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Biomedical subjects

D R Hawkins

Publications and source records attributed to D R Hawkins.

At least 19 recordsLinked to original sources
PubMed1992

Identification of metabolites of halofantrine, a new candidate anti-malarial drug, by gas chromatography-mass spectrometry.

Two previously unknown metabolites of halofantrine, a candidate anti-malarial drug, have been isolated by thin-layer chromatography from the plasma of dogs administered a single oral dose of 60 mg/kg. Their identifies were investigated after trimethylsilylation by gas chromatography-mass spectrometry under electron-impact and negative-ion chemical ionization conditions. The structural assignment was further confirmed by using a combination of elemental composition analysis of all the isotope peaks at low mass resolution and isotope pattern matching. These two metabolites were formed by modification of the dibutylaminopropyl side-chain of the parent compound involving deamination and oxidation or reduction.

Animals↗
PubMed1991

Pharmacokinetics of pyridostigmine in dogs.

The pharmacokinetics of the cholinesterase inhibitor pyridostigmine has been studied in six male Beagle dogs after iv infusion and after oral doses as an immediate-release syrup and as an extended-release tablet, all at a level of approximately 0.6 mg/kg. Pyridostigmine was characterized as a drug of relatively long terminal half-life (8.3 h +/- 2.1 SD), low systemic clearance (13 mL/min/kg +/- 1 SD) and high volumes of distribution (Vd lambda z, 8.7 L/kg +/- 1.9 SD and Vdss, 3.9 L/kg +/- 0.9 SD). The ratio of mean residence times in tissues and plasma was greater than 4, indicating a high affinity of peripheral tissues for the drug. This ratio was about twofold higher in three of the dogs than in the others. Pyridostigmine was slowly and incompletely bioavailable in these dogs; the systemic availability was 44.4% +/- 4.3 SD from the syrup and 33.6% +/- 9.5 SD from the tablet. Pyridostigmine disposition in these dogs was largely determined by distribution processes.

Administration, Oral↗
PubMed1991

Pharmacokinetics of the anti-leishmanian agent WR 6026 in dogs.

The pharmacokinetics of the anti-leishmanial agent WR 6026 (8-(6-diethylaminohexylamino)-6-methoxy-4-methylquinoline dihydrochloride) has been studied after single intravenous infusion and oral doses of 5 mg (base)/kg to 6 Beagle dogs. After single intravenous infusions of 15 min, plasma concentrations of unchanged drug declined bi-exponentially from a mean maximum of 1203 ng/ml +/- 277 SD at the end of infusion to the limit of quantitation during 16 hours. After single oral doses, the mean Cmax of 23 ng/ml +/- 14 SD occurred at a mean Tmax of 2.2 hours +/- 1.3 SD. During 72 hours after the intravenous and oral doses, 0.6% and less than 0.2% of the dose respectively was excreted unchanged in the urine. The mean terminal-life of WR 6026 after the infusion doses was +/- 0.3 SD, but after the oral doses, plasma concentrations of drug were too low to allow estimation of the terminal half-life. The systemic clearance of WR 6026 (43.5 ml/min/kg) greatly exceeded the nomina, plasma flow (ca. 22 ml/min/kg) and indicated considerable extra-hepatic and extra-renal elimination of WR 6026 in dogs. The mean systemic availability of WR 6026 after the oral doses was ca.4%. The mean volumes of distribution of WR 6026 in dogs were 3.3 litres/kg +/- 1.1 SD (V(ss)) and 7.7 litres/kg +/- 2.4 SD (V(area)). These data characterise WR 6026 as a drug of relatively high systemic clearance, large volume of distribution, relatively short half-life and low systemic availability, probably due to presystematic elimination in the liver.

Administration, Oral↗
PubMed1990

The metabolic fate of 14C-ximoprofen in rats, baboons and humans.

1. The metabolic fate of 14C-ximoprofen was compared in rat (2 mg/kg), baboon (2 mg/kg) and human (approx. 0.4 mg/kg). An oral dose was well absorbed in all three species as indicated by urinary excretion of 80%, 86% and 94% dose respectively in 5 days: excreted in the faeces were 14%, 2% and 2% dose respectively. 2. Total 14C in plasma reached peak concentrations at 1-1.5 h in humans and earlier in animals. In humans, plasma 14C was initially associated mainly with unchanged drug which declined with a half-life of about 2 h (plasma 14C t1/2 about 8 h; cf. about 6 h in animals). 3. Tissue 14C concentrations in rats were generally similar to those in baboons at 1 h after dosing, decreasing substantially at later times. The distribution of 14C was consistent with that of a compound readily eliminated. 4. The major biotransformation products of ximoprofen were formed by hydrolysis to the keto-analogue followed by reduction to the hydroxy-analogue and conjugation of these two compounds. The same major metabolites were detected in urine of rat, baboon and humans but there was (a) complete biotransformation of ximoprofen in the rat, (b) an apparent difference in the nature of the conjugated component(s) in rat urine and those in baboon and human urine, (c) only one hydroxy-analogue detected in human urine but two such compounds in animal urine as indicated by mass spectrometry. 5. In human plasma at peak concentrations, the relative importance of circulating components was ximoprofen greater than keto-analogue greater than hydroxy-analogue, whereas in the plasma of the animal species this order was reversed, consistent with the more extensive biotransformation of ximoprofen observed in rat or baboon.

Adult↗
PubMed1988

The relationship between composition of gain and circulating hormones in growing beef bulls fed three dietary crude protein levels.

Twenty-one Simmental crossbred bulls (311 +/- 11 kg, 9 mo of age) were used to determine the effect of feeding 10, 12 or 14% CP on concentration of hormones in blood and the relationship of these hormones to composition of gain. Six bulls were slaughtered on d 0 to provide an estimate of initial carcass composition (9-11 rib section). Remaining bulls were assigned to dietary treatments. Blood samples were collected every 30 min from 0800 to 2000 on d 0, 66, 136 and 202 of treatment; bulls were slaughtered on d 203. Across all treatments, growth hormone (GH) declined (P less than .05) from d 0 to d 202. Free insulin-like growth factor I (IGF-I) was lowest (P less than .05) on d 0. In four randomly selected bulls, IGF-I fluctuated during the 12-h sampling periods. Within each treatment group, insulin was greatest on d 202 (P less than .05). Testosterone (T) increased from d 0 to d 66, then declined. Cortisol (C) was lowest on d 66. Thyroid hormones increased (P less than .05) after d 0. Growth hormone and IGF-I were correlated negatively with carcass fat percentage, fat accretion rate and fat thickness. IGF-I concentrations were correlated positively with percentage of carcass protein. Testosterone:cortisol ratio was not related to composition, but high T coupled with low C may be related to carcass leanness (mean carcass fat = 24.4%). These data suggest that GH and IGF-I are the hormones most related to composition of gain in growing beef bulls.

Animals↗
PubMed1988

The effects of dietary crude protein level on rate, efficiency and composition of gain of growing beef bulls.

Two experiments were conducted to evaluate the effects of dietary CP level on rate, efficiency and composition of gain of growing beef bulls. In Exp. 1, 59 bulls (333 +/- 15.8 kg) were used. Eleven bulls were slaughtered on d 0 to provide an estimate of initial carcass composition (9-10-11 rib section chemical analyses), and remaining bulls were assigned to treatment diets containing 10, 12 or 14% dietary CP. Bulls fed the 10% CP diet grew slower (P less than .05) than bulls fed the 12 or 14% CP diets, although dry matter intake and feed-to-gain ratio did not differ. Bulls fed the 12% CP diet had fatter carcasses (P less than .05) than bulls fed the 10 or 14% CP diets and had greater daily fat accretion than bulls fed the 10% CP diet. In Exp. 2, 60 bulls (318 +/- 9.0 kg) were used. Bulls were assigned to initial slaughter (n = 6) or to one of three dietary treatments, 10, 12 or 14% CP, and were slaughtered after feeding for 66, 136 or 202 d (n = 6 . treatment -1 . slaughter time -1). Bulls fed 10% CP diets had lower (P less than .05) rates of carcass protein accretion during d 0 to 136 and d 0 to 202. Carcass fat gain was similar among treatments over the entire experiment, although bulls fed the 14% CP diet gained more fat during d 0 to 136 than bulls fed the other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Effects of tallow supplementation and protein withdrawal on ruminal fermentation, microbial synthesis and site of digestion.

The effects of tallow supplementation [0% (NT) vs 7.5% (T)] and crude protein level [8.5% (LP) vs 12.0% (HP)] on ruminal fermentation, microbial protein (MCP) synthesis, digesta passage and site of digestion were estimated using yearling Angus X Simmental steers (390 kg) fitted with ruminal and T-type duodenal cannulae. Chromium-EDTA and ytterbium (Yb) chloride were used as markers of the liquid and solid phases. Passage and site of digestion data were estimated from the concentrations of Yb in the duodenal digesta and feces. Dry matter (DM) intakes were 6.8, 6.5, 6.3 and 6.6 kg/d for the NT-LP, NT-HP and T-HP diets, respectively. Ruminal ammonia concentrations (mg/100 ml) for the NT-LP, NT-HP, T-LP and T-HP diets were 1.22, 4.75, 1.05 and 3.41, respectively. Tallow decreased (P less than .05) acetate (mol/100 mol), increased (P less than .01) propionate (mol/100 mol) and decreased the total volatile fatty acid concentration. Tallow depressed apparent ruminal DM and organic matter (OM) digestibilities only on the HP diet. High protein increased ruminal DM, OM and fiber digestibilities. Tallow and LP tended to shift the site of OM digestion to the lower tract. The liquid and solid dilution rates for the NT-LP, NT-HP, T-LP and T-HP diets were 9.53, 3.37; 5.63, 3.28; 6.66, 5.10 and 6.79, 5.34%/h, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Major mental illness and childbearing. A role for the consultation-liaison psychiatrist in obstetrics.

Considerable attention has been paid to psychiatric disorders arising in the postpartum period. However, there has been very little systematic study of mental illness during pregnancy. Although quantitatively not a major problem, it can pose several difficulties for mother and fetus. This article reviews the existing literature and along with illustrative cases discusses the management of mental illness related to pregnancy. The relationship between the consultation-liaison psychiatrist and the obstetrician-gynecologist in caring for such problems is emphasized.

Adult↗
PubMed1986

The pharmacokinetics of dichloromethane. I. Disposition in B6C3F1 mice following intravenous and oral administration.

The tissue distribution and metabolism of dichloromethane (DCM; CH2Cl2) was investigated in B6C3F1 mice following iv or oral administration. The route of exposure and the composition of the dosing solution were found to have a significant effect on the pharmacokinetics. Following single iv doses of 10 or 50 mg [14C]DCM/kg dose-dependent metabolism to 14CO2 and 14CO and rapid pulmonary clearance of unchanged 14CH2Cl2 characterized the elimination of DCM from the body. The highest concentrations of 14CH2Cl2 were found in the liver, lung and kidney, with more than 50% of the total radioactivity in these tissues represented by the parent compound. When DCM was administered orally in single gavage doses for 14 consecutive days at treatment levels of 50 mg/kg in water or 500 and 1000 mg/kg in corn oil, rapid absorption and elimination of DCM characterized the treatment in water while distinctly slower trends were found for the doses in corn oil. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing over the 2-wk treatment period.

Administration, Oral↗
PubMed1986

The pharmacokinetics of dichloromethane. II. Disposition in Fischer 344 rats following intravenous and oral administration.

The tissue distribution and metabolism of dichloromethane (DCM; CH2Cl2) was investigated in Fischer 344 rats following iv or oral administration. The route and level of exposure were found to have a significant effect on the disposition characteristics. A two-compartment model was used to describe the elimination of DCM from blood following single iv doses. The estimates of t1/2,beta were 11.9 and 23.5 min for doses of 10 and 50 mg/kg, respectively, and the disposition rate constants, beta were found to differ significantly at P less than 0.05. When DCM was administered orally (by gavage) in a daily dose of 50 or 200 mg/kg for 14 consecutive days, rapid absorption and distribution to the tissues characterized the disposition. Dose-dependent metabolism to 14CO2 and 14CO and rapid pulmonary clearance of unchanged 14CH2Cl2 were the dominant routes of elimination of DCM from the body following both iv and oral doses. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing.

Administration, Oral↗
PubMed1985

Reasons for monitoring kinetics in safety evaluation studies.

Studies of the toxicity of a potential new drug form the basis of its preclinical safety evaluation and it is important that these toxicity studies are designed and conducted in a rational manner to permit the reliable interpretation and extrapolation of the resulting data to man. It is proposed that these objectives are more likely to be met with the support of pharmacokinetic data. Generally, toxicity studies include four groups of animals, a control group and three treated groups receiving low, intermediate and high dose levels respectively. In order to assist in the proper selection of appropriate dose levels and to increase the usefulness of the data obtained from toxicity studies, information on the following should be known. Relationship between dose level and the extent of absorption of the test compound. Effect of repeated (chronic) doses on the pharmacokinetics of the test compound. Relationship between the age of the animal and pharmacokinetics of the test compound. Relationship between the dose regimen used clinically and those used in toxicity studies.

Age Factors↗
PubMed1985

Extended sleep (hypersomnia) in young depressed patients.

To test the hypothesis that young depressed patients have prolonged rather than shortened sleep, 14 depressed patients aged 17-25 and age-matched normal control subjects were allowed to sleep as long as they wanted. All subjects increased their sleep over baseline values, but the extended sleep period of the depressed patients was almost twice as long as that of the control subjects. The distribution of sleep stages in the extended period did not differ. The depressed patients had changes in the length of REM periods similar to those of older subjects. The findings suggest an interaction between age, sleep, and depression.

Adolescent↗
PubMed1985

Dietary energy density and frame size effects on composition of gain in feedlot cattle.

Experiments were conducted to evaluate the effects of dietary energy density or genetic background on protein and fat gain of growing cattle. In Exp. 1, 24 Limousin steers were used in a growing-finishing trial. A 2 X 2 factorial arrangement was used with steers randomly allotted to four treatment combinations and fed the following diets: 80% concentrate, high moisture corn-corn silage diet (HI) or a corn silage diet (LO) during both the growing (GRO) and(or) the finishing (FIN) phases. Body composition for both experiments was determined by a deuterium oxide dilution technique. Empty body weight gains were greater (P less than .05) for HI during GRO, FIN and the total trial. Daily protein gains (DPG) were greater (P less than .05) for HI during GRO and FIN, while cattle receiving HI during at least FIN had the greatest (P less than .05) overall DPG. Daily fat gains (DFG) followed the pattern of DPG, being more rapid (P less than .05) for cattle fed HI during either GRO or FIN. Cattle fed the HI diet also tended to be more energetically efficient. In Exp. 2, large frame (LG) and small frame (SM) cattle were used for the evaluation of frame size effects on protein and fat deposition. Steers were individually fed an 80% concentrate, corn-based diet during the entire trial. Average daily gains and daily dry matter intake (P less than .05, P less than .01) were greater for LG, while feed efficiency was similar for both cattle types. Large cattle had greater (P less than .05) DPG than SM cattle, however, DFG were not different. Small frame steers were energetically more efficient (P less than .05), apparently due to composition of gain difference.

Animal Feed↗
PubMed1983

The metabolism of the anti-inflammatory drug eterylate in rat, dog and man.

Oral doses of 14C-eterylate were well absorbed by rat and man and excreted mainly in the urine (94% dose by rat in three days and 91% by man in five days). Oral doses to dogs were excreted in similar proportions in both the urine and faeces, although faecal 14C was probably derived in part, from biliary-excreted material. Peak plasma 14C and drug concn. were generally reached between one and three hours after oral doses. In humans, only two metabolites, salicylic acid and 4-acetamido-phenoxyacetic acid, were detected in plasma. The latter was cleared more rapidly than the former and hence plasma salicyclate concn. reached a peak (10.9 and 19.8 micrograms/ml in Subjects 1 and 2, respectively) and initially declined with a half-life of about two-three hours. Plasma 4-acetamidophenoxyacetic acid concn. reached a peak (4.3, 10.0 micrograms/ml, respectively) and declined with a half-life of about one hour. Tissue concn. of 14C were generally greater in dogs than in rats. Highest conc. occurred at three hours in dogs and at one hour in rats. Apart from those in the liver and kidneys, tissue concn. were lower than those in the corresponding plasma. Unchanged drug was not detected in urine or plasma of any species and was rapidly metabolized in human plasma. The major 14C components in human urine were identified as salicyluric acid and 4-acetamidophenoxyacetic acid; minor metabolites were salicylic acid, gentisic acid and paracetamol. These metabolites were also detected in rat urine albeit in different proportions to those in human urine. Dog urine contained less of these metabolites and a major proportion of the 14C was associated with relatively non-polar components. Although salicylic acid and 4-acetamidophenoxyacetic acid were the only major circulating metabolites in man and rat, dog plasma also contained the non-polar urine metabolites.

Acetanilides↗
PubMed1982

A novel conjugate as a major metabolite of bromperidol in man.

The major urine metabolites of the neuroleptic drug, bromperidol, after oral doses to rats and dogs are p-fluorophenylacetic acid and its glycine conjugate resulting from oxidative N-dealkylation. While the same metabolites were also detected in human urine, also present was a major unknown component representing 50% of the total urine metabolites, which apparently was not formed by rats and dogs to any extent. Mass spectroscopic investigations a substituent attached to the tertiary hydroxyl group. The mass spectrum of the metabolite after trifluoroacetylation was consistent with an O-glucofuranosiduronolactone conjugate of bromperidol.

Biotransformation↗
PubMed1982

Effect of the triazolobenzodiazepine estazolam on hepatic drug-metabolizing enzyme activity in rats.

Oral doses of the sedative/hypnotic estazolam (500 mg kg-1 day-1) to rats for 21 days caused statistically significant increases in liver weight, ascorbate excretion, cytochrome P-450 concentrations, and in aniline hydroxylase, ethylmorphine N-demethylase and glutathione S-transferase activities, as did approximately equivalent doses of flurazepam hydrochloride. Histologically, the centrilobular hepatocytes were enlarged. Some of these parameters were also increased after doses of estazolam of 100 mg kg-1 day-1, but not after 5 mg kg-1 day-1, which is about 50-fold greater than a clinical dose. Estazolam was a much less potent enzyme inducer than phenobarbitone under the conditions of these studies.

Animals↗