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Biomedical subjects

R I Shader

Publications and source records attributed to R I Shader.

At least 343 records · Page 19Linked to original sources
PubMed1982

Lethality and behavioral side effects of chloroquine.

The antimalarial chloroquine is a widely used medication prescribed for a variety of conditions. The authors indicate that its lethality and behavioral side effects are significant and may be underestimated. Moderately low overdosage of chloroquine can result in rapid death. Moreover, therapeutic doses are known to cause psychosis, delirium, personality changes, and depression. It is hypothesized that a drug-induced alteration of mood or a toxic confusional state may result in unintended overdosage and death. Clinicians should consider prodromal signs of toxicity and not classify overdosage prematurely as attempted self-poisoning.

Behavior↗
PubMed1982

Physiologic changes in old age: relation to altered drug disposition.

Current knowledge of the effects of aging on drug disposition is reviewed. Although definitive studies are not always available, based on present evidence it appears that: 1) drug absorption is not impaired in the elderly; 2) drug distribution in the elderly may be altered by significant changes in the lipid/lean body mass ratio; 3) Phase I (non-synthetic) biotransformation reactions of the liver appear to be much more profoundly affected by aging than are Phase II (synthetic) reactions; 4) age-related effects of biotransformation can be different even for compounds that are very similar and undergo the same types of reactions. Important parameters of drug metabolism are also discussed, such as the need to use total clearance, rather than half-life, in assessing pharmacokinetics.

Aged↗
PubMed1982

Cimetidine impairs clearance of antipyrine and desmethyldiazepam in the elderly.

Sixteen young (21-40 years) and nine elderly (65-78 years) volunteers received single intravenous doses of antipyrine on two occasions: once in the control state, and again while receiving therapeutic doses of cimetidine (300 mg every six hours). In the control state, antipyrine half-life was longer in elderly than in young subjects (16.4 vs 11.0 hours), and metabolic clearance lower (0.48 vs 0.72 ml/min/kg). However, coadministration of cimetidine prolonged antipyrine half-life to a similar extent in elderly and in young groups (150 and 153 per cent of control) and reduced metabolic clearance to a similar extent in both (79 vs 69 per cent of control) groups. Three young and six elderly volunteers received a single 15 mg oral dose of clorazepate, a precursor of desmethyldiazepam, with and without cimetidine. As in the case of antipyrine, cimetidine prolonged desmethyldiazepam half-life similarly in young and elderly groups (175 vs 164 per cent of control) and similarly reduced metabolic clearance (51 vs 65 per cent of control). The elderly population may already have an impaired capacity to oxidize drugs. This capacity is further impaired by coadministration of cimetidine.

Adult↗
PubMed1982

Liquid chromatographic determination of chlordiazepoxide and metabolites in plasma.

Sensitive quantitation of chlordiazepoxide and its two principal metabolites, desmethylchlordiazepoxide and demoxepam, in human plasma is achieved by high-pressure liquid chromatography. All three compounds and the internal standard, chlorodesmethyldiazepam, are directly extracted from plasma into benzene:isoamyl alcohol (98.5 : 1.5) at physiologic pH with no sample preparation. After evaporation of the organic solvent, the redissolved residue is chromatographed using a C-18 reverse-phase column. Sensitivity limits are 0.05 microgram of either compound/ml of plasma, with coefficients of variation of less than 8%. The method is applicable to single-dose pharmacokinetic studies of chlordiazepoxide or to monitoring of plasma concentrations during long-term therapy.

Aged↗
PubMed1982

Pharmacokinetics of benzodiazepine hypnotics.

Three benzodiazepine derivatives are currently indicated specifically for the treatment of insomnia in the United States. Flurazepam is biotransformed to at least two rapidly appearing and rapidly eliminated intermediate metabolites which probably contribute to sleep induction. The final metabolite, desalkylflurazepam, appears slowly, but has a long half-life ranging from 40 to 150 h. This metabolite accumulates extensively during multiple dosage. Temazepam is a slowly absorbed drug and has an intermediate half-life in the range of 10-20 h. Triazolam has an intermediate absorption rate, but is rapidly eliminated (half-life 1.5-5 h) making it essentially non-accumulating. Understanding of the pharmacokinetics of benzodiazepine hypnotics can contribute to understanding of their clinical properties.

Anti-Anxiety Agents↗
PubMed1981

Effect of age and gender on disposition of temazepam.

Thirty-two male and female volunteers, 24-84 years of age, ingested single 30-mg doses of temazepam, a 3-hydroxy-1,4-benzodiazepine derivative used as a hypnotic agent. Kinetics of total and unbound temazepam were determined from multiple plasma temazepam concentrations measured during 48 hr after the dose. The temazepam elimination half-life ranged from 8 to 38 hr and was longer in women than in men (16.8 versus 12.3 hr, p less than 0.05). Likewise, clearance of total temazepam (assuming complete absorption) was higher in men than in women (1.35 versus 1.02 ml/min/kg, p less than 0.025). Neither half-life nor clearance was significantly related to age. The volume of distribution of total temazepam (mean 1.40 liters/kg) was unrelated to age or gender. Temazepam was extensively protein bound, with a mean free fraction of 2.6% (range 12.7-3.4%). The free fraction increased with age (r = 0.45, p = 0.01), partly due to the inverse relation of the free fraction to plasma albumin concentration (r = -0.34, p = 0.06) and the age-related decline in plasma albumin (r = -0.49, p less than 0.005). After correction for individual differences in binding, clearance of unbound temazepam in men was higher than in women (50.5 versus 39.7 ml/min/kg, 0.05 less than p less than 0.01), and it tended to decline with age in both sexes (r = -0.44 and -0.43, respectively, p = 0.1).

Adult↗
PubMed1981

Benzodiazepine overdosage: plasma concentrations and clinical outcome.

Plasma concentrations and their relation to clinical outcome were evaluated in 21 patients who reached emergency treatment facilities following acute overdosage with benzodiazepine derivatives. Diazepam was implicated in 18 of the 21 cases, with plasma diazepam levels ranging from 585-8,635 ng/ml. In four cases of overdosage with diazepam alone, patients were minimally sedated and were discharged within 24 h, despite diazepam doses as high as 750 mg and plasma levels as high as 4,792 ng/ml. However, concurrent ingestion of diazepam together with other central depressant drugs (such as ethanol, barbiturates, analgesics, or tricyclic antidepressants) produced serious intoxication in 5 of the remaining 14 patients, regardless of the diazepam dosage or plasma concentration. Thus the severity of poisoning following benzodiazepine overdosage is determined largely by co-ingestion of other central depressants rather than the amount of benzodiazepine ingested or its concentration in plasma.

Adolescent↗
PubMed1981

Effect of age and sex on disposition of desmethyldiazepam formed from its precursor clorazepate.

Desmethyldiazepam (DMDZ) disposition was evaluated in 32 healthy male and female volunteers who ingested single 15-mg doses of the precursor compound, clorazepate dipotassium. DMDZ concentrations were measured in multiple plasma samples obtained between 7 and 9 days after dosage. Appearance of DMDZ in blood was rapid, with peak concentrations attained on average 1.5 h after dosage. Absorption half-life (t1/2 a) averaged 24 min. Neither peak time nor t1/2 a were influenced by age or sex. After a rapid phase of distribution, DMDZ elimination was slow, with a mean elimination half-life (t1/2 beta) of 82 h (range 27-219 h). t1/2 beta became prolonged with age in men but not in women. Likewise, clearance of total (free bound) DMDZ declined with age in male subjects (r=- 0.47, P less than 0.1), but was unrelated to age in women. DMDZ was extensively bound to protein in all subjects. The mean free fraction (FF) was 3.1% (range 2.0-4.3%), and increased significantly with declining plasma albumin concentrations (r=-0.57, P less than 0.001). Partly due to a decline in plasma albumin with age (r=-0.47, P less than 0.01), FF tended to increase with age (r=0.23). After correction for individual differences in FF, clearance of pharmacologically active unbound DMDZ declined significantly with age in men (r=-0.65, P less than 0.01), but actually was slightly higher in elderly as opposed to young women. Thus, the age-related decline in the capacity for hepatic hydroxylation of DMDZ is highly sex-specific.

Adult↗
PubMed1981

Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs.

Twenty-six healthy subjects from 19 to 85 yr old took single 15-mg doses of flurazepam (FLZ). Concentrations of desalkylfurazepam (DAFLZ), its principal metabolite, were measured by gas-liquid chromatography in multiple samples drawn 7 or more days after the dose. For the first 6 to 8 hr after drug, several additional FLZ metabolites appeared in plasma, but only DAFLZ was detected from 12 hr onward. Its elimination half-life (t1/2) (range, 37 to 289 hr) was longer in elderly than in young men (mean 74 and 160 hr, p less than 0.05), but t1/2 in young and elderly women was much the same (90 and 120 hr, P = NS). Eighteen of the 26 subjects then received FLZ, 15 mg, nightly for 15 consecutive nights. Blood samples were drawn during FLZ dosage and in the withdrawal period, and morning self-ratings of mood and sleep patterns were obtained using visual analogue scales. DAFLZ cumulation was extensive, with a mean cumulation ratio of 7.5. Mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/ml, P less than 0.05), but values were essentially the same in elderly and young women (85 and 86 ng/ml). Single-dose t1/2 correlated with washout t1/2 after termination of FLZ treatment (r = 0.87, P less than 0.01). Clinical self-ratings indicated increases over time in perception of morning sedation; changes slowly reverted to baseline in the week after dosage. Sleep patterns also improved on FLZ (shortened latency, longer duration, "deeper" sleep). After termination of treatment, sleep parameters returned to baseline with a suggestion of "overshoot" sleep disturbance at days 5 and 7 after drug. There was no evidence of increased sensitivity to FLZ in the elderly. Subjects did not perceive any impairment of intellectual function or motor performance, and no other adverse reactions were reported.

Adult↗