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Biomedical subjects

H R Ochs

Publications and source records attributed to H R Ochs.

At least 91 records · Page 5Linked to original sources
PubMed1983

Effect of penbutolol on lidocaine kinetics.

The effect of penbutolol (Betapressin), a stereospecific beta-adrenergic antagonist, on the pharmacokinetics of a single dose of intravenous lidocaine was evaluated in seven healthy volunteers. Subjects received a single 100-mg lidocaine intravenous dose of lidocaine hydrochloride, once in the control state and a second time during coadministration of penbutolol, 60 mg daily. Lidocaine volume of distribution was significantly increased during penbutolol treatment (4.9 vs 3.4 l/kg, p less than 0.005), resulting in a significant prolongation of elimination half-life (2.5 vs 2.0 h, p less than 0.025). The mechanism of the distributional shift is not established, but may result from a change in the pattern of peripheral blood flow and therefore the profile of tissue uptake of lidocaine. Total metabolic clearance of lidocaine, however, was not significantly altered by penbutolol (23.0 vs 19.4 ml/min/kg). The present study of healthy volunteers suggests that penbutolol increases lidocaine volume of distribution. If the finding also applied to patients, a higher loading dose of lidocaine might be necessary.

Adult↗
PubMed1983

Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex.

Twenty-two healthy volunteers aged 20-78 years received single 5-mg doses of diazepam by intravenous injection, by mouth in the fasting state, and by a deltoid intramuscular injection. The kinetic profile of diazepam by each route was determined from multiple plasma diazepam concentrations measured 7-14 days after each dose. After intravenous injection, diazepam volume of distribution (Vd) was larger in women than in men, but increased with age regardless of sex. Elimination half-life was longer in elderly than in young men (101 v 32 h, P less than 0.025), partly due to the increased Vd as well as to a significant reduction in total metabolic clearance (0.24 v 0.46 ml/min/kg, P less than 0.05). However, the prolonged half-life in elderly as opposed to young women (99 v 44 h; P less than .01) was due mainly to increased Vd because clearance was not significantly changed (0.29 v 0.35 ml/min/kg). In all subjects, oral diazepam was rapidly absorbed; peak plasma levels were reached an average of 0.9 h after dosage. Absolute bioavailability averaged 94%, indicating essentially complete absorption. Neither age nor sex significantly influenced oral absorption. In all male subjects, and in 8 of 12 women, absorption of diazepam after deltoid intramuscular injection was rapid and essentially complete. However, in three young and one elderly women, absorption was slower and apparently incomplete. Age as such did not significantly influence absorption of intramuscular diazepam.

Administration, Oral↗
PubMed1982

Kinetics and cardiac effects of propranolol in humans.

Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (+/- SE) kinetic variables for IV propranolol were: elimination half-life (t 1/2 beta), 5.3 (+/- 0.6) h; volume of distribution, 2.3 (+/- 0.3) l/kg; total clearance, 4.9 (+/- 0.3) ml/min/kg; predicted extraction ratio, 0.23 (+/- 0.02). After single oral doses, t 1/2 beta (3.8 +/- 0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60 +/- 0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47 +/- 5 ng/ml) tended to be less than those predicted based on the single oral dose (61 +/- 5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).

Administration, Oral↗
PubMed1982

Desmethyldiazepam kinetics after intravenous, intramuscular, and oral administration of clorazepate dipotassium.

The pharmacokinetics and bioavailability of desmethyldiazepam (DMDZ), formed from its precursor clorazepate (CZP) dipotassium, were assessed in a series of 17 healthy volunteers aged 21--66 years. After a single 20-mg intravenous dose of CZP, mean kinetic variables for DMDZ were: volume of distribution, 1.24 l/kg; elimination half-life, 65 h; total clearance, 0.24 ml/min/kg. Among males, DMDZ half-life tended to be prolonged and clearance reduced with age, but this was not true for females. After oral administration of 20 mg CZP, appearance of DMDZ in the circulation was rapid; the mean peak plasma level was 356 ng/ml, reached an average of 0.9 h after dosage. Based on comparison with IV dosage, systemic availability of DMDZ was complete (100% absorption). Ten of the subjects also received a single 20-mg intramuscular dose of CZP. Mean peak DMDZ levels were 290 ng/ml, reaching an average of 2.7 h after dosage. Systemic availability of DMDZ was complete. Elimination half-life of DMDZ for a given individual was highly replicable from trial to trial regardless of the route of CZP administration.

Administration, Oral↗
PubMed1982

Diazepam absorption: effects of age, sex, and Billroth gastrectomy.

The kinetics of diazepam absorption were assessed in 37 healthy volunteers, aged 19--79 years, who ingested a single 5-mg tablet in the fasting state. Diazepam plasma concentrations were measured by gas chromatography in multiple samples drawn over the next 72 hr. After a lag time averaging 12 min elapsed between tablet ingestion and the start of absorption, first-order absorption proceeded with a mean half-life of 19 min (range: 0--96 min), with peak plasma concentrations reached 0.9 hr after dosage (range: 0.25--2.5 hr). Age and sex did not influence absorption kinetics. Peak plasma concentrations averaged 157 ng/ml, and tended to be higher in women than in men because of lower body weights in women. Peak levels also declined with age, probably due to increased volume of distribution of diazepam in the elderly. Absolute systemic availability of oral diazepam was evaluated in seven of the subjects who received intravenous diazepam on another occasion. Based on areas under the oral versus intravenous plasma concentration curve, bioavailability of diazepam averaged 97%. Six male patients, at least 2 years after undergoing Billroth gastrectomy, also participated in the diazepam absorption study. Absorption kinetic parameters were nearly identical to those in six healthy age-matched male volunteers without gastrointestinal disease. Thus absorption of oral diazepam in the fasting state is rapid and nearly complete, and is minimally influenced by age, sex, or Billroth gastrectomy.

Administration, Oral↗
PubMed1982

Kinetics of high-dose i.v. diazepam.

The pharmacokinetics of high-dose i.v. diazepam were studied in two patients in an intensive care unit. The first patient received up to 240 mg of diazepam daily for 21 days while the second received 60 mg daily for 30 days. Plasma concentrations of diazepam and its major metabolite, desmethyldiazepam, were very large but, despite severe underlying disease and simultaneous administration of several other drugs, the half-lives of diazepam and desmethyldiazepam washout were consistent with those found in healthy persons. Washout half-lives in the first patient were, if anything, shorter than expected, possibly caused by simultaneous administration of phenobarbitone. Thus the kinetics of diazepam are apparently not altered by administration of large doses.

Adult↗
PubMed1982

Digitoxin accumulation.

1 Nine healthy volunteers received single 1 mg intravenous doses of digitoxin, following which serum digitoxin concentrations were measured at multiple points in time over the next 14 days. 2 Mean kinetic variables for digitoxin were: volume of distribution, 0.76 l/kg; elimination half-life, 8 days; total clearance, 0.049 ml min-1 kg-1. 3 After a drug-free interval of at least 4 months, subjects took 0.07 mg of oral digitoxin daily for 28 consecutive days. Serum digitoxin concentrations were measured during the period of dosage and in the 21 day post-dosage washout. 4 Digitoxin accumulation was slow, proceeding with a mean half-life (7.9 days) that was nearly identical to the single-dose half-life. However, the two were not significantly correlated. 5 Mean observed steady-state serum concentrations (15.4 ng/ml) also were nearly identical to those predicted from the single-dose study (15.3 ng/ml), but again the two were not significantly correlated. 6 Steady state is very slowly attained after initiation of maintenance therapy with digitoxin. The kinetic data suggest that a loading dose on the average should be 12 times the maintenance dose.

Adult↗
PubMed1982

Automated electron-capture gas chromatographic analysis of flunitrazepam in plasma.

Nanogram quantities of flunitrazepam and its major metabolite, desmethylflunitrazepam, can be reliably quantitated in human plasma using electron-capture gas-liquid chromatography. After addition of methylnitrazepam as the internal standard, plasma samples are extracted with an organic solvent (benzene:isoamyl alcohol). The organic extract is separated, evaporated to dryness, reconstituted, and injected onto the chromatograph using an automatic sampling system which allows up to 100 analyses/24 h. The sensitivity limits are 0.5 ng/ml for flunitrazepam and 1-2 ng/ml for desmethylflunitrazepam. Use of the method is illustrated in a study of the pharmacokinetic properties of flunitrazepam following a single 1.0-mg intravenous dose.

Adult↗
PubMed1982

Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies.

Plasma concentrations of 5-(2-chlorophenyl)-7-ethyl-1,3-dihydro-1-methyl-2H-thieno[2,3-e][1,4]diazepin-2 -one (clotiazepam, CTZ, Trecalmo), a thienodiazepine anti-anxiety agent, and two of its metabolites (hydroxy- and desmethyl-clotiazepam) are reliably quantified by electron capture GLC. After addition of diazepam as internal standard, 1-ml plasma samples are extracted with benzene-isoamyl alcohol (98.5:1.5). The organic extract is evaporated to dryness, reconstituted, and directly chromatographed using a 3% SP-2250 liquid phase at 260 degrees C. Sensitivity limits are 1-3 ng of each of the 3 compounds per ml of plasma. The method is applicable to clinical pharmacokinetic studies in humans. After p.o. ingestion of a single 5-mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed. Values of elimination half-life were 6.5, 7.0, and 17.8 h, respectively. The two metabolites appeared and disappeared approximately in parallel with the parent compound. Clotiazepam was more than 99% bound to plasma protein.

Adult↗
PubMed1982

Increased metabolic clearance of acetaminophen with oral contraceptive use.

The effect of chronic low-dose oral contraceptive steroid use on the pharmacokinetics of intravenous acetaminophen was determined. Eight women using low-dose (under 50 micrograms) estrogen oral contraceptive steroid for more than 3 months were matched for age and weight (mean age, 25.9 years; mean weight, 58.3 kg) with 8 female controls not using the steroid (mean age, 26.0 years; mean weight, 55.5 kg). No subject was taking other drugs. Oral contraceptive steroid subjects had a lower elimination half-life of acetaminophen (2.12 hours) than controls (2.71 hours) (P less than .005). Volume of distribution was similar for both groups (oral contraceptive group, 1.04 liters/kg; controls, 0.96 liters/kg; NS). Total metabolic clearance was significantly higher in oral contraceptive subjects (5.81 ml/min/kg, versus 4.12 ml/min/kg for controls; P less than .02). As volume of distribution and body weight are similar for both groups, the decrease in acetaminophen elimination half-life among contraceptive steroid users is the result of increased total metabolic clearance. Thus, low-dose estrogen oral contraceptive steroid may stimulate the metabolism of a conjugatively metabolized drug such as acetaminophen, in contrast to contraceptive steroid impairment of the clearance of some oxidatively metabolized drugs, with antipyrine being the prototype.

Acetaminophen↗
PubMed1982

Pharmacokinetics and metabolism of antipyrine (phenazone) after intravenous and oral administration.

To 12 healthy male volunteers, 6 smokers and 6 non-smokers, 10 mg/kg antipyrine (phenazone) was administered i.v. and p.o. in random order. Following i.v. administration, antipyrine kinetics could be described best by an open two-compartment model. Absolute bioavailability of an aqueous solution of antipyrine was on average 97%. Antipyrine half-life in smokers was significantly shorter (mean 9.7 h) as compared to non-smokers (mean 11.7 h). Smokers excreted significantly more 3-hydroxymethyl-antipyrine (17.2 +/- 2.4 vs. 14.2 +/- 1.9%) than non-smokers, and clearance to this metabolite was significantly increased in smokers. In addition, cumulative urinary excretion of 4-hydroxy-antipyrine, norantipyrine and 3-hydroxymethyl-antipyrine was on average higher in smokers (77.1 +/- 5.0%) as compared to non-smokers (69.5 +/- 10.8%). Thus, 3-hydroxymethyl-antipyrine formation is induced in smokers.

Administration, Oral↗