WO1992022299A2 - Use of antiarrhythmic agents to lower cholesterol - Google Patents
Use of antiarrhythmic agents to lower cholesterol Download PDFInfo
- Publication number
- WO1992022299A2 WO1992022299A2 PCT/US1992/004857 US9204857W WO9222299A2 WO 1992022299 A2 WO1992022299 A2 WO 1992022299A2 US 9204857 W US9204857 W US 9204857W WO 9222299 A2 WO9222299 A2 WO 9222299A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cholesterol
- type
- quinidine
- agent
- antiarrhythmic
- Prior art date
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/49—Cinchonan derivatives, e.g. quinine
-
- 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
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- results of 22 randomized cholesterol- lowering clinical trials to reduce the risk of coronary heart disease indicate an average reduction of 23 percent in the risk of non-fatal myocardial infarction and cardiac death in treated compared with control patients.
- a 10 percent decrease in the cholesterol level was associated with a reduction of approximately 20 percent in the incidence of new coronary events (S. Yusef et al., JAMA, 260, 2259 (1988)).
- LDL-C low density lioprotein- cholesterol
- hypolipidemic agents include bile acid sequestrants (cholestyramine and cholestipol) , nicotinic acid, probucol, fibric acid derivatives (gemfibrizol and clofibrate), HMG-CoA reductase inhibitors, and the omega-3 unsaturated fatty acids found in various fish oil supplements. To date, no other classes of lipid-lowering agents have been approved for clinical use.
- colestyramine and cholestipol are associated with constipation and abdominal discomfort. Cholestyramine can cause vitamin , A and D deficiencies. Probucol clofibrate and gemfibrizol can cause diarrhea, abdominal pain and nausea, and the first two agents have been associated with arrhythmias.
- the present invention provides a therapeutic method to lower serum lipids or lipid components selected from the group consisting of cholesterol, total triglycerides, apoprotein B and/or low-density lipoprotein-cholesterol (LDC-C) comprising administering to a mammal in need of such treatment an effective amount of at least one type IA antiarrhythmic agent.
- Preferred type IA antiarrhythmic agents for use in the present method include quinidine, procainamide, disopyramide (including the pharmaceutically acceptable salts thereof) and mixtures thereof.
- the pharmaceuti ⁇ cally acceptable salts thereof include the addition salts of inorganic and organic acids, some of which are commercially available, such as the phosphate, hydrochloride, sulfate, gluconate, galacturonate. polygalacturonate, dihydrobomide trihydrate, and ethiodide monohydrate salts.
- type IA antiarrhythmic agent is not limited to these three discrete chemical moieties and their salts, but includes the derivatives and analogs thereof, which are recognized by the art to function as Type IA antiarrhythmic agents. A number of such derivatives have been disclosed in the patent and scientific literature, and are discussed in detail hereinbelow. Although, for reasons such as the need to minimize side effects, and the need to simplify the administration schedule, the use of a single Type IA agent is preferred, the administration of a plurality, e.g., 2-5, of such agents is within the scope of the invention, and may be useful to manage lipid levels in certain refractory patients.
- Antiarrhythmic or "antidysrhythmic” agents are frequently prescribed to patients with coronary heart disease and associated cardia arrhythmias. Presently, antiarrhythmic agents are classified by their presumed mechanism of action at the myocellular level. All Type I antiarrhythmic agents are characterized by their blocking effect on fast inward sodium current (J.T. Bigger et al., in The Pharmacoloqic Basis of
- Type I agents quinidine, procainamide, disopyramide, lidocaine, tocainide, mexilitine, flecainide, encainide, and the recently released moricizine and propafenone
- the presently available Type I agents differ in the way they interfere with the sodium channel (potential and frequency dependent block) , in their effects on other myocellular ionic channels, and in their binding characteristics to cardiac membranes (E. Carmeliet et al., in Clinical Aspects of Life- Threatening Arrhythmias, H.M.
- Type IA quinidine, procainamide and disopyramide
- Type IB lidocaine, tocainide, mexilitine
- Type IC flecainide, encainide, propafenone
- Total serum cholesterol was reduced about 5-15% over the course of the study as compared with patients not treated with the type IA agents.
- Total triglycerides were reduced about 12-35% and apoprotein B was reduced about 7.5-20%.
- longer courses of medication and/or higher doses may enhance the therapeutic effect of a given Type IA antiarrhythmic agent.
- quinidine, procainamide and disopyramide were substantially equivalent in their effectiveness, within the variation of the assay methods.
- Example 1 In the study reported in Example 1, the course of treatment evaluated was 30 months. However, substantial lipid lowering was observed after 6 months. and shorter courses of treatment are likely to be effective.
- Type IA antiarrythmic agents are also effective to lower said serum lipids or lipid components when administered in unit dosages or in daily dosages that are substantially less than the unit dosages (or daily dosages) conventionally employed to achieve antiarrhythmic effects.
- Such unit dosage forms comprise about 25-50% of the amount of the Type IA antiarrythmic agent or agents that are conventionally provided, e.g., via a capsule, tablet, injectable dosage or the like. Therefore, the present invention also provides a pharmaceutical unit dosage form comprising an amount of a Type IA antiarrhythmic agent which is effective to lower the serum concentration of said lipid or lipid components recited above, which amount is substantially less than that which is employed to exert antiarrythmic effects.
- the amounts which are employed to exert antiarrythmic effects are extensively defined and discussed below.
- Type IA antiarrhythmic agents for use in the present invention include quinidine, procainamide and disopyramide, as well as the salts, derivatives and analogs thereof that retain the Type IA profile of antiarrhythmic bioactivity, e.g., that have substantially similar electrophysiologic and pharmacodynamic properties. See E.M.V. Williams, cited supra.
- Dosage forms of quinidine glucuronate which are available include an 80 mg/ml injectable form and 324 mg extended release tablets.
- Dosage forms of quinidine sulfate which are available include: capsules: 100, 200, and 300 mg; injection: 200 mg/ml; tablets: 100,
- quinidine gluconate is available as Duraquin (330 mg sustained-release tablets) from Parke- Davis, Morris Plains, NJ; quinidine polyglacturonate is available as Cardioquin (275 mg tablets) from The Purdue Frederick Co., Norwalk, CT; quinidine sulfate is available in 200 mg tablets from Lederle Laboratories, Wayne, NJ.
- Oral adult dosages are up to 100-600 mg 3-6 times a day; infants and children, 6 mg/kg five times a day.
- Ri is hydrogen, hydroxy, halogen, trifluoromethyl, (Cj-C alkyl, (C,-C )alkoxy, or when is 2, with an adjacent R x , is also methylenedioxy; and R 2 is ethyl or vinyl. See, for example, U.S. Patent Nos. 3,864,347 and 3,898,237.
- Procainamide hydrochloride (4-amino-N-[2- (diethylamino)ethyl]benzamide monohydrochloride has the formula:
- Free procainamide can be prepared by condensing p-nitrobenzoyl chloride with -diethylaminoethylamine and then reducing the nitro group to amino by conventional methodology.
- the hydrochloride is formed by passing HC1 into a solution of procainamide in an appropriate organic solvent.
- Other useful acid addition salts can be formed by reaction of the free base with the appropriate acid.
- Procainamide and its dosage forms are discussed extensively in Merck at page 7759 and in Remington's at pages 799-800.
- procainamide-HCl Dosage forms of procainamide-HCl which are available include capsules: 250, 375 and 500 mg; injection: 100 and 500 mg/ml; tablets 250, 375 and 500 mg.
- Procainamide- HC1 capsules are available (250, 375 and 500 mg) from Lederle Laboratories.
- Useful adult dosages range from 250-500 mg twice a day to 500 mg to 1.0 g every 4-7 hours, to 3.0- 4.5 g doses administered once daily, taken orally.
- Procainamide can also be infused intravenously, e.g.. 200 mg - 1 g can be infused at 25-50 mg/min in an appropriate intravenous solution.
- Useful derivatives and analogs of procainamide include compounds of the general formula:
- R*. and R 2 are individually H, OH, Cl or 0(C,-C 3 )- alkyl;
- R 3 is (C,-C 3 ) lkyl, acetyl, 2-pyridyl, hydroxy or benzyl;
- R 4 is (Cj-C 3 )alkyl and
- R 5 is (C ⁇ ⁇ alkyl or p- chlorobenzyl, and the pharmaceutically acceptable salts thereof.
- Disopyramide ( a-[2-bis(1-methylethyl)amino] ethyl]- ⁇ -phenyl-2-pyridineacetamide) has the formula:
- Disopyramide is prepared by heating 4- diisopropylamino-2-phenyl-2-(2-pyridyl)butyronitrile with concentrated sulfuric acid to convert it into the amide (Chem. Abstr., 58, 12522e (1963)). Disopyramide and its phosphate salt are discussed extensively in Merck at pages 3360-61 and in Remington's at page 799. Dosage forms of disopyramide phosphate include 100 and 150 mg capsules. It is typically administered orally to adults at 100-200 mg every 6 hours. Disopyramide capsules are available from Lederle Laboratories.
- disopyramide examples include those wherein the phenyl ring is replaced by tolyl, xylyl, naphthyl, halophenyl, anisyl and dimethoxyphenyl and/or the pyridine ring is substituted with halo, preferably chloro. See U.S. Pat. No. 3,225,054.
- Type IA antiarrhythmic agents can be administered singly or in combination, and are effective to lower blood lipids when administered * in daily dosages essentially equivalent to those employed to achieve antiarrhythmic effects.
- oral administration in tablets or capsules is preferred, parenteral routes of administration are also effective, and include, for example, injection and intravenous administration of the agents, in combination with a suitable liquid vehicle.
- the study population consisted of 1567 survivors of the original cohort of 2466 post-infarction patients enrolled in the Multicenter Diltiazem Post- Infarction Trial on whom lipid and lipoprotein specimens were obtained at study termination. The details of patient recruitment, data acquisition, data management, and follow-up have been previously reported, in New Engl. J. Med ⁇ , 319, 385 (1988). Patients were randomly assigned to diltiazem or placebo and were followed at periodic intervals throughout the trial. All patients were followed for at least 12. months, to a maximum of 52 months; the average duration of follow-up was 25 months.
- Serum cholesterol and triglyceride concentrations were determined on a Gilford System 3500 Computer Directed Analyzer by the methods of C.C. Allain et al. Clin. Chem. , 20, 470 (1973) and G. Bucolo et al., Clin. Chem., 19, 476 (1973), respectively.
- High density lipoprotein-cholesterol (HDL-C) values were determined using methods identical to those of the Lipid Research Clinics program, as described in Manual of Lipoprotein Operations, Vol. 1, Dept. of HEW, Publication No. (NIH) 75-628 (1974), with the exception that the isopropanol and zeolite extraction steps are not required with the enzymatic methods.
- Apoprotein A-I and apoprotein A-II were measured by validated double antibody radioimmunoassay techniques, as disclosed by M.C. Cheung, J. Clin. Invest., 60, 43 (1977).
- Apoprotein B (Apo B) levels were determined by both a radioi munoassay (RIA) , as described by J.J. Albers et al.. Metabolism, 24, 1339 (1975) and by a radial immunodiffusion assay (RID) (Fahey et al., J. Immunol. , 94, 84 (1965).
- RIA radioi munoassay
- RID radial immunodiffusion assay
- the cardiac medications that the patients were receiving were identified at baseline, at each follow-up contact, and at closeout utilizing a prespecified medication dictionary.
- the medication categories included antiarrhythmic agents, beta blockers, digitalis preparations, diuretic agents, nitrates other than sublingual preparations, and the trial medication (diltiazem or placebo) . Each category was subcategorized for specific agents.
- 76 patients were on Type IA antiarrhythmic medication (41 were on various quinidine preparations, 29 were on procainamide, and 6 were on disopyramide) . Twenty-seven patients were on a variety of other Type I antiarrhythmic agents (21 on Type IB and 6 on Type IC) and these agents had no apparent effect on serum lipids. No patient was on moricizine, which can also be classified as a Type IA antiarrhythmic agent.
- a regression model was developed involving selected dichotomized covariates that had an influence (p ⁇ 0.05) on the serum lipid level. Antiarrhythmic medication was then stepped-up into the model to evaluate the magnitude and significance of its independent effect on the lipid level, i.e., after adjustment for relevant covariates.
- Pulmonary congestion categorized as mild, moderate, or severe. p ⁇ 0.05.
- Type IA antiarrhythmic agents were more likely to be males with a history of hypertension, pulmonary rales during the index myocardial infarction, a reduced radionuclide ejection 5 fraction, and frequent and repetitive ventricular ectopics on the ambulatory electrocardiogram, than those not on these agents. Digitalis and diuretics were more frequently utilized by the patients on antiarrhythmic agents than those not receiving Type IA medications,
- Figures are mean serum cholesterol concentrations ⁇ SD in mg/dl .
- Type IA antiarrhythmic medication taken as a whole as well as the effect of quinidine, procainamide, and disopyramide individually on the various lipid fractions at closeout, are:
- Figures are mean serum lipid concentrations ⁇ SD in mg/dl.
- P values relate to comparisons between the indicated value and the value i the 1491 patients on no Type IA antiarrhythmic agents: * p ⁇ 0.01, + p ⁇ 0.001, * p ⁇ 0.0001.
- Type IA medications were associated with a
- Stepwise multiple linear regression analyses were performed to adjust for relevant covariates .
- a regression model was developed in which all dichotomized variables from Table 1 that had an influence (p ⁇ 0.05) on the lipid fraction were included in the model .
- Type IA antiarrhythmic agents were then stepped into the covariate model to determine the independent effect that Type I agents had on the specified lipid fraction.
- the negative sign indicates an elevation in HDL-C.
- Type I A antiarrhythmic agents are associated with significant reductions in total cholesterol , triglycerides, Apo A-II, and Apo B fractions. There was no significant effect of Type IA antiarrhythmic agents on HDL-C or Apo A-I levels. The magnitude of the lipid- lowering effect of Type IA antiarrhythmic agents on serum total cholesterol was approximately 9 percent, and the percent reduction in total cholesterol was similar at three different cholesterol levels, as shown on Table 2.
- LDL the major cholesterol carrying particle in serum
- Apo B-100 a single surface apoprotein
- S.G. Young, Circulation, 82, 1574 (1990) An elevated level of LDL-C is a major risk factor for the premature development of coronary atherosclerotic disease, and there is considerable interest in lowering LDL-C by diet and medication.
- LDL- C is usually computed from directly measured total cholesterol, HDL-C, and triglyceride values, as reported by W.T.
- LDL-C 127 ⁇ 47 mg/dl
- LDL-C 145 ⁇ 45 mg/dl
- Type IA agents also lowered the concentration of Apo A-II, an important component of HDL, yet the HDL- C concentration was not affected by these agents (Table 3).
- the exact role of Apo A-II in the composition of HDL is unclear.
- HDL has considerable particle heterogeneity, some subfractions of HDL contain no Apo A-II, and Apo A-II is not an essential core protein of HDL.
- Apo A-II reduction can occur without concomitant lowering of HDL-C.
- Type IA antiarrhythmic agents A major concern is that patients selected for therapy with Type IA antiarrhythmic agents in the study might have had lower cholesterol levels as a result of confounding factors such as diet, the severity of the cardiac disease, and the effects of concomitant medication. In an attempt to control for this, we carried out multiple linear regression analyses adjusting for a large number of measured clinical variables. Even after adjustment, the Type IA agents were associated with significant (p ⁇ 0.001) reductions (> 10%) in total cholesterol, triglyceride Apo A-II, and Apo B levels. Of course, covariates could not be adjusted that were not measured. It would be noted that at 22 months post-infarction, the average weight of the patients receiving Type IA antiarrhythmic agents was slightly greater than those not on these agents.
- this example shows that the long- term administration of Type IA antiarrhythmic medications to patients is associated with significant reductions in serum total cholesterol, triglyceride, Apo A-II, and Apo B levels. These reductions were independent of age, gender, body weight, diabetes, smoking status, concomitant medications, and a variety of measured covariates relating to the severity of the index infarct event. Therefore, Type IA antiarrhythmic agents are believed to represent a new class of hypolipidemic agent. All patents and publications cited hereinabove are incorporated by reference herein. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.
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Abstract
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/712,510 US5166142A (en) | 1991-06-10 | 1991-06-10 | Use of type ia antiarrhythmic agents to lower blood lipids |
US712,510 | 1991-06-10 |
Publications (2)
Publication Number | Publication Date |
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WO1992022299A2 true WO1992022299A2 (en) | 1992-12-23 |
WO1992022299A3 WO1992022299A3 (en) | 1993-02-18 |
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ID=24862423
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1992/004857 WO1992022299A2 (en) | 1991-06-10 | 1992-06-03 | Use of antiarrhythmic agents to lower cholesterol |
Country Status (6)
Country | Link |
---|---|
US (1) | US5166142A (en) |
EP (1) | EP0543001A1 (en) |
JP (1) | JPH06500801A (en) |
AU (1) | AU2226992A (en) |
CA (1) | CA2089164A1 (en) |
WO (1) | WO1992022299A2 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US5627172A (en) * | 1994-03-04 | 1997-05-06 | Natural Supplement Association, Incorporated | Method for reduction of serum blood lipids or lipoprotein fraction |
US5753262A (en) * | 1995-06-07 | 1998-05-19 | Aronex Pharmaceuticals, Inc. | Cationic lipid acid salt of 3beta N- (N', N'-dimethylaminoethane) - carbamoyl!cholestrol and halogenated solvent-free preliposomal lyophilate thereof |
EP3355914B1 (en) * | 2015-09-29 | 2024-03-06 | The General Hospital Corporation | A composition comprising bcg for reducing cholesterol. |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5675427A (en) * | 1979-11-21 | 1981-06-22 | Ayanori Takabe | Antiarteriosclerotic agent containing procainamide hydrochloride |
WO1989010743A1 (en) * | 1988-05-03 | 1989-11-16 | Basf K & F Corp. | Long lasting composition of propafenone and quinidine for treatment of cardiac conditions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3864347A (en) * | 1968-07-02 | 1975-02-04 | Hoffmann La Roche | {60 {8 3(R)-alkyl-4(R) piperidyl methyl{9 -{62 -(6,7 substituted-4 quinolyl)-2-alkanoyloxy propane and racemates |
US3898237A (en) * | 1971-07-27 | 1975-08-05 | Hoffmann La Roche | Process for preparing 1,1-dichloro-3-(4-piperidinyl)propan-2-ols |
-
1991
- 1991-06-10 US US07/712,510 patent/US5166142A/en not_active Expired - Fee Related
-
1992
- 1992-06-03 CA CA002089164A patent/CA2089164A1/en not_active Abandoned
- 1992-06-03 AU AU22269/92A patent/AU2226992A/en not_active Abandoned
- 1992-06-03 EP EP92914180A patent/EP0543001A1/en not_active Withdrawn
- 1992-06-03 WO PCT/US1992/004857 patent/WO1992022299A2/en not_active Application Discontinuation
- 1992-06-03 JP JP5500983A patent/JPH06500801A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5675427A (en) * | 1979-11-21 | 1981-06-22 | Ayanori Takabe | Antiarteriosclerotic agent containing procainamide hydrochloride |
WO1989010743A1 (en) * | 1988-05-03 | 1989-11-16 | Basf K & F Corp. | Long lasting composition of propafenone and quinidine for treatment of cardiac conditions |
Non-Patent Citations (8)
Title |
---|
Advances in Myocardiology, vol. 3, 1982; H. Stam et al.: "Intracellular origin and regulation of endogenous lipolysis in rat heart", pages 499-507, see abstract; pages 499, 500, 505 * |
Biochimica et Biophysica Acta, vol. 187, no. 4, 1969; H.B. Markus et al.: "Inhibition of lipolytic processes in rat adipose tissue by antimalarial drugs", pages 486-491, see summary; pages 486, 491 * |
Chemical Abstracts, vol. 90, no. 10, 5 March 1979 (Columbus, Ohio, US) see page 286, abstract 76582v, & CS,B,74733 (SIKL, DOBROSLAV) 31-03-1977 * |
Circulation, vol. 85, no. 6, June 1992; W.E. Boden et al.: "Hypolipidemic effect of type Ia antiarrhythmic agents in postinfarction patients", pages 2039-2044, see abstract; pages 2040, 2042-2043 * |
Dr. W. Forth et al.: "Allgemeine und spezielle Pharmakologie und Toxikologie", 4th edition, 1983, B.I. Wissenschaftsverlag, pages 334-335, see page 334 * |
Indian Journal of Experimental Biology, vol. 30, no. 3, March 1992; A.K. Singh et al.: "Correlative effects of quinidine on ECG pattern and serum cholesterol concentration in acridotheres tristis", pages 190-192, see abstract, whole article * |
Patent Abstracts of Japan, vol. 5, no. 140 (C-70)(812) 4 September 1981, & JP,A,56075427 (AYANORI TAKABE) 22 June 1981, see abstract * |
Rote Liste, 1987, (Aulendorf/W}rtt.) no. 09001-09004, see abstract no. 09002 * |
Also Published As
Publication number | Publication date |
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JPH06500801A (en) | 1994-01-27 |
WO1992022299A3 (en) | 1993-02-18 |
US5166142A (en) | 1992-11-24 |
EP0543001A1 (en) | 1993-05-26 |
AU2226992A (en) | 1993-01-12 |
CA2089164A1 (en) | 1992-12-11 |
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