James Bogan

Pharmacokinetics of albendazole in man

SummaryThe pharmacokinetics of albendazole were investigated in healthy volunteers and in patients receiving albendazole for treatment of hydatid disease. Unchanged albendazole was below detectable limits in plasma, urine, bile and cyst fluid. The major metabolite present in all fluids was the sulfoxide. Maximum concentrations of albendazole sulfoxide in plasma were very variable, probably due to variable absorption of albendazole.

The binding and subsequent inhibition of tubulin polymerization in Ascaris suum (in vitro) by benzimidazole anthelmintics

Benzimidazole anthelmintics may act by interfering with the microtubule system in Ascaris suum. Binding of benzimidazole anthelmintics, and their inactive metabolites, to A. suum tubulin was demonstrated by the inhibition of intestinal extracts of the nematode to bind [3H]colchicine. In addition, these compounds inhibited the polymerization of tubulin into microtubules in vitro.

Effect of parasitism with Ostertagia circumcincta on pharmacokinetics of fenbendazole in sheep

Plasma and abomasal fluid concentrations of fenbendazole and its two major metabolites in sheep experimentally infected with Ostertagia circumcincta were compared with those in the same sheep when non-parasitised. Bio-availability of the drug was reduced in the parasitised state. There was also a reduction in the proportion of drug present in the form of metabolites in parasitised as compared with non-parasitised animals.

The relation between primidone and phenobarbitone blood levels

A dose of primidone or one fifth of the same weight of phenobarbitone produced equal levels of phenobarbitone in the blood.

Level of Benzimidazole resistance in a strain of Ostertagia circumcincta studied over several infections in lambs

A benzimidazole-resistant strain of Ostertagia circumcincta (HFRO) was used experimentally to infect lambs. The level of resistance, measured by an egg hatch assay, was studied throughout each infection and also after treatment of the lambs with fenbendazole. The HFRO strain was highly resistant to benzimidazoles. There was day-to-day variation in the level of resistance throughout a single infection with a high level of resistance in the early part of the infection, around Day 27 post-inoculation of infective larvae, falling to a lower level later in the infection. Egg hatch assays on the 3 days immediately post-treatment with fenbendazole showed the resistance level was high then resistance fell to the pre-treatment level after 7 days. Selection for benzimidazole resistance using fenbendazole treatment at the normal dose rate of 5 mg kg-1 over five passages of the HFRO strain in lambs failed to increase the resistance level. Storage of larvae over a 5-month period at 4 degrees C, prior to infection of lambs, did not produce any alteration in the resistance level. The possible reasons for the variations in resistance found with the HFRO strain are discussed along with the implications for sheep parasite control and further development of benzimidazole resistance.

Pharmacological modulation of the pneumotoxicity of 3-methylindole

The nature of the reactive metabolite of 3-methylindole is investigated using microsomal preparations prepared from the lungs of cattle. Nucleophilic thiol agents, glutathione, L-cysteine and N-acetyl-L-cysteine, protected microsomal proteins against alkylation by the reactive metabolite of 3-methylindole. The cytosol fraction from the lungs of cattle increased the protective effect of these thiol agents. Pretreatment of sheep with diethylmaleate, which depletes glutathione, increased the severity of the pneumotoxic effect of 3-methylindole, whereas pretreatment with L-cysteine decreased the severity of this effect. These findings are consistent with a hypothesis that an electrophilic reactive metabolite of 3-methylindole is responsible for its pneumotoxic effect and implies that glutathione and glutathione S-transferases are involved in the detoxification of this reactive metabolite. Nucleophilic thiol agents can be useful in the prevention of reactive metabolite induced-lung injury.

The Detection of Barbiturates and Related Drugs by Thin Layer Chromatography

Summary This paper describes a method for the detection and identification of barbiturates and a few related compounds. The whole process can be completed in thirty to forty minutes and is a valuable aid in situations where the rapid identification of barbiturates is important, e.g. pre-race testing of racing animals. Detection without identification may be completed within fifteen minutes. (Readers are also referred to an interesting paper on Barbiturate Detection Using Thin Layer Chromatography by Sunshine et al. in Clinical Chemistry, 1963, 9, 312. Ed.)

Fatal Poisoning by Primidone

The investigation of a case of Primidone poisoning showed typical signs of barbiturate poisoning. The amounts of Phenobarbitone found were such that death was due largely if not wholly to its effects.

The fumarate reductase system as a site of anthelmintic attack inAscaris suum

Various benzimidazole compounds have been shown to be highly eIIective as inhibitors (up to 50% reduction of activity) in vitro of the helminth-specilic enzyme, fumarate reductase, ofAscaris suum. Anthelmintically active and inactive benzimidazoles were similarly effective as inhibitors of enzyme activity. Albendazole-induced inhibition of Iumarate reductase was not observed when the enzyme was preincubated with NADH.

Effect of SKF 525A on the fate of thiopentone

The initial rapid decline in thiopentone blood concentrations in all species after intravenous injection is attributed mainly to redistribution either into lean tissue (Price, Kevnat & others, 1959), or lean tissue and fat (Mark & Brand, 1963). The further slow decline of thiopentone blood levels may be due to further redistribution or to a combination of the two. Mark, Brand & others (1965) in man, and Saidman & Eger (1966) in the dog, have demonstrated an arterial hepatic venous difference in thiopentone concentrations and have claimed that metabolism by the liver is of importance in lowering the blood concentrations of thiopentone. Many of the estimations of thiopentone metabolism by the liver both in vivo and in vitro (Winters, Spector & others, 1955; Spector & Shideman, 1959) are of doubtful validity because they use methods which result in the degradation of thiopentone to pentobarbitone (Bush, Maze1 & others 1961) ; thus, the rate of thiopentone metabolism has been variously put at 2, to 40%/h. A method of demonstrating the contribution of metabolism in the termination of the anaesthetic action of thiopentone would be by measuring the effect of a liver enzyme inhibitor. Shideman, Kelly & Adams (1947) have shown that carbon tetrachloride markedly prolongs thiopentone sleeping times in rats and this was assumed to arise from the hepatotoxicity of carbon tetrachloride. Megirian (1964) however, has since shown that carbon tetrachloride alters the distribution of thiopentone and that its action in prolonging sleeping times may be due to this effect. SKF 525A (P-diethylaminodiphenylpropyl acetate), an inhibitor of liver microsoma1 enzymes, has been shown to prolong the sleeping times in rats produced by hexobarbitone and other barbiturates (Fouts & Brodie, 1956). It was of interest, therefore, to measure the effect of SKF 525A on thiopentone blood concentrations and on thiopentone sleeping times. Five dogs (3 greyhounds, 2 terriers) were given SKF 525A (10 mg/pg) intravenously and after 30 min thiopentone (30 mg/kg) intravenously. Blood samples were taken at intervals. Thiopentone blood concentrations were measured by the method of Brodie & others (1950) except that ethylene dichloride was used as the extraction solvent, whereby less than 1% degradation of thiopentone occurs in the extraction procedure. It should be noted that the greyhounds maintained higher blood concentrations of thiopentone, presumably through lack of body fat, and were correspondingly anaesthetized and ataxic for longer than the other two dogs. SKF 525A did not produce any alteration in the rate of decline of thiopentone blood levels in the five dogs. Hooded inbred rats were injected intraperitoneally with SKF 525A (10 mg/kg) 30 min before thiopentone. A control group of rats were given saline. The rats were then injected with thiopentone (25 mg/kg) in a tail vein and the sleeping times measured. SKF 525A did not produce any significant difference in thiopentone sleeping times in rats (52.2 f 10.8, n = 13) compared with animals given thiopentone alone (47.8 f 5.5, n = 12) (P > 0.4). These results would indicate that hepatic metabolism is not important in the termination of the anaesthetic action of thiopentone.