Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Patent
1982-05-04
1984-01-03
Schwartz, Richard A.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
424263, 424267, 424273R, 424274, 424282, 424319, 548201, A61K 31425
Patent
active
044242280
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention is directed to novel compositions for use as antihypertensive agents.
BACKGROUND OF THE INVENTION
N-(Mercaptoacyl)amino acids, inhibitors against angiotensin I converting enzyme, have been approved as drugs for the treatment of renal hypertension.
On the other hand, probenecid, a drug for the treatment of gout having uricosuric action, has been known to suppress the elimination of some organic acids from renal tubules. To date, this suppressive action of probenecid on the renal secretion has been useful to prolong the duration of drugs, especially, the concomitant use of penicillin and probenecid is known.
Generally, diuretics are used together with antihypertensive drugs. However, there is no report about the concomitant use of inhibitors against angiotensin I converting enzyme and probenecid.
SUMMARY OF THE INVENTION
We investigated the concomitant effect of probenecid and N-(mercaptoacyl)amino acid which reveal antihypertensive effect because of the inhibition against angiotensin I converting enzyme.
The concomitant effect of probenecid was observed to reduce the effective dose of N-(mercaptoacyl)amino acid and prolong the duration of the effect against angiotensin I converting enzyme.
This invention therefore relates to an antihypertensive agent comprising N-(mercaptoacyl)amino acid and probenecid.
DETAILED DESCRIPTION OF THE INVENTION
The above-mentioned N-(mercaptoacyl)amino acid is represented by the ##STR1## wherein R.sup.1 is hydrogen or lower alkyl; indolyl-alkyl, which may be substituted by lower alkyl, hydroxy, acylhydroxy, methylenedioxy, mercapto, acylmercapto, amino, guanidino or carboxy; or thiazolidine ring, and each ring may be substituted by lower alkyl, aralkyl, phenyl, furyl, thienyl, pyridyl or naphthyl, which may be further substituted by lower alkyl, hydroxy-lower alkyl, mercapto-lower alkyl, hydroxy, lower alkoxy, alkylenedioxy, halogen, nitro, amino, lower alkylamino or acylamino; salts thereof.
The antihypertensive effect is shown by the following pharmacological test.
Pharmacological Test
N-(mercaptoacyl)amino acid inhibiting angiotensin I converting enzyme can suppress the pressor response to angiotensin I. The concomitant effect of probenecid to N-(mercaptoacyl)amino acid was evaluated pharmacologically by determing the suppressive activity against the blood pressor response to angiotensin I according to the following procedure.
Experimental procedure
Male wistar strain rats weighing 200-300 g were used.
Under ether anesthesia, polyethylene cannulas were inserted into the femoral artery and vein. The cannula to the femoral artery was connected to a pressure transducer apparatus. After complete recovery from anesthesia, 300 ng/Kg of angiotensin I was injected intravenously and the pressure responce was recorded by polygraph(Nihon Koden, RM-6000). Probenecid and N-(mercaptoacyl)amino acid were suspended in 0.5% tragacanth solution, respectively. At 30 minutes after the oral administration of probenecid, 0.5 ml/Kg (1 mg/Kg) of N-(mercaptoacyl)amino acid was administered orally and the pressor response to angiotensin I injected intravenously was measured with time.
The inhibitory effect against angiotensin I converting enzyme was presented as the percentage inhibition of pressor response to angiotensin I.
Experimental result
FIG. 1 shows that 1 mg/Kg of orally administrated (2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinecarboxyl ic acid (compound A), one of N-(mercaptoacyl)amino acids, suppressed the pressor response to angiotensin I.
The concomitant effect of probenecid intensified and the prolonged suppressive effect were produced by the compound A. The concomitant effect of probenecid (1-100 mg/Kg) was found to depend upon the dose of probenecid.
BRIEF EXPLANATION FOR FIGURE
FIG. 1 shows the time course of the suppressive effect of N-(mercaptoacyl)amino acid with or without probenecid.
In the FIGURE, line 1 is the effect produced by 1 mg/Kg of compound A; line 2, by 1 mg/Kg of compound A with 1 mg/Kg of probenecid;
REFERENCES:
Med., 1971, 155(3), 234-244!.
Vtter, W. et al., Z. Gesamte Exp. Med., 1971, 155(3), 234-244.
Osaka-fu Byoin Yakuzaishikai-ken, "Iyakuhin Yoran", pp. 100-101, 8/20/76.
Iso Tadashi
Yamauchi Hideyasu
Santen Pharmaceutical Co. Ltd.
Schwartz Richard A.
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