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Biomedical subjects

H R Ochs

Publications and source records attributed to H R Ochs.

At least 109 records · Page 6Linked to original sources
PubMed1981

Disposition of oxazepam in relation to age, sex, and cigarette smoking.

The kinetics of single 30-mg oral doses of oxazepam were determined in 22 male and nine female volunteers aged 20-86 years. Oxazepam plasma concentrations were measured in multiple plasma samples drawn during 36 h after each dose. Mean kinetic variables in males and females, respectively, were: elimination half-life, 7.5 and 8.5 h; volume of distribution, 0.96 and 1.17 l/kg; clearance, 1.48 and 1.70 ml/min/kg. Sex differences were not significant, nor were any of the kinetic variables significantly related to age. However, oxazepam clearance increased significantly with heavier cigarette smoking (r = 0.48, p less than 0.01). Mean clearance in smokers (1.98 ml/min/kg) was significantly higher than in nonsmokers (1.23 ml/min/kg, p less than 0.01). Thus, smoking is a more important determinant of oxazepam clearance than age or sex.

Adult↗
PubMed1981

Clinical implications of serum digoxin concentrations.

Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=-0.36, p less than 0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS durations, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.

Acetyldigoxins↗
PubMed1981

Impairment of digoxin clearance by coadministration of quinidine.

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.

Adult↗
PubMed1981

Effect of dose on bioavailability of oral digoxin.

Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F = 0.64; d.f. = 4.32; N.S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F = 2.87; d.f. = 4.32; p = 0. 05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.

Administration, Oral↗
PubMed1981

Intravenous quinidine in congestive cardiomyopathy.

Eight male patients with compensated congestive cardiomyopathy received single 300-mg doses of intravenous quinidine by 15-min infusion. Left ventricular (LV) performance was evaluated by echocardiography at multiple points in time during the next 24 h. Quinidine kinetics and protein binding were determined from multiple serum samples drawn for up to 36 h after dosage. LV function was not impaired. Instead, quinidine transiently increased ejection fraction (mean: +39%) and rate of circumferential shortening (mean: +46%). Endsystolic and end-diastolic LV internal diameter likewise were decreased (means: -13% and -7%). Blood pressure and ventricular rate were not significantly altered. Compared to 8 healthy controls matched for age, sex, and weight, quinidine volume of distribution among patients was smaller (means: 2.27 vs 1.90 l/kg), as was total quinidine clearance (3.49 vs 2.84 ml/min/kg); however, differences were not statistically significant. Well-controlled, slow intravenous infusion of quinidine does not impair LV performance and is safe for patients with compensated congestive cardiomyopathy. However, such patients may have reduced quinidine clearance and hence require lower doses than expected based on age and weight.

Adult↗
PubMed1981

Diazepam interaction with antituberculosis drugs.

The influence of antituberculosis drugs on diazepam disposition was assessed in a series of volunteers and patients who received single intravenous doses of diazepam. In study 1, nine healthy subjects received diazepam in the drug-free control state and again during treatment with isoniazid (INH), 180 mg/day. INH did not alter diazepam volume of distribution (Vd) or protein binding, but prolonged mean elimination half-life (t1/2) from 34 to 45 hr (p less than 0.02), and reduced total clearance from 0.54 to 0.40 ml/min/kg (p less than 0.02). In study 2, diazepam disposition in a group of seven tuberculous patients on triple therapy with INH, ethambutol (EMB), and rifampin (RIF) was compared with that in healty drug-free controls matched for age and sex. Diazepam Vd and protein binding were nearly identical between groups, but mean t1/2 among patients (14 hr) was significantly shorter than in controls (58 hr, p less than 0.01) and total clearance correspondingly increased (to 1.50 from 0.37 ml/min/kg, p less than 0.01). Study 3 compared six newly diagnoses tuberculous patients receiving initial therapy with EMB alone with age- and sex-matched controls. Diazepam unbound fraction in patients tended to be higher than in controls, and diazepam Vd and clearance tended to be lower but the differences were not statistically significant. Thus, diazepam clearance is impaired and t1/2 prolonged by administration of INH alone. Markedly increased clearance and shortened t1/2 in triple-therapy patients is probably due to enzyme-inducing effects of RIF. Dosage of diazepam may require adjustment in patients with tuberculosis on chemotherapy.

Adult↗
PubMed1981

Automated gas chromatography for studies of midazolam pharmacokinetics.

Plasma midazolam concentrations following single therapeutic doses can be quantitated using electron-capture gas-liquid chromatography. After addition of a benzodiazepine analogue as an internal standard, samples are extracted with benzeneisoamyl alcohol (98.5:1.5). The organic extract is evaporated to dryness, reconstituted, and chromatographed on an SP-2250 liquid phase. The automatic sampler allows up to 100 chromatographic analyses per 24-h period. The sensitivity limits are 2-3 ng of midazolam per ml of plasma, and the variation of identical samples is 7 per cent or less. The method was used in a study of six females who received single intravenous doses of midazolam for purposes of anesthetic induction prior to minor gynecologic procedures. Mean (+/- SE) kinetic variables for midazolam were: volume of central compartment, 0.37 (+/ 0.06 l/kg; total volume of distribution, 1.72 (+/- 0.05) l/kg: initial distribution half-life, 7.2 (+/- 1.6) min; elimination half-life, 2.5 (+/- 0.2) h; total clearance, 8.1 (+/- 0.52) ml.min-1.kg-1.

Adult↗
PubMed1981

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.

Diazepam↗
PubMed1981

Diazepam kinetics in relation to age and sex.

27 male volunteers aged 20 to 91 years, and 13 female volunteers aged 21 to 33 years, received single 5 to 10 mg doses of diazepam intravenously. Diazepam pharmacokinetics were determined from concentrations measured in multiple plasma samples drawn during 7 days after each dose. Diazepam elimination half-life among males (mean: 66 h) increased significantly with age (r = 0.53, p less than 0.005). Volume of distribution (mean: 1.39 liters/kg) also increased significantly with age (r = 0.67, p less than 0.001). Clearance of total diazepam in males (mean: 0.42 ml/min/kg) tended to decline with age (r = 0.32), but the association was of borderline significance (p = 0.1). Diazepam was extensively bound to plasma protein, with a mean free fraction among male subjects of 1.34%. Free fraction tended to increase with age (r = 0.14). Correction of volume of distribution and clearance for individual differences in binding did not alter the conclusions. Compared to young males, young females had larger volumes of distribution (1.87 vs. 1.34 liters/kg) and higher total clearance (0.63 vs. 0.49 ml/min/kg). These differences were even greater after correction for sex-related changes in protein binding. Elimination half-life did not differ between sexes. Since both age and sex can influence diazepam disposition, both should be considered as independent variables in studies of diazepam pharmacokinetics.

Adult↗
PubMed1981

[Plasma levels following high diazepam doses in intensive-care medicine (author's transl)].

Two patients were hospitalized in moderately deep coma after ingestion of large doses of diazepam with suicidal intent. Three other patients required unusually high diazepam doses for therapeutic reasons (acute alcohol withdrawal, severe tetanus). In all patients, plasma levels of diazepam and its main active metabolite, desmethyl-diazepam, could be determined. The elimination of both substances seems to be dose-independent. Rapid clinical recovery after high diazepam doses is not attributable to rapid elimination of active compounds from the body, but more likely to adaptation or tolerance to their depressant effects. On the other hand, prolonged coma after long-term therapy with high doses is possible.

Adult↗
PubMed1980

Entry of diazepam and its major matabolite into cerebrospinal fluid.

Five dogs received a single 1.0 mg/kg dose of diazepam (DZ) IV. Concentrations of DZ and its major metabolite desmethyldiazepam (DMDZ) were simultaneously measured in plasma and cisternal cerebrospinal fluid (CSF) for up to 8 h after the dose by electron-capture gas-liquid chromatography. DZ was rapidly eliminated from plasma (half-life 0.3--1.3 h); DZ disappearance was mirrored by formation of DMDZ, which in turn was eliminated slowly, Both DZ and DMDZ rapidly penetrated CSF and concentrations in CSF declined parallel with those in plasma. Despite rapid uptake, the extent of CSF transfer of DZ and DMDZ was limited by plasma protein binding. Mean CSF:plasma concentrtion ratios for DZ (range 0.023--0.137) and DMDZ (range 0.047--0.119) were highly correlated with the unbound fraction in plasma (r = 0.95 and 0.80, respectively). Thus DZ and DMDZ concentrations in CSF, presumed to reflect concentrations at the site of action, are determined by unbound plasma concentrations. The intensity of pharmacologic action is more likely to correlate with unbound than with total plasma concentrations.

Animals↗
PubMed1980

Entry of quinidine into cerebrospinal fluid.

Some of the unwanted effects of quinidine commonly occurring in clinical practice involve the central nervous system. We therefore assessed the rate and extent of quinidine passage into cerebrospinal fluid (CSF) in humans and dogs. In eight human subjects receiving oral quinidine therapy, lumbar CSF quinidine concentrations averaged 16% of unbound serum concentrations (range: 4% to 37%). The findings were confirmed when simultaneous serum (total and unbound) and CSF quinidine concentrations were followed for up to 8 hours after a single intravenous dose of quinidine in anesthetized dogs. Quinidine appeared promptly in CSF of all animals, but CSF concentrations averaged only 37% to 46% of unbound serum levels. The in vitro octanol:water partition coefficient for quinidine at physiologic pH was greater than 100, indicating that unbound quinidine should readily traverse the blood-brain barrier. Thus, passage of quinidine into CSF appears not to be governed by passive diffusion alone. Quinidine may participate in an active transport system such as that which removes certain other basic substances from CSF.

Anesthesia, Intravenous↗