Metabolism of piromidic acid, a new antibacterial agent. III. Determination of piromidic acid and its metabolites in blood, urine and bile of rats and humans.
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Biomedical subjects
Publications and source records attributed to M Hashimoto.
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Hemodynamic studies (using (131)I-labeled albumin [RISA]) Were performed before and 5 and 42 weeks after the oral administration of pindolol (av. 30 mg/day), oxprenolol (av. 216 mg/day), propranolol (av. 75 mg/day) or bufetolol hydrochloride (av. 30 mg/day) in 40 patients with essential hypertension. Responders to the antihypertensive actions of short-term (5 weeks) pindolol or bufetolol showed a reduction in total peripheral resistance (pindolol, from av. 2622 to 2022 dyne-sec-cm-5-m2; befetolol, from av. 3301 to 2620, p less than 0.05), without significant changes in cardiac index, while hypotensive actions of propranolol or oxprenolol appeared to be due mainly to a decrease in cardiac output (propranolol, from av. 4.03 to 2.99 L/min/m2; oxprenolol, from av. 3.97 to 3.29 L/min/m2), although the decrease in cardiac output was not significant. In long-term (42 weeks) oxprenolol therapy, antihypertensive effects seemed to be related to reduced cardiac output and a readaptation of peripheral resistance to chronic reduction of cardiac output was not always observed. Circulation time was determined in 9 patients with oxprenolol therapy and 8 with pindolol therapy by the measurement of the arrival time in the cerebral hemisphere of the intravenously injected radioisotope. The patients with oxprenolol therapy showed significant prolongation in circulation time (short-term administration, av. 6.6 to 8.4 sec; long-term administration av. 6.6 to 9.2 sec, p less than 0.05), while no prolongation was observed in pindolol therapy. These results suggest that hemodynamic responses to beta-blocking agents are not uniform and that the antihypertensive actions of beta-blockers depend on the effects on both cardiac output and peripheral vascular resistance.
1. Metabolism of the antibacterial, piromidic acid (5,8-dihydro-8-ethyl-5-oxo-2-pyrrolidinopyrido[2,3-d]pyrimidine-6-carboxylic acid) was investigated in rats and human subjects. Ten metabolites and the unchanged drug were found in the urine and the bile of both species after oral administration. 2. Metabolites were identified by comparison with authentic materials, except for the unstable metabolite, M-VI, for which a probable structure is proposed. The metabolic pathway of piromidic acid involved hydroxylation in the pyrrolidine ring to give the 2- and 3-hydroxy-derivatives (M-II and M-V). M-II was further metabolized to the corresponding gamma-aminobutyric acid derivative (M-IV) and the 2-5-dihydroxypyrrolidine derivative (M-VI) which was further metabolized to the 2-amino-pyridopyrimidine carboxylic acid (M-III). Piromidic acid, M-V, M-II, M-III and M-IV were partly excreted as respective glucuronides. 3. Metabolites, except glucuronides, exhibited antibacterial activity; M-V and M-II showed greater activity than piromidic acid. 4. The metabolism of piromidic acid is discussed in relation to the physicochemical properties of the drug and its metabolites.
The structures of nocardicins A and B, novel monocyclic beta-lactam antibiotics produced by a strain of Nocardia, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence. They are the first examples of monocyclic beta-lactam antibiotics possessing relatively high antimicrobial activity, and are stereochemically and biologically related to penicillins and cephalosporins.
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HEP Flury strain of rabies virus was propagated in chick embryo cells under maintenance media of different pH. It was found that viral growth was better and reached a markedly higher maximum titer when the initial pH of maintenance medium was 8.2 to 9.0 than when it was 7.4. The enhancement of viral growth was not ascribable to mere neutralization of acids produced from infected cells, because the different media became almost equally neutral within an early phase of growth curve. Serial passage of the virus in chick embryo cells using pH 8.2 maintenance medium resulted in altered growth characteristics of the progeny virus; first, the virus so passaged could now grow equally well under alkaline and neutral maintenance media, and, secondly, autointerference observable with the parent virus eventually lowered virus yield when neutral maintenance medium was used, but this effect of undiluted passage was eliminated by the use of pH 8.2 maintenance medium.
Erythrocytes of human, monkey, dog, rat, mouse, guinea pig, hen, or frog were incubated with [U-14C]adenosine at a concentration of 0.23 muM, a level roughly corresponding to its plasma level in mammals. Direct utilization of adenosine by phosphorylation (the kinase pathway) and indirect utilization via hypoxanthine (the hypoxanthine pathway) were analyzed from the ratio of the specific radioactivities of nucleotide and base, as described previously (1,2). Both human and monkey cells efficiently utilized adenosine only by the kinase pathway, while rodent cells used the same route with an efficiency which varied with the species. Canine cells incorporated adenosine in extremely small amounts both by the kinase pathway and via the hypoxanthine pathway with a marked predominance of the former. Frog erythrocytes were similar to dog cells in mechanism of utilization, but the efficiency was of the same level as that of the primates. In contrast to other animals tested, the avian cells utilized twice as much adenosine via the hypoxanthine pathway as by the kinase pathway.
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