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M Gumbleton

Publications and source records attributed to M Gumbleton.

42 records · Page 3Linked to original sources
PubMed1988

Dose-response and time-response biochemical and histological study of potassium dichromate-induced nephrotoxicity in the rat.

This study provides quantitative toxicological data on potassium dichromate-induced renal damage and considers the possible difficulties arising from the non-invasive in vivo assessment of renal damage, with particular attention to enzymuria. Renal damage induced in male Wistar rats by single sc injections of potassium dichromate was assessed 52 to 72 hr after doses ranging from 3 to 20 mg potassium dichromate/kg body weight and throughout a 9-day period following a dose of 20 mg potassium dichromate/kg. The earliest and most sensitive non-invasive functional change in the dose-response and time-response studies was an elevation in the rate of urinary excretion of protein. Evidence of tissue damage was observed with elevations in the urinary excretion rates of the brush border enzymes, gamma-glutamyltransferase, alkaline phosphatase and leucine aminopeptidase, the cytosolic enzymes, aspartate aminotransferase and lactate dehydrogenase and the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase. Such changes occurred as early as the abnormal urinary protein excretion, but returned to control or sub-control values sooner. Urinary brush border enzyme excretion returned to control values within 48 hr following potassium dichromate injection, despite histological and histochemical evidence of extensive renal damage and renal dysfunction. Elevations in plasma aspartate aminotransferase and lactate dehydrogenase levels were observed, but histochemical and isoenzyme studies would be needed to determine the source of these increases. The simplest and most persistent indicators of renal damage were the urinary excretion of protein and N-acetyl-beta-D-glucosaminidase.

Acetylglucosaminidase↗
PubMed1988

In-vivo effects of itraconazole on hepatic mixed-function oxidase.

The effects of itraconazole, a triazole antifungal agent, on cytochrome P450 were investigated by measuring the anti-convulsant activity of phenytoin in mice, and zoxazolamine paralysis time, tolbutamide clearance, and plasma dicoumarol concentrations after a single injection of dicoumarol, in rats. Itraconazole, given either as a single dose of 5 or 10 mg/kg, or daily at these levels for five days, had no significant effect on any of the measures. The drug therefore appears to be free of enzyme inhibiting or inducing activity, although an effect on other cytochrome P450 isozymes can not be discounted. Thus itraconazole may possibly show fewer clinically significant drug interactions at the level of hepatic mixed function oxidase than other azole antifungal agents.

Animals↗
PubMedDate not supplied

Possible hemodynamic basis to urethane anesthesia-induced reductions in renal clearance.

The hemodynamic basis of reported urethane anesthesia-induced reductions in the clearance of some renally eliminated compounds has been investigated in the laboratory rat. The use of urethane as an anesthetic in pharmacokinetic studies still persists, particularly in experiments of long duration. Using a microsphere technique, the per cent distribution of cardiac output to the kidneys, in both ip urethane- and ip Hypnorm/Hypnovel-anesthetized animals was significantly (p less than 0.01) lower than that observed in ip pentobarbital-anesthetized animals. However, the cardiac index in the Hypnorm/Hypnovel-anesthetized animals was 42% greater (p less than 0.01) than in the pentobarbital-treated animals and 86% greater (p less than 0.01) than in the urethane-treated group. Additionally, the cardiac index in the pentobarbital-anesthetized animals was significantly greater (p less than 0.01) than in the urethane-anesthetized animals. The lower cardiac index and reduced cardiac distribution to the kidneys in the urethane-treated group resulted in significant (p less than 0.01) reductions of approximately 40% in renal blood flow and glomerular filtration rate compared with the animals anesthetized with pentobarbital or Hypnorm/Hypnovel. The transport capacity of the basolateral organic anion secretory mechanism was not compromised by an ip injection of urethane, as demonstrated by p-aminohippuric acid transport studies conducted in isolated renal tubule fragments prepared from anesthetized animals. In conclusion, urethane anesthesia results in significant alterations of renal hemodynamics compared with pentobarbital and Hypnorm/Hypnovel anesthesia in the rat. For primarily renally eliminated compounds, such alterations are likely to influence pharmacokinetic data generated using this anesthetic agent.

Anesthesia↗
PubMedDate not supplied

The renin-angiotensin system and intraperitoneal toxicity: possible basis to urethane anaesthesia-induced reductions in renal clearance in the rat.

With the aim of examining the possible basis to i.p. urethane anaesthesia-induced reductions in renal clearance, this study has investigated: (a) the influence that some anaesthetic regimens may have on the renin-angiotensin system (RAS); and (b) the ability of these anaesthetic regimens to initiate intraperitoneal toxicity. In the rat, i.p. urethane anaesthesia, compared with pentobaritone i.p. and "Hypnorm/Hypnovel" i.p. anaesthesia, resulted in significantly lower mean arterial pressure (MAP) and elevations in plasma renin activity (PRA) in both surgically-prepared and surgically-intact animals. Urethane anaesthesia also produced intraperitoneal toxicity, which was characterized by a greater peritoneal fluid volume and peritoneal cavity total protein content. The elevated protein content in the peritoneal cavity resulted in part from plasma leakage from the vascular compartment, as demonstrated by i.v. Evans' blue dye studies. Intraperitoneal toxicity was absent following administration of urethane by either i.v. or oral routes. A reduction in systemic perfusion pressure and an elevation in renal vascular resistance, via activation of the RAS are likely to be responsible for i.p. urethane-induced reductions in renal clearance. Intraperitoneal toxicity is likely, only in part, to be responsible for such changes.

Anesthesia↗