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Biomedical subjects

H R Ochs

Publications and source records attributed to H R Ochs.

At least 37 records · Page 2Linked to original sources
PubMed1987

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15-30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml-1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half-life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min-1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.

Chromatography, Gas↗
PubMed1987

Hepatic vs. gastrointestinal presystemic extraction of oral midazolam and flurazepam.

An experimental model was developed to elucidate the site of presystemic extraction of drugs with incomplete bioavailability due to high extraction after p.o. dosage. Domestic pigs received single i.v. or p.o. doses of midazolam (1 mg/kg) or flurazepam (2 mg/kg), two benzodiazepine derivatives with high presystemic extraction after p.o. dosage. Multiple blood samples were simultaneously drawn from the portal vein and from a systemic vein during 8 hr after dosage. After i.v. administration, both drugs had high systemic serum clearance, averaging 24 ml/min/kg. Area under the serum concentration curve (AUC) for systemic vs. portal sites was nearly identical for midazolam (769 vs. 737 ng/ml x hr); for flurazepam, systemic AUC exceeded portal AUC (1035 vs. 778 ng/ml x hr, P less than .01). After p.o. dosage, the systemic/portal AUC ratio averaged 0.15 for midazolam and 0.11 for flurazepam; for both drugs, portal AUC after p.o. dosage did not differ significantly from systemic AUC after i.v. administration. Thus, the extensive presystemic extraction of orally administered midazolam and flurazepam are mainly attributable to hepatic biotransformation rather than metabolism either within the gastrointestinal tract or during absorption into the portal circulation.

Administration, Oral↗
PubMed1986

Influence of beta-blocker coadministration on the kinetics of isosorbide mononitrate and dinitrate.

The influence of beta-blocker coadministration on the kinetics of oral isosorbide-5-mononitrate (ISMN) and isosorbide dinitrate (ISDN) was studied in healthy volunteers. In the first study, 12 subjects ingested 20 mg ISMN on three occasions: in the control state, during coadministration of metipranolol (20 mg 3 times daily), or during metoprolol (100 mg twice daily). There were no significant differences among the three phases in peak serum ISMN concentration (470 ng/ml), the time of peak (0.6 h after dose), elimination half-life (4.5 h), or oral clearance (142 ml/min). In the second study, 10 subjects received 20 mg ISDN in the control state and again during coadministration of propranolol (80 mg 3 times daily). There were no differences between the two phases in peak serum ISDN concentration (20 ng/ml) or the time of peak (0.6 h). Propranolol increased, although not significantly, ISDN clearance (16.5 vs 12.3 L/min, P less than 0.1), and had no effect on total area under the curve for ISMN, the major metabolite of ISDN. Thus, therapeutic doses of these beta-blockers have a minimal influence on the kinetics of single doses of ISMN or ISDN in healthy individuals.

Adrenergic beta-Antagonists↗
PubMed1986

Influence of propranolol coadministration or cigarette smoking on the kinetics of desmethyldiazepam following intravenous clorazepate.

The influence of propranolol coadministration or of cigarette smoking on the kinetics of desmethyldiazepam following a single 20-mg intravenous dose of clorazepate dipotassium was evaluated in healthy volunteers. In Study One, intravenous clorazepate was given once in the control condition, and again during coadministration of propranolol, 80 mg twice daily. Compliance with the prescribed propranolol regimen was verified by measurement of serum propranolol concentrations (mean, 37 ng/ml). In control vs propranolol treatment conditions, there was no significant difference in desmethyldiazepam volume of distribution (1.27 vs 1.23 liters/kg) or in free fraction in serum (1.83 vs 1.80% unbound). There was a small although statistically significant prolongation of desmethyldiazepam half-life (55 vs 61 h, P less than 0.05) and reduction in clearance (0.281 vs 0.247 ml/min/kg, P less than 0.02) attributable to propranolol. In Study Two, desmethyldiazepam kinetics were compared in eight cigarette smokers (mean, 19 cigarettes/day) and in 11 nonsmoking controls matched for age, sex, and body weight. There was no significant difference between controls and cigarette smokers in desmethyldiazepam volume of distribution (1.29 vs 1.34 liters/kg), elimination half-life (55 vs 59 h), clearance (0.284 vs 0.276 ml/min/kg), or free fraction in serum (1.96 vs 1.92% unbound). Thus, propranolol slightly although significantly impairs the clearance of desmethyldiazepam and prolongs its half-life. Cigarette smoking has no apparent influence on desmethyldiazepam kinetics.

Adult↗
PubMed1986

Pharmacokinetics and dynamics of penbutolol in humans: evidence for pathway-specific stereoselective clearance.

The pharmacokinetics and dynamics of the D- and L-isomers of the beta-adrenergic blocking agent penbutolol were investigated in healthy human volunteers. In Study One, subjects received a single 40-mg oral dose of L-penbutolol (the pharmacologically active stereoisomer), and matching placebo on two occasions. A mean peak serum penbutolol concentration of 268 ng/ml was reached at 0.9 h after dosing. Elimination half-life averaged 1.6 h, and total clearance 16.6 ml/min per kg body weight. Changes in blood pressure, ventricular rate, and rate of circumferential fiber shortening (Vcf) did not differ between L-penbutolol and placebo. In Study Two, subjects received 40 mg D-penbutolol, L-penbutolol, and placebo on three occasions. Total clearance of D-penbutolol was higher than for the L-isomer (43.7 vs 15.9 ml/min/kg; P less than 0.01); this was reflected in correspondingly increased area under the serum concentration curve for conjugates of the oxidized metabolite 4-hydroxy penbutolol (2.25 vs 0.66 micrograms/ml X h; P less than 0.005). In contrast, direct conjugates of L-penbutolol achieved higher serum concentrations than conjugates of D-penbutolol. Alterations in blood pressure, ventricular rate, and Vcf for D-penbutolol, L-penbutolol, and placebo were quantitatively small. Thus the clearance of penbutolol after oral administration in humans is stereoselective, but the oxidative pathway is more stereosensitive than the parallel conjugative pathway. Penbutolol causes minimal alterations in parameters of cardiac function after single 40-mg doses in healthy humans.

Administration, Oral↗
PubMed1986

Influence of age, gender, and obesity on salicylate kinetics following single doses of aspirin.

Salicylate kinetics following single, 650-mg intravenous and oral doses of aspirin were evaluated in humans in 2 studies. Complete conversion of aspirin to salicylate was assumed. The first study involved 25 young (25-40 years) and 21 elderly (66-89 years) healthy male and female volunteers. Mean salicylate clearance was lower in elderly females compared with that in young females; however, the difference between young men and elderly men was not significant. Salicylate free fraction in plasma increased significantly with age in men and women. After correction for free fraction, unbound mean clearance was reduced in elderly men compared with young men, and in elderly women compared with young women. Peak plasma salicylate concentrations after taking oral aspirin were not significantly influenced by age, and systemic availability of salicylate in all groups was complete. The second study compared 20 obese subjects (mean weight 113 kg) with 20 normal weight controls (mean weight 67 kg) matched for age, sex, height, and smoking habits. Small differences between obese and control groups were observed in total salicylate volume of distribution (Vd), unbound Vd, and mean clearance of total or unbound salicylate. Following normalization for total weight, however, values of total Vd and mean clearance were significantly smaller in obese subjects than in normal weight subjects. Rate and completeness of salicylate absorption were not influenced by obesity when aspirin was ingested, although peak levels were lower in obese subjects. If applied to multiple doses, the reduced unbound clearance of salicylate in the elderly would imply increased accumulation unless doses are appropriately adjusted downward. During long-term therapy, salicylate dosage for obese individuals should not be adjusted upward in proportion to total weight.

Administration, Oral↗
PubMed1986

Effect of cirrhosis and renal failure on the kinetics of clotiazepam.

The kinetics of a single 5-mg oral dose of the thienodiazepine clotiazepam was evaluated in a series of patients with biopsy-proven cirrhosis, and in patients with renal insufficiency requiring maintenance hemodialysis, compared to healthy matched controls. Clotiazepam volume of distribution (Vz) was significantly smaller in cirrhotic patients than in controls (1.83 vs 2.57 l/kg), and total clearance was likewise reduced (2.15 vs 3.15 ml/min/kg). Elimination half-life was similar between groups (10.0 vs. 10.2 h). There were no significant differences between renal failure and control patients in clotiazepam Vz, oral clearance, or elimination half-life. Thus cirrhosis is associated with reduced clearance of clotiazepam, probably due to impairment of its microsomal oxidation. However clotiazepam disposition is not significantly altered in dialysis-dependent renal insufficiency patients.

Adult↗
PubMed1986

Obesity effects on nitrazepam disposition.

Nitrazepam pharmacokinetics were studied in 14 obese (mean +/- s.e. mean body weight 107 +/- 9 kg; percent ideal body weight [IBW] 166 +/- 12%) and 14 normal body weight (63 +/- 3 kg; percent IBW 98 +/- 2%) subjects. After an overnight fast, each subject ingested 10 mg nitrazepam orally. Nitrazepam concentrations were determined in plasma samples obtained over the following 72 h. Comparison of peak nitrazepam plasma concentration (94.2 +/- 10.3-obese vs 119 +/- 14.6 ng ml-1; NS) and time required after drug administration to reach peak concentration (1.52 +/- 0.24-obese vs 1.59 +/- 0.36 h; NS) indicated no differences between obese and control subjects. Elimination half-life was markedly increased in obese subjects (33.5 +/- 2.2 vs 23.9 +/- 1.2 h; P less than 0.001) due to increased apparent volume of distribution (Vd) (290 +/- 45 vs 137 +/- 12 l; P less than 0.005). Oral clearance was also increased in the obese subjects (101 +/- 12.4 vs 66.8 +/- 12.4 ml min-1; P less than 0.02). Extent of nitrazepam binding to plasma proteins was slightly decreased in obese subjects (% unbound--19.7 +/- 0.4-obese vs 17.9 +/- 0.3%; P less than 0.005). Correction of both Vd (2.62 +/- 0.17-obese vs 2.22 +/- 0.19 l kg-1; NS) and clearance (0.93 +/- 0.06-obese +/- 1.07 +/- 0.07 ml min-1 kg-1; NS) for total body weight (TBW) suggested that increases in obese subjects of both of these parameters were a function of body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Temazepam clearance unaltered in cirrhosis.

The kinetics of a single oral dose of the benzodiazepine hypnotic temazepam was evaluated in nine patients with biopsy-proven cirrhosis and in seven healthy controls matched for age and sex. Peak serum temazepam concentrations were reached later in cirrhotics than in controls (2.9 versus 0.6 h after dosage; p less than 0.05), indicating slower temazepam absorption in patients with cirrhosis. Temazepam volume of distribution was smaller in cirrhotics compared to controls, and elimination half-life shorter (10.6 versus 14.6 h). However, these differences were not significant. There were no significant differences between cirrhotics and controls in clearance of total temazepam (1.03 versus 1.03 ml/min/kg), clearance of unbound temazepam (27 versus 31 ml/min/kg), or free fraction in serum (3.9 versus 3.5% unbound). In two cirrhotic patients who received 20 mg of temazepam daily for 8 days, the extent of accumulation was consistent with the dosage interval relative to the elimination half-life, and was similar to the accumulation profile in healthy volunteers. Thus the onset of temazepam hypnotic activity may be delayed in cirrhotic patients, but the rate of elimination and the extent of accumulation are not altered compared to healthy persons of similar age and sex.

Administration, Oral↗
PubMed1986

Absence of interaction of cimetidine and ranitidine with intravenous and oral midazolam.

Eight healthy volunteers received a single 5-mg intravenous dose of the imidazobenzodiazepine derivative midazolam on three occasions in random sequence: a, control, with no other treatment; b, during coadministration of cimetidine, 300 mg every 6 hr; c, during coadministration of ranitidine, 150 mg every 12 hr. Midazolam kinetics in each trial were determined from multiple plasma midazolam levels measured by gas chromatography for 24 hr after each dose. High pressure liquid chromatography analysis of plasma also verified compliance with cimetidine (mean level, 0.61 microgram/ml) and ranitidine (mean level, 0.36 microgram/ml) regimens. Analysis of variance indicated no significant differences in mean values for trials a, b, and c in midazolam elimination half-life (2.25 vs 2.02 vs 2.05 hr), volume of distribution (2.13 vs 2.14 vs 2.16 L/kg) or total clearance (10.8 vs 12.2 vs 12.3 ml . min-1 . kg-1). In a second study, six subjects received a 15-mg oral dose of midazolam on three occasions identical to those described above. Again, there were no significant differences among trials a, b, and c in midazolam peak plasma level (90 vs 95 vs 117 ng/ml), time of peak level (0.65 vs 1.45 vs 0.90 hr after dose), elimination half-life (3.04 vs 3.38 vs 3.30 hr), or apparent oral clearance (16.2 vs 14.3 vs 13.8 ml . min-1 . kg-1). Thus the usual therapeutic doses of cimetidine or ranitidine do not significantly alter the kinetics of intravenous or oral midazolam in healthy individuals.

Administration, Oral↗
PubMed1986

Oxaprozin pharmacokinetics in patients with congestive heart failure.

12 patients aged 26-71 years with stable, compensated congestive heart failure (CHF) and 12 healthy controls matched for age, sex, height, weight, and serum albumin, received a 1200-mg oral dose of the nonsteroidal antiinflammatory agent 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin). Serum oxaprozin levels were measured by high pressure liquid chromatography during the next 14 days. Oxaprozin elimination half-life was not different between controls and CHF patients (63 vs 69 h), but peak serum levels were lower (79 vs 63 micrograms/ml, p less than 0.01), apparent volume of distribution was larger (0.22 vs 0.29 l/kg, p less than 0.05) and clearance tended to be higher, although not significantly so, (0.042 vs 0.053 ml/min/kg) in CHF patients. These differences might have been due to reduced serum protein binding (increased free fraction) in CHF patients (0.25 vs 0.44% unbound, p less than 0.1). After correction for individual values of free fraction, groups did not differ in peak free oxaprozin serum levels (0.20 vs 0.26 micrograms/ml), unbound volume of distribution (92 vs 83 l/kg), or unbound clearance (17.5 vs 15.0 ml/min/kg). Thus protein binding of oxaprozin in the present study was reduced in CHF due either to the underlying disease or to the concurrent medications. This in turn caused reciprocal reduction in total (free plus bound) oxaprozin levels and elevated estimates of volume of distribution and clearance. Although protein binding is altered, CHF causes no significant alteration in distribution of free oxaprozin nor free clearance of oxaprozin, which is accomplished by a combination of oxidation and conjugation.

Adult↗
PubMed1986

Alprazolam kinetics in patients with renal insufficiency.

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.

Adolescent↗
PubMed1985

Kinetics of 1,2-dinitroglycerin following sustained release nitroglycerin: influence of propranolol and metoprolol.

Ten healthy volunteers ingested a single 18-mg oral dose of sustained release nitroglycerin (TNG) (Giulini-Pharma) on three occasions: once in the control state, once during coadministration of propranolol (80-mg three times daily), and once during coadministration of metoprolol (100-mg twice daily). The degree of beta adrenergic blockade was evaluated by the metaproterenol infusion test. Plasma concentration of TNG and its major metabolite, 1,2-dinitroglycerin (DNG), during 12 h after each dose were measured by gas chromatography-mass spectrometry. Intact TNG was not detected in the plasma of any patient. The major metabolite, DNG, was easily measurable in blood, and had a biphasic plasma concentration profile. Coadministration of the beta-blockers had no influence on any of the kinetic variables for DNG. The mean values during control, propranolol, and metoprolol trials of DNG elimination half-life were: 1.35, 1.10, and 1.09 h; total area under the curve: 42, 38, and 42 ng/ml X h; oral clearance: 6.6, 7.2, and 6.4 liters/min. Thus TNG when administered as a sustained release oral preparation is rapidly and completely transformed to DNG. There was no pharmacokinetic interaction between sustained release TNG and two commonly used beta-blocking agents, suggesting that any clinical interaction that may-occur between sustained release nitroglycerin and beta-blocking agents is pharmacodynamic rather than pharmacokinetic in nature.

Adult↗
PubMed1985

Diltiazem, verapamil, and quinidine in patients with chronic atrial fibrillation.

The comparative effects of diltiazem and verapamil in 30 patients with long-standing atrial fibrillation were evaluated in a prospective clinical trial. After a one- to two-day washout period during which drugs other than digoxin were withdrawn, patients were randomly assigned to diltiazem or verapamil treatment groups. All therapy was double blind. Both drugs were given in ascending doses as follows: days 1-6 (part I): diltiazem, 180 mg/d, or verapamil, 240 mg/d; days 7-12 (part II): diltiazem, 360 mg/d, or verapamil, 480 mg/d. Patients failing to convert to sinus rhythm after 12 days had dosage reduced to 180 mg/d of diltiazem or 240 mg/d of verapamil, and quinidine, 750 mg/d, was coadministered for another six days (part III). Medication compliance was verified by frequent measurement of serum drug concentrations. Three verapamil patients dropped out during part I due to adverse reactions (dyspnea, pulmonary congestion, skin rash, or hepatotoxicity). The higher dosage of either verapamil or diltiazem in part II was not well tolerated, and in eight patients part III had to be initiated early due to symptomatic bradycardia. Only one patient in the diltiazem group converted to sinus rhythm, whereas five converted with verapamil (two with verapamil alone, three when combined with quinidine). Thus, diltiazem and verapamil alone are unlikely to convert atrial fibrillation to sinus rhythm. The combination of verapamil and quinidine, however, is a potentially useful pharmacologic approach, having converted atrial fibrillation to sinus rhythm in nearly 50% of patients.

Anti-Arrhythmia Agents↗
PubMed1985

Effect of alprazolam on digoxin kinetics and creatinine clearance.

Eight healthy men received a single, 1.25 mg dose of digoxin on two occasions, once in an otherwise drug-free control state and again while concurrently receiving alprazolam, 1.5 mg/day. There was no significant difference between control and alprazolam conditions in digoxin volume of distribution (11.0 vs. 11.2 L/kg), elimination t1/2 (46 vs. 41 hours), or total clearance from serum (2.8 vs. 3.6 ml/min/kg). Alprazolam coadministration slightly reduced mean 96-hour urinary excretion of digoxin (37.6% vs. 30.9% of dose; P less than 0.01), but there was no significant difference between treatment conditions in projected total cumulative excretion of digoxin (45.2% vs. 40.9% of dose) or in renal clearance of digoxin (1.23 vs. 1.44 ml/min/kg). Creatinine clearance also did not differ between the control and alprazolam conditions (164 vs. 142 ml/min). Thus therapeutic doses of alprazolam do not significantly alter digoxin clearance in healthy man.

Adolescent↗