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Biomedical subjects

F M Williams

Publications and source records attributed to F M Williams.

At least 109 records · Page 6Linked to original sources
PubMed1986

Substrate specificity of the mouse skin mixed-function oxidase system.

The metabolism of nine model substrates for the mixed-function oxidase system was studied in skin and liver microsomes from Balb/C mice. Rates of skin metabolism per mg microsomal protein ranged from 0.5-15% of liver rates depending on the substrate. Relative to liver, mouse skin preferentially metabolized ethoxyresorufin, benzo[alpha]pyrene and diphenyloxazole over aldrin, coumarin and the C1-C4 7-alkyl umbelliferone ethers. NADPH-cytochrome P-450-dependent metabolism of aldrin and ethoxyresorufin was differentially inhibited in skin microsomes by metyrapone and alpha-naphthoflavone, respectively. Biphasic Eadie-Hofstee plots were obtained in both skin and liver microsomes for the metabolism of aldrin, whereas metabolism of ethoxyresorufin in both systems was described by linear kinetics. It is concluded that mouse skin contains multiple forms of cytochrome P-450, and that forms functionally analogous to those induced by polycyclic hydrocarbons in rodent liver are present in untreated mouse skin.

Aldrin↗
PubMed1985

2,5-Diphenyloxazole as a probe for microsomal mono-oxygenation in human and rat liver.

2,5-Diphenyloxazole (PPO) is metabolized to one major fluorescent product by human liver and rat liver microsomes. PPO metabolism by human-liver microsomes involves more than one cytochrome P-450 isozyme, termed low-affinity and high-affinity components. At a substrate concentration of 0.1 microM, 95% of activity is due to the high-affinity component whereas at 100 microM 69% of activity is due to the low-affinity component. Inhibition studies with metyrapone and alpha-naphthoflavone at 0.1 microM and 100 microM suggest that the high-affinity component may reflect a 3-methylcholanthrene-inducible form of cytochrome. Therefore studies at low substrate concentrations may be a useful tool for cytochrome P-450 studies in man. Rat liver microsomes show linear kinetics indicating the involvement of one major form of cytochrome P-450.

Animals↗
PubMed1984

A comparative study of the effects of aspirin and paracetamol (acetaminophen) on platelet aggregation and bleeding time.

In a double blind, randomised trial, the effects of 1 g aspirin and 1 g paracetamol were compared on bleeding time and platelet aggregation in 40 volunteers (20 females). Also investigated was the relationship between plasma aspirin esterase activity and both bleeding time and platelet aggregation after aspirin. Following 1 g aspirin there was a significant increase in bleeding time at 24 h (p less than 0.01). A significant reduction (P less than 0.01) in platelet aggregation with collagen was observed at 1, 6 and 24 h after aspirin, but no significant reduction (P greater than 0.05) was observed with ADP. Paracetamol had no effect on bleeding time or platelet aggregation. Plasma aspirin esterase activity ranged from 0.26-0.6 mumol/ml/min. A significant negative correlation (R = -0.55, P less than 0.001) was observed between percentage increase in bleeding time (24 h) and plasma aspirin esterase activity. Further significant correlations were observed between plasma aspirin esterase activity and change in platelet aggregation with collagen at 1 h (R = 0.68, P less than 0.001), 6 h (R = -0.73, P less than 0.001) and 24 h (R = -0.67, P less than 0.001). These results suggest that it might be possible to predict an individual's haemostatic response to aspirin from knowledge of their plasma aspirin esterase activity.

Acetaminophen↗
PubMed1984

The effect of alcoholic cirrhosis on the two kinetic components (high and low affinity) of the microsomal 0-deethylation of 7-ethoxycoumarin in human liver.

The activities of the two kinetic components (high and low affinity) of the microsomal 0-deethylation of 7-ethoxycoumarin have been measured in liver from patients with alcoholic cirrhosis and in normals. The activity (expressed as pmol 7-OH coumarin formed/mg microsomal protein/min) of both components of the enzyme was significantly lower in alcoholic cirrhosis (high affinity = 3.27 +/- 1.18, low affinity 60.9 +/- 11.6) than in normals (high affinity 9.43 +/- 2.37, low affinity 111.3 +/- 9.2). These results are further evidence that there is a broad impairment of hepatic microsomal mono-oxygenase activity in alcoholic cirrhosis.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1984

Division synchrony and the dynamics of microbial populations: a size-specific model.

A discrete, environmentally coupled, size-specific model of microbial population dynamics in continuous culture is presented. It is mathematically simpler than other models based on similar assumptions and lends itself to numerical and analytic solutions. It displays several phenomena which have been reported in the experimental literature but which are not well understood; specifically, a loose relationship between biomass and numbers (i.e., a time lag between mass growth and cell division) and a critical damping of biomass while numbers continue to oscillate. In addition, the model provides several new predictions: The stable biomass distribution is independent of the environmental factors considered in the model and uniformly distributes the biomass among the size classes. The rate of approach to stability and the frequency of waves through the size distributions are a function of the flow rate and the variance in rate of growth and size at division. The model should provide a useful basis for studying the effects of size specificity on the dynamics of microbial populations cultured in chemostats.

Bacteria↗
PubMed1984

The effect of age on pathways of drug metabolism in human liver.

The effect of age on some important pathways of drug metabolism in human liver biopsy specimens was examined. Five parameters were investigated: two microsomal mono-oxygenases; aldrin epoxidation and 7-ethoxycoumarin-O-de-ethylation; microsomal protein recovery; epoxide hydrolase activity and concentrations of reduced gluthatione. No correlation was observed between age and any of these measurements. It is concluded that, contrary to conventionally held views, impaired clearance of some drugs in the elderly is unlikely to be due to decreased hepatic microsomal enzyme specific activity. Any increase in adverse drug reactions in the elderly liver is unlikely to be due to impaired detoxification of reactive metabolites.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1984

Reduction of antipyrine clearance in psoriasis.

Antipyrine clearance was determined in 41 psoriatics and age-sex matched controls, using sequential measurements of salivary concentration. Antipyrine clearance and elimination rate constant were less in psoriatics (P less than 0.05) and apparent volumes of distribution were similar. These differences were greater between female psoriatics and controls (P less than 0.025; P less than 0.05) and the differences between male psoriatics and controls were not significant. Correlation of simultaneous measurements of saliva and plasma antipyrine concentration in six psoriatics and age-sex matched controls showed no differences between the two groups. We conclude that antipyrine clearance is reduced in psoriasis but the underlying mechanism is unclear.

Adolescent↗
PubMed1984

Aspirin metabolism and efficacy in postoperative dental pain.

Aspirin 1200 mg was compared with placebo in a randomised, double-blind, crossover study in 15 patients with postoperative pain after removal of impacted lower third molars. Over a 5 h investigation period, patients reported significantly less pain (P less than 0.01) after treatment with aspirin, than after treatment with placebo. Peak concentrations of aspirin occurred at 15 min after dosage. Significant negative correlations were observed between plasma aspirin esterase activity and both AUC aspirin (r = -0.904, P less than 0.001) and AUC analgesia (r = -0.91, P less than 0.001). Similarly, a significant correlation was observed between AUC aspirin and AUC analgesia (r = 0.96, P less than 0.001). Evidence from this study would suggest that an individual's pain relief in postoperative dental pain is determined by the rate of aspirin hydrolysis to salicylate.

Adolescent↗
PubMed1984

An investigation into the characteristics of reperfusion-induced arrhythmias in the anaesthetized rat and their susceptibility to antiarrhythmic agents.

Reperfusion-induced arrhythmias were elicited in the pentobarbitone-anaesthetized rat by occlusion of the left main coronary artery and subsequent release. These arrhythmias were rapid in onset, occurring within 20 s after release of the ligature, and were of short duration (1-2 min). Their severity was dependent upon the duration of the preceding occlusion. A 5 or 15 min occlusion period produced the most severe arrhythmias on release, the incidence of ventricular fibrillation being 56 and 50% respectively. Evidence that reperfusion had occurred was provided by fluorescein dye distribution and intramyocardial temperature studies. The severity of reperfusion arrhythmias and mortality was unaffected by bilateral vagotomy, beta-adrenoceptor blockade by atenolol (2 mg kg-1 i.v.) or a combination of the two. The incidence of reperfusion-induced ventricular fibrillation was significantly reduced by Org 6001 (which blocks the fast inward sodium current), melperone (which acutely prolongs the cardiac action potential duration) and bepridil (which blocks both fast and slow inward currents). It was unaffected by nitroglycerine and the calcium antagonists verapamil, prenylamine and nifedipine. We have shown that reperfusion-induced cardiac arrhythmias can be consistently elicited in the anaesthetized rat and that they are particularly susceptible to drugs that can block the fast inward sodium current.

Anesthesia↗
PubMed1983

The effect of alcoholic cirrhosis on the activities of microsomal aldrin epoxidase, 7-ethoxycoumarin O-de-ethylase and epoxide hydrolase, and on the concentrations of reduced glutathione in human liver.

Activities of the microsomal mono-oxygenases 7-ethoxycoumarin O-de-ethylase (EOC) and aldrin epoxidase (AE), together with microsomal epoxide hydrolase (EH) activity and concentrations of reduced glutathione (GSH) have been measured in liver from patients with alcoholic cirrhosis and in normals. Activities of both mono-oxygenases were significantly reduced in alcoholic cirrhosis. EOC activity (pmol 7-OH coumarin formed/mg microsomal protein/min) was 108.0 +/- 10.6 (n = 8) in normals and 60.9 +/- 11.6 (n = 8) in alcoholic cirrhosis (P less than 0.01). AE activity (pmol dieldrin formed/mg microsomal protein/min) was 58.9 +/- 9.5 (n = 11) in normal liver biopsies and 29.9 +/- 8.6 (n = 9) in alcoholic cirrhosis (P less than 0.05). Microsomal EH activity (nmol styrene glycol formed/mg microsomal protein/min) was similar in normals (39.2 +/- 4.4, n = 11) and alcoholic cirrhosis (40.5 +/- 9.1, n = 6). GSH concentrations (microgram GSH/g liver tissue) were lower (P less than 0.01) in alcoholic cirrhosis (792 +/- 73, n = 10) compared to normals (1182 +/- 76, n = 6).

7-Alkoxycoumarin O-Dealkylase↗
PubMed1980

Plasma timolol levels and systolic time intervals.

The beta-blocking potency of timolol was compared with that of propranolol under steady-state conditions in eight healthy subjects. The effects on systolic time intervals in healthy subjects and patients (n = 6) with coronary artery disease were evaluated in relation to varying timolol dose schedules and plasma concentrations. The beta-blocking potency was assessed by the inhibition of exercise-induced tachycardia. Timolol was eight times as potent as propranolol. There was wide between-patient variation (2.6 to 13.8) in timolol plasma concentration, and correlation between dose and peak (r = 0.61, p < 0.01) or nadir (r = 0.5 p < 0.01). There was a relatively weak correlation between timolol plasma concentration and degree of beta-blockade (r = 0.45, p < 0.05) and a linear correlation with dose (r = 0.98, p < 0.001). In healthy subjects timolol and propranolol had variable effects on systolic time intervals but in patients with coronary artery disease equipotent doses prolonged the preejection period, isovolumetric contraction time, and the ratio of the preejection period over the left ventricular ejection time. In patients as well as in normal subjects, the data indicated considerable beta-blocking effects for both drugs at the end of a 12-hourly dosing schedule, suggesting that twice-daily timolol and propranolol may be clinically practical.

Adult↗
PubMed1978

The effect of chemical fixatives on cell walls of Bacillus subtilis.

Cell walls of Bacillus subtilis were treated with several chemical fixatives which are commonly used preparatory to electron microscopy; i.e., osmium tetroxide, formaldehyde, acrolein, crotonaldehyde, and glutaraldehyde. Dimensional analysis was performed on thin sections of fixed walls from plastic embeddings and, by means of the statistical technique of multiple comparisons, significant differences were found between wall thicknesses from the various fixations. These differences varied with the fixation time and the type of fixative used in the reaction. When compared to embedded walls which had been stained before fixation, the overall effect was a reduction in wall thickness which was attributed to fixative action and not to the embedding or staining processes. The reduction of wall thickness was even more apparent when dimensions of fixed walls were compared to published dimensions of both frozen sections and freeze-etch profiles. Since these fixatives bind to reactive sites within the wall fabric, a change in electrochemical charge density is effected which can be monitored in terms of heavy-metal-binding capacity. Most monoaldehyde fixatives and osmium tetroxide render the wall as reactive, or less reactive, to uranyl acetate as unfixed walls, whereas glutaraldehyde can significantly increase the binding capacity.

Acrolein↗
PubMed1976

Trial of combination of guanethidine and oxprenolol in hypertension.

Thirteen hypertensive patients entered a double-blind crossover trial of guanethidine and oxprenolol in combination. In nine patients who completed the trial there was an additive effect on blood pressure, but the combination had a smaller effect on heart rate than was expected from the individual effects, and side effects were not increased. During treatment with oxprenolol the plasma potassium concentration rose from 3.6 mmol (mEq)/1 to 3.9 mmol (mEq)/1. No correlation was found between the plasma oxprenolol concentration and changes in blood pressure or response to injected isoprenaline, but measurements of plasma oxprenolol concentrations were of value in determining compliance with the protocol.

Blood Pressure↗
PubMed1976

Maternal and neonatal elimination of amobarbital after treatment of the mother with barbiturates during late pregnancy.

Plasma half-lives of amobarbital were determined in newborn children of 10 mothers who had been treated with barbiturates for hypertension in pregnancy for 6 to 42 days prior to delivery. Five mothers had received amobarbital, 200 mg daily, and 5, phenobarbital, 60 to 180 mg daily. Half-lives in 7 of the babies ranged from 16.6 to 49.4 hr, comparable to those previously reported in babies of mothers who had received only a single dose of amobarbital. Thus there was no evidence of induction of amobarbital hydroxylation in these children. Two babies who had a greater than normal rise in serum bilirubin had longer half-lives (86.1 and 117.7 hr). In 1 baby whose mother had membranous glomerulonephritis, plasma amobarbital concentration did not significantly change over the period of the study.

Adult↗
PubMed1976

Amylobarbitone hydroxylation kinetics in small samples of rat and human liver.

1. Two micro methods for determining amylobarbitone hydroxylase activity from less than 3 mg liver are described. One is based on single-ion monitoring g.l.c.-mass spectrometry and the other on t.l.c. separation of 14C-labelled product. 2. Km and Vmax have been determined with rat liver and both needle and open biopsy samples of human liver. 3. Both methods are sufficiently sensitive and reproducible for use with 20 mg needle biopsies.

Amobarbital↗