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Biomedical subjects

R A Branch

Publications and source records attributed to R A Branch.

248 records · Page 14Linked to original sources
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Nitric oxide does not contribute to sodium retention and peripheral vasodilation induced by partial portal vein ligation in rats.

The role of nitric oxide (NO) synthesis in the peripheral vasodilation and sodium retention that occurs after partial portal vein ligation (PVL) was investigated. Hemodynamic studies in PVL rats with sodium retention and in sham-operated controls were conducted on the day when PVL rats developed transient and maximal sodium retention. Measurements were obtained before and during two consecutive periods after NO synthesis inhibition with NG-monomethyl-L-arginine (L-NMMA). Under baseline conditions, PVL rats with sodium retention were hypotensive, with equivalent decreases in total peripheral resistance and glomerular filtration rate in comparison to the control group. After L-NMMA, peripheral resistance and arterial pressure increased by similar extent in both groups. As compared with controls, PVL rats with sodium retention remained hypotensive and vasodilated. Furthermore, L-NMMA-induced natriuresis was attenuated in the PVL group. Additionally, serum and urinary levels of nitrate and nitrite did not vary before surgery and at the time of sodium retention. These results suggest that in PVL rats (1) vasodilation is not NO mediated; (2) vasodilation is not a sufficient explanation for sodium retention, and (3) a sodium-retaining factor acting on the renal tubules is responsible for sodium retention.

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PubMedDate not supplied

Amphotericin B nephrotoxicity.

The frequency of fungal infections is increasing. Amphotericin B remains the anti-fungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects. In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading. New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.

Amphotericin B↗
PubMedDate not supplied

A re-evaluation of intersubject variation in enzyme induction in man.

It has previously been suggested that subjects who are initially slow metabolisers of drugs have a greater potential for induction of their drug metabolising enzymes than subjects with initial high rates of metabolism. This inference is based on observations made of changes in half-life of antipyrine. The purpose of this presentation is to reanalyse data previously presented in the literature with reference to clearance, a more precise estimate of drug metabolising activity, and half-life a parameter derived from both clearance and distribution. In one study in non-obese subjects, approximately 80% of intersubject variation in the change of total antipyrine clearance can be explained by differences in body size, particularly differences in liver volume. Furthermore, the relationship between initial antipyrine half-life and the percentage change in antipyrine half-life following induction can be explained by the association between each parameter and body weight. These observations imply that the potential for enzyme induction, and therefore for drug interactions based on enzyme induction, is present in all subjects and that intersubject variance in steady-state drug concentrations are as wide following induction as before induction.

Antipyrine↗
PubMedDate not supplied

Extrahepatic glucuronidation of morphine in the dog.

The pharmacokinetic disposition of morphine was studied in sham-operated dogs, dogs with hepatic devascularization, and dogs with bile duct and ureter ligation after iv administration of 1 mg/kg of morphine. In sham-operated dogs, morphine is rapidly distributed and eliminated, with a terminal half-life of 65 +/- 30 min. Morphine glucuronide appeared in plasma within 5 min and rose rapidly to levels an order of magnitude higher than morphine levels, before both declined in parallel. In hepatic devascularized dogs, there was a marked delay in morphine elimination due to a 47% reduction in clearance. The appearance of morphine glucuronide in plasma was not delayed, but the AUC of morphine glucuronide was reduced by 56% compared to control for the first 180 min. In bile duct- and ureter-ligated dogs, elimination of morphine was increased and morphine glucuronide elimination from plasma was decreased, suggesting that glucuronide normally excreted in bile is hydrolyzed back to the parent compound and reabsorbed in sham-operated control animals. In conclusion, morphine was glucuronidated by both hepatic and extrahepatic glucuronyltransferases to an approximately equal extent in the dog.

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PubMedDate not supplied

Induction of drug-metabolizing enzymes by the enantiomers of normephenytoin in the rat.

The influence of the S- and R-enantiomers of normephenytoin on various hepatic drug-metabolizing enzyme systems has been investigated in the rat. Both enantiomers proved to be potent enzyme inducers. In vivo, 14C-aminopyrine breath test half-life was decreased and 24-hr urine recovery of 14C after 14C-diphenylhydantoin administration was increased. In vitro, hepatic cytochrome P-450 concentration was increased and there were increases in activity of oxidative metabolism of aminopyrine, aniline, hexobarbital, and p-nitroanisole, and in activities of glucuronyltransferase and glutathionetransferase enzymes. There were differences in the disposition of R- and S-enantiomers indicating that (S)-normephenytoin was eliminated more rapidly. Taking this into consideration, the two enantiomers were equipotent enzyme-inducing agents.

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PubMedDate not supplied

Monoacetyldapsone inhibition of dapsone N-hydroxylation by human and rat liver microsomes.

Dapsone (DDS) is metabolized by N-hydroxylation and N-acetylation to DDS hydroxylamine (DDS-NOH) and monoacetyldapsone (MAD), respectively. The activities of these two alternative and independent reactions vary widely between individuals and show an inverse relationship during chronic DDS therapy. Toxicity observed during DDS therapy has been attributed to DDS-NOH. The observation of reduced toxicity in rapid acetylators, who are also poor hydroxylators, therefore, raised the possibility that MAD may be inhibiting DDS-NOH formation. This hypothesis was tested in human and rat liver microsomes. Human liver microsomes hydroxylated DDS with a lower affinity (KM 2-fold greater) and lower maximal catalytic activity (Vmax 12-fold lower) than that of the rat. The relative catalytic activity (Vmax/KM) was 22-fold higher in rat compared with human liver microsomes. Furthermore, MAD was a potent inhibitor of DDS N-hydroxylation by rat liver microsomes (52% inhibition at 0.01 mM MAD) compared with human liver microsomes (23% inhibition at 0.4 mM MAD). Human, but not rat, liver microsomes deacetylated MAD to DDS by an NADPH independent mechanism. These results show that substantial differences exist in DDS N-hydroxylase between rats and humans, with respect to substrate affinity, enzyme activity, and susceptibility to inhibition, such that information obtained from the rat should not be extrapolated to humans. We conclude that MAD is a potent inhibitor of DDS-NOH formation in rat liver microsomes. The degree of inhibition in human microsomes, however, suggest that MAD is unlikely to be a significant modulator of enzyme activity in vivo.

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