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Biomedical subjects

D G Upshall

Publications and source records attributed to D G Upshall.

51 records · Page 3Linked to original sources
PubMed1976

Species and phenobarbitone-induced differences in the kinetic constants of liver microsomal harmine O-demethylation.

1. The apparent kinetic constants for the O-demethylation of harmine to harmol by 10 000 g supernatant fractions from livers of mice, rats, guinea-pigs, rabbits, cats and cows have been determined. The Km values were 10-39 muM and Vmax 0-25 and 1-65 nmol/mg protein/min. 2. Optimal conditions of incubation time and NADP requirements differed between species. In all species except cat and cow the rate of O-demethylation of harmine was linear for 5 min, but in the latter species was linear for 15 min. Maximum stimulation of O-demethylation occurred at NADP concn. of between 50 and 375 muM. 3. Phenobarbitone pre-treatment of weanling, young adult and mature adult mice increased the Vmax for O-demethylation by 2.9- to 4.6-fold but did not change Km. Increased Vmax values were greatest in young and least in old mice and these changes were directly correlated with a decrease of hexobarbitone sleeping time.

Animals↗
PubMed1976

Aspects of the teratology of cyclophosphamide (NSC-26271).

Wistar-derived rat embryos were most sensitive to maternally administered cyclophosphamide on Days 9.5 and 10.5 of gestation and to chlorambucil on Day 9.5 of gestation. The spectrum of malformations and the dose-response behavior of both drugs were similar. Chlorambucil was three times more potent than cyclophosphamide on an mg/kg basis. The drugs showed additive behavior when administered in combination. The teratogenic effects of the individual or combined drugs were reduced by protective doses of cysteine or glutathione. Studies with analogs of cyclophosphamide have suggested that the whole molecule is involved in teratogenesis.

Abnormalities, Drug-Induced↗
PubMed1975

Pharmacokinetics and metabolism of two carbamate insecticides, carbaryl and landrin, in the rat.

1. A pharmacokinetic model for distribution of carbaryl and landrin (0-5 mg/kg) in male rat has been derived. Distribution of both compounds is adequately described in terms of two kinetically distinct compartments equilibrating slowly or rapidly with the blood circulatory system. The role of the slowly equilibrating tissue compartment is particularly important for carbaryl and as a result this carbamate has a longer half-life (77 min) than landrin (42 min). 2. Less than 1% of the carbamate was excreted unchanged. The kinetics of metabolism have been studied by decline in plasma carbamate concentrations, urinary excretion, and production of 14CO2 from the 14C-carbamyl group. Enterohepatic circulation of carbamate metabolites prolongs the duration of radioactivity in the body. 3. Comparison of different routes of administration shows that oral or hepatic portal administration results in lower plasma carbamate levels than those achieved by jugular vein injection, due to a liver first-pass effect.

Animals↗
PubMed1975

Further studies using carbamate esters as model compounds to investigate the role of lipophilicity in the gastrointestinal absorption of foreign compounds.

In order to examine the validity of models proposed previously for the gastrointestinal absorption of foreign compounds, the absorption behavior of a series of N-methylated carbamates has been studied in the rat. An optimal partition coefficient for the intestinal absorption of these compounds was demonstrated but this value was approximately one order higher than that reported earlier for a related series of unsubstituted carbamates. It is suggested that this difference is due to the modification in hydrogen bonding arising from N-methyl substitution. In contrast, an optimal partition coefficient for gastric absorption could not be demonstrated within the range of the apparent partition coefficient studied. The absorption behavior of the N-methylated carbamates tends to confirm the different trends previously observed between drug absorption from the intestine and that from the stomach.

Absorption↗
PubMedDate not supplied

Structure-pulmonary toxicity/retention relationships of inhaled fluorocyclobutenes.

Hexafluorocyclobutene (HFCB) and derivatives have been used as fumigants, refrigerants and polymerization monomers. When inhaled they produce a potentially fatal pulmonary oedema similar to that induced by perfluoroisobutene (PFIB), a by-product of Teflon manufacture. This study determined the relationship between the chemical structure, respiratory retention and toxicity of HFCB and five analogues in rats and mice. Retention in the rat was determined using a flow-through system combining nose-only exposure and plethysmography. Structural changes to HFCB modified retention. At concentrations of ca. 1 ppm, where uptake was independent of exposure time, the rate of uptake was increased by halogen substitution in the order 3-Br = 1-Br = 1-Cl > 3-Cl = 1-H > HFCB, and was a function of volatility. At concentrations of 6 or 30 ppm, the percentage retained and rate of uptake decreased with time. The total mass retained (micromol kg(-1)) was not proportional to inhaled concentration and was best described by the calculated partition coefficient (octane-water). No clear relationship between retention and reactivity was apparent. The contribution of volatility, partition coefficient and reactivity to the uptake process depended on inhaled concentration. The toxicity of the fluorocyclobutenes agreed with reactivity relationships based on electrophilicity (lowest unoccupied molecular orbital energy), carbanion stability and leaving-group mobility. Toxicity is based principally on the number of successive alkylations (1, 2 or 3) that can occur with tissue nucleophiles.

Administration, Inhalation↗
PubMedDate not supplied

Retention of inhaled hexafluorocyclobutene in the rat.

Hexafluorocyclobutene (HFCB), a cyclic analogue of perfluoroisobutene (PFIB), is a reactive gas that induces a fulminating pulmonary oedema in rats from which animals may die after an apparently asymptomatic period between 24 and 30 h, depending on the dose. To determine the dose of inhaled gas to the respiratory tract, the retention of HFCB has been determined in the rat at three inhaled concentrations with simultaneous measurement of respiratory parameters. Rats exposed continuously to HFCB retained 25%, 19% and 16% of the inhaled dose after exposure to 1.2, 6 and 30 ppm, respectively, which fell to 24%, 17% and 9% at 30 min and 21%, 16% and 6.5% after 1 h. The rate of uptake of HFCB decreased markedly at the highest concentration from 200 to 112 nmol min-1 kg-1 after 30 min and to 90 nmol min-1 kg-1 after a further 30 min. Ventilatory parameters were unchanged throughout the experiment and there was no evidence of pathological or histopathological damage at the end of the exposure. On renewal of exposure to gas after a 15-min pause, the percentage of gas retained was unchanged from that determined previously. The results indicate that there is a saturable component within the respiratory tract that is both time and concentration dependent. Hexafluorocyclobutene does not produce direct pathological damage outside the lung, which indicates that it may react rapidly with tissue components within the lung.

Administration, Inhalation↗
PubMedDate not supplied

Biological consequences of multiple vaccine and pyridostigmine pretreatment in the guinea pig.

An investigation of the possible interactions between combinations of vaccines and pyridostigmine bromide (PB) has been undertaken in the guinea pig. This study is part of a research programme funded by the UK Government to determine any effects of the pretreatment regimes given to UK Forces during the Persian Gulf conflict of 1990-1991. The study was designed to simulate PB administration and to model multiple vaccination protocols that were experienced by UK Forces, modelling a "worst case" situation in which all ten vaccines and PB were administered within a short period of time. Seven of the vaccines were health and hygiene (H+H) vaccines given to protect against endemic diseases and two vaccines to protect against the biological warfare agents anthrax and plague. In addition, pertussis vaccine was administered as an adjuvant to reduce the time to achieve immunity against anthrax. Four groups of eight animals were treated with 1/20th, 1/10th or 1/5th human doses of vaccines or vehicles, respectively. The PB or saline was delivered by implanted 28 day mini-osmotic pumps to achieve a mean red blood cell acetylcholinesterase (AChE) inhibition of around 30%. Body weight, temperature, immunological response, biochemical indices and spontaneous activity were monitored for 72 days. Although immunological responses to bacterial vaccines were observed, there were no remarkable findings in the parameters measured other than minor changes in body weight (4.9% decrease at the 1/5th human dose of vaccines) and temperature increases in response to vaccination. Animals in all groups remained generally healthy and active without visible adverse signs throughout the study. Reproduced with the permission of Her Majesty's Stationery Office. Published by John Wiley & Sons, Ltd.

Acetylcholinesterase↗