for this application because the S (-) isomer exhibits both of these desired
characteristics.
The present method is useful for treating cardiac disorders, for example, associated with angina pectoris and/or hypertension.
Brief Description of the Drawings
Figure 1 is a graph showing the effects of various amounts of RS, R or S atenolol on
isoprenaline (0.05 μg/kg, iv) induced tachycardia
(heart rate, HR) and diastolic blood pressure (DBP) responses in the pithed rat.
Figure 2 is a graph showing the effects of various amounts of RS, R or S atenolol on the resting heart rate in the pithed rat.
Figure 3 is a graph showing the effects of various amounts of propanolol (RS), or RS, R or S atenolol on the contractile tension of an isolated, electrically driven atrial muscle preparation.
Detailed Description of the Invention
The present invention relies on the beta- blocking activity of the S (-) levorotatory
enantiomer of atenolol, referred to as S (-) atenolol, to provide enhanced beta-blocking
activity, for example, after a heart attack or associated with hypertension and to reduce the undeaurable side effects associated with
beta-blockers.
The letters R and S refer to the configuration or relative positions of the chemical substituents that form the enantiomeric center. For atenolol,
the S configuration is the levorotatory, or (-), enantiomer and the R configuration is, therefore, the detrorotatory, or (+), enantiomer.
In the present method, S (-) - atenolol, which is substantially free of its R(+) enantiomer, is administered alone, or in combination with other drugs in adjunctive treatment, to an individual suffering from a cardiovascular disorder, such as heart disease, angina or hypertension. " S (-) atenolol" as used herein refers to the S
levorotatory isomer of 4-[2'-hydroxy-3'-[(1- methylethyl)amino] propoxybenzene acetamide. The term "substantially free of the R(+) enantiomer" as used herein means that the composition contains at least 90% by weight S (-) atenolol and 10% by weight or less of R(+) atenolol. S (-) atenolol is
obtainable by purification from racemic atenolol or by asymmetric synthetic techniques.
Racemic atenolol contains a mixture of the R (+) and S (-) enantiomers. The S (-) enantiomer is the more active beta blocker of these enantiomers; it is the more pharmacologically effective form of
atenolol. Thus, a smaller quantity of the S (-) enantiomer than of the racemic mixture is needed to produce an effect. The S (-) enantiomer is about twice as potent as the racemic mixture; thus, a dose of the S enantiomer which is approximately one half that of the racemic mixture has the same beta blocking activity.
The unwanted side effects associated with the administration of atenolol are attributable, only
in part, to ita beta blocking action, so that the reduction in dose which is made possible by using the more potent beta blocking stereoisomer, that is, the S (-) enantiomer, will result in a lower
incidence of adverse effects.
In the present method, S (-) atenolol is
administered to an individual suffering from a cardiovascular disorder, such as angina pectoris or hypertension. For example, S (-) atenolol is
administered therapeutically to an individual after a heart attack or to reduce or ameliorate hypertension and regulate heart beat. Alternatively, S (-) atenolol can be administered prophylactically to reduce the probability of occurrence of a heart attack.
All amounts and percentages are by weight unless otherwise specified.
The drug can be administered orally, by subcutaneous or other injection, intravenously, topically, parenterally, transdermally, rectally or via by sustained release methods, e.g., an implanted reservoir containing S (-) atenolol. The form in which the drug will be administered (e.g., powder, tablet, capsule, solution, emulsion) will depend on the route by which it is administered. The quantity of the drug to be administered will be determined on an individual basis, and will be based at least in part on consideration of the individual's size, the severity of the symptoms to be treated and the result sought. In general, quantities of S (-) atenolol sufficient to reduce hypertension or
regulate heart beat will be administered. For example, less than about 100 mg per day of S (-) atenolol (and, for example, less than 40 mg per day) is given in one dose or more doses to produce the desired effect. Some patients having angina
pectoris, however, may require up to about 200 mg per day; in such patients, 80 mg per day may be given. Typically, a dose of about 20 to about 50 mg of S (-) atenolol (e.g., 20-40 mg) per day will be administered.
In the method of the present invention, S (-) atenolol can be administered along with one or more other drugs. For example, other anti-hypertensive agents, such as thiazide-type diuretics, calcium antagonists, hydralazine, prazosin, and alpha-methyl dopa, and, in some patients, angiotensin converting enzyme inhibitors, can be given with or in close temporal proximity to administration of S (-)
atenolol. The two (or more) drugs S (-) atenolol and another drug can be administered in one composition or as two separate entities. For example, they can be administered in a single capsule, tablet, powder, liquid, etc. or as individual compounds. The components included in a particular composition, in addition to S (-) atenolol and another drug or drugs, are determined primarily by the manner in which the composition is to be administered. For example, a composition to be administered orally in tablet form can include, in addition to the drugs, a filler (e.g., lactose), a binder (e.g., carboxymethyl cellulose, gum arabic, gelatin), an adjuvant, a
flavoring agent, a coloring agent and a coating material (e.g., wax or a plasticizer). A
composition to be administered in liquid form can include the combination of drugs and, optionally, an emulsifying agent, a flavoring agent and/or a coloring agent.
In general, according to the method of the present invention, S (-) atenolol, alone or in combination with another drug (s), is administered to an individual periodically as necessary to reduce or ameliorate symptoms of the hypertension or angina being treated while reducing or avoiding undesirable side effects associated with beta-blockers.
The length of time during which the drugs are administered and the dosage will depend on the disorder being treated, the type and severity of the symptoms, and the physical condition of the individual being treated.
The invention is illustrated by the following examples. These examples are not to be viewed as being limiting of the invention.
EXAMPLE 1 Preparation of S ( -) Atenolol
a. Preparation of m-nitrobenzene sulfonyl
chloride:
112.5g (0.5 mole) of m-nitrobenzenesulfonic acid sodium salt was placed in a 3-neck round bottom flask equipped with a paddle stirrer.
To the solid was added thionyl chloride (119g., 1 mole, 73 mL). The thick mass was slowly stirred as 25 mL of DMF was added over
approximately 1 min. The mass began to heat up and liquify (T approximately 40°C). After stirring 1 hour, the clear solution was poured into ice/water to provide an oil which quickly solidified. The solid was washed well with water, dissolved in methylene chloride, and dried over anhydrous magnesium sulfate. The methylene chloride was stripped to provide crude m-nitrobenzenesulfonyl chloride as an oil which quickly solidified.
Yield - 110.8g (100%) This material was recrys tallized from
EtOAc/hexane (approximately 50/50) to give 72.8g of pure material (66%). b. Preparation of gylcidyl m-nitrobenzene
sulfonate:
A solution of (R)-glycidol (148g, 2.0 mole) and Et3N (304ml, 2.2 mole) in 3 liters of toluene was cooled with ice water (ca.5ºC).
m-Nitrobenzenesulfonyl chloride (426g, 1.92 mole) was added in portions while maintaining the temperature below 10°C. During addition, a white precipitate (Et3N-HCl) was formed. The mixture was stirred at RT for 22 hours. The
mixture was then diluted with small volume of EtOAc and filtered. The solid residue was washed thoroughly with EtOAc. The filtrate was then concentrated to dryness to give a yellow oil which on standing and cooling became a solid. The solid was recrystallized twice from EtOAc/hexane until the optical rotation did not change.
1st crop: wt: 321g [alpha]D25 =+22.5
(c-2.16, CHCl3) 2nd crop: wt : 72g [alpha]D25 =+23
(c-2.16, CHCl3) ---------
393g 79% yield
lit[alpha]D25 =+23
(c=2.14,CHCl3 )
3rd crop wt. 36g [alpha]D25 = +17.5
(c=2.14, CHCl3)
Preparation of S (-) atenolol:
240g of p-hydroxyphenylace tamide was dissolved in 600mL of dry DMF in a 2 liter 3-neck round-bottom flask equipped with an overhead stirrer. The solution was cooled to ca. 15ºC with ice water. KOMe (117g) was added in portions via a solid-powder addition funnel over 30 minutes while keeping the temperature below 15°C (act. 10°C-15°C). After addition,
the ice water was removed and the resulting white suspension was stirred at ambient
temperature for 1 hour. The glycidyl
m-nitrobenzene sulfonate in 400mL of DMF was then added while keeping the temperature below 20°C with ice water. During addition, the mixture became very thick and stirring was difficult and a local exotherm was observed. Therefore, the mixture was transferred to a 4 liter reactor with the aid of 1.5 liter of DMF. The resulting suspension was then stirred for 23 hours (TLC: complete reaction).
The mixture was then filtered and the residual solid was washed thoroughly with small portions of DMF. The combined filtrate was then concentrated to ca. one liter in volume.
The concentrate was placed in a 2 liter 3-neck round bottom flask equipped with a reflux condenser and a magnetic stir bar.
510mL of i-PrNH2 and 10mL of H2O were added to the flask. The resulting solution (orange) was refluxed for 5 hours until all the glycidyl epoxide was consumed.
The solution was then cooled and
concentrated under vacuum to remove DMF. The yellow solid obtained was then stirred with 2 liter 3% NaOH solution until a fine suspension was formed. The mixture was filtered and the resulting solid was washed thoroughly with small portions of water until the filtrate became colorless.
The resulting S (-) atenolol solid was then recrystallized from i - PrOH and water (16:1 v/v).
EXAMPLE 2 Comparison of the Pharmacological Effects of S (-), R(+) and Racemic Atenolol a. Experimental Preparations and Procedures (i) Isolated Tissue Preparations:
Studies were carried out on both rat and guinea pig isolated atria and tracheal rings. All tissues were allowed to equilibrate for 60 minutes with Krebs-Henseleit physiological salt solution; the composition of which in mmol/1 is
NaCl, 118; KCl 4.7; MgSO4, 1.2; CaCl2, 2.5; KH2PO4, 1.2; NaHCO, 25; glucose 11.1 and EDTA, 0.0025.
Cumulative concentration-response curve s were obtained in each preparation as described by Van Rossurn (Archiv. Int. Pharmacodyn., 143,
299-329, 1963), and curves were fitted by computer analysis according to Zaborowsky e t al . , (J. Pharmacol . Meth., 4, 165-178, 1980). For measurement of antagonist activity the appropriate agent was added to the organ bath at least 45 minutes after the first control concentration- response curve and allowed to equilibrate for 20 minutes before the next concentration response curve wwas established.
The shift in this curve to the right was
calculated as a pA2 value (Mackay. J. Pharm. Pharmacol., 30 312-313, 1978).
(ii) Pithed Rat Preparation:
Rats weighing approximately 200-250 g were anaesthetised with halothane and the left carotid artery and left jugular vein was cnnulated and the trachea exposed and
cannulated. The animal was artificially respired and then finally pithed. Blood pressure and heart rate were measured from the left carotid artery while drugs were
administered in normal saline via the left jugular vein. Under these conditions the pithed rat preparation was stable for at least 4 hours.
(a) Antagonist Activity
For measurement of beta adrenoceptor antagonist activity, isoprenaline 0.05 μg/kg was initially given three times at intervals of 10 minutes to establish control responses to heart rate. When these effects were
reproducible, the first does of test drug (antagonist) was given followed by a standard dose of isoprenaline 5 minutes later. The protocol was repeated at intervals of 15 minutes using successively higher doses of antagonist. The dose range was based on a
logarithmic series, 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300, 1000, 3000 and 10, 000 ug/kg.
(b) Agonist Activity
For measurement of agonist activity the effects on heart rate (beta1) and blood
pressure (beta2) were studied by examining cumulative drug effects of increasing IV doses of the test drug or isoprenaline in the dose range 0.1 to 10,000 ug/kg. Pharmacological Effects
(i) Activity on Beta-1 and Beta-2
Adrenoceptors:
(a) Isolated Preparations
The relative potencies of the
stereoisomers as competitive antagonists at different beta adrenergic receptor sites can be presented as pA2 values (Tables 1 and 2).
The method used to determine the pA2 value was taken from the description of MacKay. To determine the ρA2 for inhibition of tachycardia the response to isoprenaline was first recorded alone, and then the response to isoprenaline in the presence of antagonist was recorded. The concentration of isoprenaline which produced 50% inhibition of the maximal response (the
IC50 ) was determined in the presence and absence of the antagonist and the dose ratio is defined as the difference between the log concentrations D1 and D2. The pA2 was then determined from the equation in MacKay using the dose ratio and molar concentration of the antagonist.
In vitro pharmacological studies were carried out on both rat and guinea pig isolated atria and tracheal rings and rate uterus.
The results obtained in rat atria are shown in Table 1. In these studies the R and S isomers were those supplied by Sepracor, Inc. The racemic mixture was obtained either from Sigma, as a standard commercial preparation, or from a combination of equal amounts of the Sepracor isomers. Thus in rat atria, a beta-1 adrenoceptor preparation, pA2 values of the S-atenolol were of the order of 7.6 compared to values of 5.9-6.5 for the R-atenolol. This represents a relative potency for the S-isomer of 18-52 times that for the R. The pA2 of racemic atenolol obtained from either Sigma or Sepracor was of the order of 7.2-7.5 indicating a potency of 10-20 times greater than for the R-isomer alone but only 1.8 to 2.5 times less than the S-isomer.
The results obtained in guinea pig atria were similar.
Two beta-2 adrenoceptor preparations were used. They were the isolated rat uterus and
the isolated guinea pig trachea, again using isoprenaline as the agonist (Table 2). In the rat uterus the pA2 values for S-atenolol were approximately 6 versus 4.7 for R-atenolol, and the racemic atenolol (from Sigma) was 5.8.
Thus the S and the racemic were 19 and 11 times more potent, respectively, than the R atenolol. The results obtained in the second beta-2 preparation, the guinea pig trachea, were similar with the S isomer being 11 times more potent than the R isomer and the racemic mixture 8 times more potent than the R isomer.
(b) Pithed Rat Preparation
In a second series of experiments the pithed rat preparation was used. Anaesthetized animals were prepared for blood pressure and pulse recording and then pithed. This
preparation was used to assess beta
adrenoceptor antagonist activity: a standard dose of isoprenaline was given, 0.05 μg/kg, producing a beta-1 mediated tachycardia, and the inhibition of this response by successive doses of the antagonist was assessed. The ID50 of the antagonist is the concentration that inhibits the isoprenaline tachycariac response by 50%.
The isoprenaline also produces a beta-2 adrenoceptor mediated fall in blood pressure.
As shown in Figure 1 and Table 3, both S and racemic atenolol inhibited the agonist effect of isoprenaline on heart rate in a dose- dependent way, but only inhibited the effect of isoprenaline on blood pressure at concentrations > 10,000 μg/kg indicating they both had significant beta-1 selectivity in this model. From the ID50 's the S isomer was 6 times more potent than the racemic and 90 times more potent than the R isomer. Again the S isomer was the most potent form in inhibiting the ability of isoprenaline to reduce blood pressure but the relative potency to the other forms could not be clearly established because
ID50's could not be accurately determined in this preparation.
(ii) Intrinsic Sympathomimetic Activity (ISA)
The pithed rat preparation was also used to assess the presence of agonist activity (ISA) in the stereoisomers of atenolol. This would be apparent as a dose-dependent increase in heart rate (beta-1) or a dose-dependent fall in blood pressure (beta-2) which would be blocked by propranolol. There was no evidence of either beta-1 or beta-2 ISA with any of the forms of atenolol studied. By
contrast, all three forms of atenolol showed a similar level of dose-dependent inhibition of resting heart rate
independent of consistent blood pressure changes (Figure 2).
(iii) Cardiac Depressant Effects:
The negative inotropic effects of the stereoisomers were explored in detail in an electrically driven atrial
preparation. The negative inotropic effect was estimated by comparing the contractions in the presence of atenolol against control contractions. The data are presented as the % changes in tension. Propranolol (R/S) was used in this
preparation and produced a clear dose dependent effect at high concentrations.
The different isomers of atenolol were also effective in reducing the force of contraction but to a much lesser extent than propranolol. It was not possible to differentiate between the different forms of atenolol (Figure 3).
Claims (9)
1. Use of S (-) atenolol, which is substantially free of R(+) atenolol, for the manufacture of a medicament for the treatment of cardiovascular disorders and, at the same time, for reducing or eliminating undesirable side-effects
associated with beta-blocking drugs.
2. The use of Claim 1 wherein the cardiovascular disorder is hypertension or angina pectoris.
3. The use of Claim 1 wherein the amount of S (-) atenolol in said medicament is greater than about 90% by weight.
4. The use of Claim 3 wherein the amount of S (-) atenolol in said medicament is greater than about 99% by weight.
5. The use of Claim 1 wherein the amount of S (-) atenolol in said medicament is sufficient to reduce, ameliorate or eliminate the symptoms of the cardiovascular disorder.
6. The use of Claim 1 for the manufacture of a
medicament in unit dosage form having about 100 mg or less of S (-) atenolol and preferably about 50 mg S (-) atenolol.
7. Use of S (-) atenolol and at least one other drug for the manufacture of a medicament for the treatment of cardiovascular disorders and, at the same time, for reducing or eliminating undesirable side-effects associated with beta-blocking drugs.
8. The use of Claim 7 wherein said other drug is an anti-hypertensive agent, e.g., thiazide-type diuretics, calcium antagonists, hydralazine, prazosin or alpha-methyldopa.
9. S (-) atenolol, substantially free of R (+)
atenolol, for use as a medicament for the treatment of cardiovascular disorders.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44003689A | 1989-11-21 | 1989-11-21 | |
US440036 | 1989-11-21 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU6893391A AU6893391A (en) | 1991-06-13 |
AU643487B2 true AU643487B2 (en) | 1993-11-18 |
Family
ID=23747155
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU68933/91A Ceased AU643487B2 (en) | 1989-11-21 | 1990-11-21 | Use of optically pure s(-) atenolol for the treatment of cardiovascular disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0519925A1 (en) |
JP (1) | JPH05503510A (en) |
AU (1) | AU643487B2 (en) |
CA (1) | CA2069404A1 (en) |
WO (1) | WO1991007175A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0591434A4 (en) * | 1991-06-26 | 1994-09-14 | Sepracor Inc | Method and compositions for treating emesis, nausea and other disorders using optically pure r(+) ondansetron |
CA2124445A1 (en) * | 1991-11-26 | 1993-06-10 | James W. Young | Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine |
US7417038B1 (en) * | 1998-10-15 | 2008-08-26 | Imperial Innovations Limited | Methods of treating cachexia |
WO2000051582A2 (en) | 1999-03-01 | 2000-09-08 | Sepracor Inc. | Methods for treating apnea and apnea disorders using optically pure r(+)ondansetron |
FR2927538B1 (en) * | 2008-02-14 | 2010-02-19 | Servier Lab | ASSOCIATION OF IF SINUSAL CURRENT INHIBITOR AND BETA BLOCKING. |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS62245353A (en) * | 1986-04-18 | 1987-10-26 | Hitachi Ltd | Prevention circuit for data rewriting of eeprom |
JPS62271031A (en) * | 1986-05-20 | 1987-11-25 | Fujitsu Ltd | Protecting system for stored data |
GB8618324D0 (en) * | 1986-07-28 | 1986-09-03 | Shell Int Research | Phenylacetate/atenolol |
-
1990
- 1990-11-21 CA CA002069404A patent/CA2069404A1/en not_active Abandoned
- 1990-11-21 AU AU68933/91A patent/AU643487B2/en not_active Ceased
- 1990-11-21 JP JP3501087A patent/JPH05503510A/en not_active Expired - Lifetime
- 1990-11-21 EP EP19910900463 patent/EP0519925A1/en not_active Ceased
- 1990-11-21 WO PCT/US1990/006824 patent/WO1991007175A1/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
CA2069404A1 (en) | 1991-05-22 |
WO1991007175A1 (en) | 1991-05-30 |
JPH05503510A (en) | 1993-06-10 |
AU6893391A (en) | 1991-06-13 |
EP0519925A1 (en) | 1992-12-30 |
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