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Biomedical subjects

H G Giles

Publications and source records attributed to H G Giles.

At least 37 records · Page 2Linked to original sources
PubMed1983

In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.

Factors influencing the rate and extent of benzodiazepine uptake into cerebrospinal fluid (CSF), peripheral tissue distribution and electroencephalographic (EEG) effects were evaluated in a model utilizing anesthetized male cats. A single (0.25-10 mg/kg) dose of the following eight benzodiazepines was administered i.v.: diazepam, desmethyldiazepam, midazolam, lorazepam, alprazolam, triazolam, flunitrazepam and clobazam. Multiple samples were simultaneously drawn from arterial blood and cisternal CSF over the next 4 hr and the EEG was continuously monitored. Concentrations of benzodiazepines in plasma and CSF samples were measured by electron-capture gas-liquid chromatography and plasma protein binding determined by equilibrium dialysis. Physicochemical properties of lipophilicity of each benzodiazepine were determined by measurement of the octanol/buffer partition ratio at physiologic pH and by the high-pressure liquid chromatographic (HPLC) retention on a reverse-phase C18 column at neutral pH. Disappearance of all benzodiazepines from plasma was consistent with a linear sum of two or three exponential terms. After correction for individual differences in protein binding, volume of distribution (Vd) of unbound drug was highly correlated with HPLC retention (r = 0.91), but not significantly related to octanol/buffer partition coefficient. Diazepam and midazolam, having the longest HPLC retention also had the largest unbound Vd. All benzodiazepines rapidly entered CSF, with peak concentrations usually attained within 15 min of dosage. More lipophilic drugs tended to enter CSF most rapidly, but associations of entry rate and in vitro lipophilicity were not significant. After distribution equilibrium was attained, disappearance of benzodiazepines from both plasma and CSF occurred in parallel. Equilibrium CSF/total plasma concentration ratios of all drugs were much less than unity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Plasma protein binding of phencyclidine.

In healthy male subjects (n = 12) phencyclidine (PCP) free fraction was 22.0 +/- 2.8 % (mean +/- SD). In male patients with mild to moderate alcoholic liver disease (n = 16) free fraction (23.0 +/- 3.4%) was of the same order as in healthy subjects although age and the concentrations of albumin, bilirubin, and high-density lipoproteins were different (P less than 0.05). Free fraction (76.2 /+- 0.06%) in fatty acid free human serum albumin (HSA, 4.4 gm/dl) was far greater than in plasma. Both the increased binding of PCP in plasma over HSA and the lack of a difference in PCP binding between normals and patients was associated with alpha 1-acid glycoprotein (alpha 1-AGP). This protein is an acute-phase reactant that binds cationic drugs and rises nonspecifically in a variety of diseases. Free fraction of PCP in alpha 1-AGP (75 mg/dl) was 36.4 +/- 1.7%. Half of the variance in PCP binding can be accounted for (r = 0.67, P less than 0.01) from percentage of free PCP = 39.24 - 2.18 (albumin) - 0.094 (alpha 1-AGP). Male rats (n = 14, weight = 251 +/- 7 gm) were alternatively assigned to pretreatment with either saline or alpha 1-AGP (11.6 mg) by cardiac puncture. PCP brain concentrations were reduced (11%, P less than 0.05) in the protein-treated group 5 min after cardiac 3H-PCP (0.17 mg) administration, demonstrating that increased plasma protein binding can reduce free drug concentration during the distribution phase and, thereby, the rate and extent of drug distribution.

Adult↗
PubMed1981

Acute and chronic drug abuse emergencies in Metropolitan Toronto.

From 3,548 drug overdose or abuse cases presenting at 21 Metropolitan Toronto hospitals' Emergency departments, data concerning demographic and medical characteristics, investigative and management procedures, drug analysis services, and disposition of patients were collected. Of the 3,548 cases, 2,723 (77%) were acute overdose and 816 (23%) were drug abuse. Drug overdose was more common than drug abuse for both sexes, but was more characteristic of females. The drugs most frequently alleged ingested were benzodiazepines (34%), ethanol (32%), salicylates (16%), and barbiturates (14%). The frequency with which particular classes of drugs are alleged in overdose corresponds closely to the frequency of prescribing these drugs in Ontario.

Adult↗
PubMed1980

Intravenous diazepam and oral ethanol interaction.

The mechanism of the interaction between ethanol and diazepam is not known. Six healthy male subjects (aged 21 to 32 yr) were randomly assigned in a balanced crossover study to each of two treatments, 28 days apart: (1) diazepam 10 mg intravenously over 20 min, preceded by 60 min with ethanol 0.7 gm/kg (diluted to 20% v/v) orally over 15 min and followed for 8 hr by ethanol 0.15 gm/kg/hr to maintain the blood alcohol concentrations between 800 to 1,000 mg/l; (2) diazepam 10 mg intravenously over 20 min. The area under the curve (AUC) for total diazepam increased in all subjects (30.1 +/- 10.7%, mean = SD, p < 0.02) after ethanol. Since AUCfree diazepam also rose in all (mean - 26.5 +/- 17.3%) and AUC of the metabolite N-desmethyldiazepam fell (mean = 50.5 +/- 11.7%, p < 0.01) there had been inhibition of hepatic intrinsic clearance of free drug. The susceptibility of individuals to inhibition of N-desmethylation by ethanol is qualitatively determined by total drug concentrations. Estimation of free diazepam concentration coupled with measurement of metabolite affords a qualitative and quantitative evaluation of the mechanism of this interaction.

Administration, Oral↗
PubMed1980

Diurnal variations in plasma diazepam concentrations associated with reciprocal changes in free fraction.

1 The characteristics and mechanism of fluctuations in diazepam and N-desmethyldiazepam concentrations and diazepam free fraction were studied in six volunteers, who received diazepam (10 mg, i.v. over 20 min) and in five chronic diazepam users. 2 Within a day total diazepam and N-desmethyldiazepam concentrations varied significantly (P less than 0.001) and were lower than predicted between 23.00 and 08.00 h and higher by 09.00 h. In contrast, diazepam free fraction also varied significantly (P less than 0.001) and was highest between 23.00 and 08.00 h and lower by 09.00 h. Coincident increases in total diazepam concentrations (P less than 0.005) and decreases in diazepam free fraction were associated with food intake (P less than 0.05). 3 The coincident diurnal variations in diazepam and N-desmethyldiazepam concentrations and the negative correlation between total diazepam concentration and diazepam free fraction (r = 0.73, P less than 0.001) suggest that the mechanism of the fluctuations is intravascular and tissue redistribution rather than effect on drug biotransformation. 4 These variations may introduce large between and within investigator experimental differences in the determination of kinetic parameters. Free drug concentration varies over the day, and within day variations in clinical effect may be observed.

Adolescent↗
PubMed1980

Differential effects of benzodiazepine disposition by disulfiram and ethanol.

The disposition of chlordiazepoxide, diazepam, oxazepam and lorazepam was studied before and after disulfiram administration to normal subjects and alcoholic patients. Similar studies to determine the effect of ethanol administration on diazepam and oxazepam disposition were also performed. After disulfiram, decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05; diazepam, 41% p < 0.05) and their active metabolites were observed. Oxazepam and lorazepam have no important active metabolites and the effect of disulfiram on their net disposition was minimal. In normal subjects ethanol (> 800 mg/l maintained for 8 h) increased the AUC free diazepam (26.6 +/- 17.3% mean +/- SD, p < 0.05) and decreased the AUC for N-desmethyldiazepam (50.5 +/- 11.7%, p < 0.05) indicating inhibition of diazepam N-desmethylation. In contrast, there was no significant change in the disposition of oxazepam in four healthy subjects after a single oral dose of ethanol. Thus, disulfiram and ethanol appear not to inhibit the metabolic disposition of oxazepam or lorazepam, benzodiazepine derivatives principally biotransformed by glucuronidation. On pharmacokinetic grounds oxazepam and lorazepam may be the drugs of choice if benzodiazepine therapy is required in chronic alcoholics.

Adult↗
PubMed1979

Chlordiazepoxide and oxazepam disposition in cirrhosis.

When disease impairs clearance of drugs, multiple-dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy-proven cirrhosis. In the normal subjects, mean (+/- SE) kinetic parameters were: t 1/2 beta, 10.0 (+/- 0.9) hr; Vd, 0.38 (+/- 0.04) l/kg; clearance, 0.54 (+/- 0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = -0.63). Values in cirrhotic patients were: t 1/2 beta, 34.9 (+/- 8.7) hr; Vd, 0.34 (+/- 0.024) 1/kg; and clearance, 0.185 (+/- 0.34) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean t 1/2 beta for oxazepam (7.1 +/- 1.0 hr) was 27% longer than in control subjects (5.6 +/- 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.

Adult↗
PubMed1979

High-performance liquid chromatographic determination of plasma propylthiouracil.

A reversed-phase high-performance liquid chromatographic analysis was developed for propylthiouracil in plasma (1 ml). After protein precipitation with acetonitrile, the solution was diluted with water and injected into a liquid chromatograph equipped with C-18 and C-8 columns in series. The peak area was linear over the 0.25-10-mg/liter range, and the recovery was 101 +/- 4.5%. This assay has the advantages of specificity, simplicity, and speed over previously published methods and requires smaller sample volumes. None of 19 drugs tested interfered with the assay.

Chromatography, High Pressure Liquid↗
PubMed1979

Use of the overturn end point in goldfish to measure the interaction of diazepam and ethanol and the effects of the binding of diazepam to bovine serum albumin.

Over the ranges 2.8 X 10(-5) to 8.78 X 10(-5) M diazepam and 4.85 X 10(-2) to 1.22 X 10(-1) M ethanol, addition of the effects of these agents on the overturn end point in goldfish was observed. The addition of bovine serum albumin (1.56 X 10(-5) M) to aqueous solutions of diazepam modifies the diazepam effect by reducing the "free" drug concentrations.

Animals↗