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The aim of prescribing strict bed rest for acute deep venous thrombosis is to reduce the risk of pulmonary embolism and pain in the legs, as well as swelling. This study was performed in order to compare outcome of mobilization against 5 days of strict bed rest in patients with acute proximal deep venous thrombosis (DVT).103 in-patients with proximal DVT or patients admitted to the hospital because of proximal DVT were recruited to a randomized study. All patients were treated in hospital and given a lower leg and thigh compression bandage as well as therapeutic doses of the low molecular weight heparin, dalteparin-sodium (Fragmin).Seven of 52 patients (13.5%) in the mobile group versus 14 of 50 patients (28.0%) in the immobile group suffered at least one of the outcomes defined under the combined primary endpoint (clinically relevant pulmonary embolisms, pulmonary embolisms detectable by scintigraphy or computer tomography, progression of thrombosis or new thrombosis, nosocomial infections and/or serious adverse events) (p = 0.088), whereby serious adverse events occurred once in the mobile group and three times in the immobile group. New pulmonary embolisms over the course were seen in 10 of 50 patients (20%) with a perfusion disorder at baseline scintigraphy, while such was ascertained only in one of 52 patients (1.9%) without a perfusion disorder at baseline scintigraphy. Leg pain was reduced from 54.1 (+/-30.4) to 20.7 (+/-19.2) in the mobilized group and from 41.0 (+/-26.8) to 14.0 (+/-11.1) in the immobilized patients. Leg pain was assessed using the visual analogue scale (0 = no pain, 100 = maximum pain). More immobilized patients complained of increasing back pain (23% versus 6%) and disturbed micturition (10% versus 2%) as well as defecation (13% versus 6%) on day 5. More patients in the mobile group reported increased stress from the thrombosis and its treatment (15% versus 6%).No benefit of prescribing bed rest in patients with deep venous thrombosis could be detected in this study. Based on data available, strict bed rest for at least 5 days is not justified if adequate therapy with low molecular weight heparin and adequate compression is assured. It remains open whether patients with initial signs of pulmonary embolism might profit from a brief immobilization.

Background Recent genome-wide association studies have identified several genetic loci linked to coronary artery disease (CAD) and myocardial infarction (MI). The 9p21.3 locus was verified by numerous replication studies to be the first common locus for CAD and MI. In the present study, we investigated whether six single nucleotide polymorphisms (SNP) rs1333049, rs1333040, rs10757274, rs2383206, rs10757278, and rs2383207 representing the 9p21.3 locus were associated with the incidence of an acute MI in patients with the main focus on the familial aggregation of the disease. Methods The overall cohort consisted of 976 unrelated male patients presenting with an acute coronary syndrome (ACS) with ST-elevated (STEMI) as well as non-ST-elevated myocardial infarction (NSTEMI). Genotyping data of the investigated SNPs were generated and statistically analyzed in comparison to previously published findings of matchable control cohorts. Results Statistical evaluation confirmed a highly significant association of all analyzed SNP's with the occurrence of MI (p < 0.0001; OR: 1.621-2.039). When only MI patients with a positive family disposition were comprised in the analysis a much stronger association of the accordant risk alleles with incident disease was found with odds ratios up to 2.769. Conclusions The findings in the present study confirmed a strong association of the 9p21.3 locus with MI particularly in patients with a positive family history thereby, emphasizing the pathogenic relevance of this locus as a common genetic cardiovascular risk factor.

Domestic pigs received single intravenous and oral doses of lorazepam or clonazepam (1 mg/kg), benzodiazepine derivatives biotransformed by glucuronide conjugation and nitroreduction, respectively. Blood samples were simultaneously drawn from portal venous and systemic venous sampling sites during 8 h after dosage. After intravenous dosage with either drug, the area under the serum concentration curve (AUC) for the intact drug, as well as for the principal metabolites (lorazepam glucuronide and 7-aminoclonazepam, respectively), was nearly identical between portal and systemic serum. After oral dosage, absolute systemic availability (relative to intravenous administration) of both lorazepam and clonazepam was incomplete (mean values: 29 and 49%, respectively); however, metabolite levels were also correspondingly lower between oral and intravenous dosages. First-pass hepatic extraction also occurred for both drugs, with mean systemic/portal AUC ratios of 0.60 for lorazepam and 0.74 for clonazepam. Pretreatment with neomycin (1.0 g) had a minimal effect on portal or systemic AUC for intact clonazepam after oral dosage, but 7-aminoclonazepam concentrations were reduced by neomycin pretreatment. Thus incomplete absorption, together with first-pass hepatic biotransformation, appears to explain the incomplete systemic availability of orally administered lorazepam or clonazepam. Biotransformation within the gastrointestinal tract or during absorption through the gastrointestinal mucosa contributes minimally.

Serum lidocaine concentrations were measured in a series of patients during and after topical administration of lidocaine used to anesthetize the nasal mucosa, pharynx, and larynx for diagnostic fiberoptic bronchoscopy. In one group of patients (N = 9) the trachea and bronchi were sprayed with a 2% lidocaine solution administered in 2 mL volumes. Another group (N = 14) received a 2% lidocaine solution which was administered by inhalation of lidocaine dispensed by a high-frequency nebulizer. Multiple serum samples drawn over a 1-hour period were analyzed by gas chromatography with nitrogen-phosphorous detection. In the spray group versus the inhalation group, there were no differences in mean age (54 vs 55 years), total lidocaine dose (572 vs 525 mg), or time of peak serum lidocaine concentration (43 vs 41 minutes after dose). However, the peak serum lidocaine concentrations were significantly lower in the inhalation group vs the spray group (1.40 vs 3.63 micrograms/mL). Thus, administration of lidocaine via inhalation by ultrasonic nebulization results in lower peak serum concentrations, and a reduction in the likelihood of toxicity, than when administered by conventional topical spray.

Eight patients with mild to moderate renal insufficiency (mean serum creatinine: 2.4 mg/100 ml) and 9 matched control subjects with normal renal function received a single 5-mg oral dose of nitrazepam, cleared mainly by hepatic nitroreduction. Serum nitrazepam levels were determined by gas chromatography during the 72 hours after dosage. Renal patients and controls were well-matched for age (74 vs. 63 years), height (165 vs. 164 cm), and weight (68 vs. 64 kg). Patients and control subjects did not differ significantly in nitrazepam elimination half-life (32 vs. 24 hour) or volume of distribution (4.2 vs. 3.6 liters/kg). Clearance was higher in patients than in controls (4.2 vs. 1.7 ml/min/kg), but the difference was not significant. Nitrazepam free fraction in serum was increased in renal patients (16.8 vs. 15.0% unbound, p = 0.08). After correction for individual values of free fraction, the two groups still did not differ in kinetic variables for nitrazepam. Thus, mild to moderate renal insufficiency does not alter the kinetics of nitrazepam.

Sixteen healthy volunteers, aged 19 to 62 years, took a single 20-mg oral dose of clobazam and the serum concentrations of clobazam and desmethylclobazam were measured for the following 7 days. The mean kinetic variables for clobazam were: volume of distribution 1.31/kg, elimination half-life 24 h, total clearance 0.47 ml/min/kg. 13 of the volunteers then took clobazam 5 mg twice daily for 22 consecutive days. Serum concentrations were measured during and after this period. Both clobazam and desmethylclobazam showed slow and extensive accumulation, their steady-state kinetics being entirely consistent with those observed after single doses. Elimination of both compounds after termination of treatment was equally slow. Clinical self-rating of morning sedation indicated a significant increase over baseline in subjective perception of sedation during the treatment period, and this effect persisted into the washout period. However, sedation did not increase in parallel with accumulating levels of clobazam and desmethylclobazam, probably due to functional adaptation or tolerance.

Factors influencing the disposition of clotiazepam in man were evaluated in a series of pharmacokinetic studies in healthy volunteers given a single 5 mg dose. Old age caused an increased volume of distribution of clotiazepam in women, and its clearance tended to be reduced in elderly men. Use of oral contraceptives, cimetidine, isoniazid or a single dose of ethanol had no significant effect on the kinetics of clotiazepam. Although clotiazepam is biotransformed by microsomal oxidation, its clearance appears to be relatively uninfluenced by factors known to alter the clearance of other oxidized benzodiazepines.

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.

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.

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.

Factors influencing hepatic oxidation of antipyrine and conjugation of acetaminophen were evaluated in volunteers who received 1.0 g of antipyrine intravenously and on a different occasion a 650 mg intravenous dose of acetaminophen. In study one, subjects received both drugs in the control state and at another time during coadministration of isoniazid (INH), 180 mg daily. In control versus INH conditions, mean clearance of antipyrine was reduced from 0.67 to 0.60 ml/min/kg as was clearance of acetaminophen from 4.97 to 4.23 ml/min/kg, but these differences were not statistically significant. In study two, females on low-dose estrogen oral contraceptives (OC) and drug-free controls matched for age received both drugs. Compared to controls, OC users had reduced total clearance of antipyrine (0.71 vs. 0.50 ml/min/kg; p less than 0.005) and prolonged antipyrine t1/2 (9.6 vs. 13.3 h; p less than 0.005). For acetaminophen, however, OC users had higher clearance (5.2 vs. 6.1 ml/min/kg) and shorter t1/2 (2.2 vs. 1.9 h) although differences did not attain statistical significance. Clearance of antipyrine and acetaminophen across both studies was not statistically significantly correlated within individuals (r = 0.22). The capacities for drug oxidation and conjugation appear to be controlled by different mechanisms.

Eight healthy volunteers received a single 500 mg intravenous dose of procainamide hydrochloride by 30-min infusion on three occasions in random sequence. The three modes of administration were (a) control, without concurrent drugs; (b) during coadministration of propranolol, 80 mg three times daily; and (c) during coadministration of metoprolol, 100 mg two times daily. Procainamide kinetics were determined from multiple serum concentrations measured by enzyme-multiplied immunoassay (EMIT) during 10 h after each dose. A metaproterenol infusion study verified a high degree of beta-blockade during trials 2 and 3. Mean procainamide half-life during the three trials (1.9, 2.2, and 2.3 h, respectively) tended to show prolongation during beta-blocker treatment, but the overall difference was of borderline significance (0.05 less than p less than 0.1). Total procainamide clearance (16.2, 14.1, and 13.7 ml/min/kg) did not differ significantly between the three trials, nor was there a significant change in area under the serum concentration curve for N-acetylprocainamide, the major metabolite. Thus the kinetics of procainamide in healthy persons are not importantly altered by typical therapeutic doses of two beta-adrenergic blockers.

Ten otherwise healthy cigarette smokers (mean, 31 cigarettes per day), and ten nonsmoking control volunteers matched for age, weight, and sex received single intravenous doses of diazepam (5 to 10 mg), midazolam (5 mg), and lorazepam (2 mg) on three separate occasions. Kinetics of each benzodiazepine were determined from multiple serum concentrations measured after each dose. In non-smoking vs smoking subjects, there was no significant difference in mean clearance of diazepam (0.44 vs 0.47 ml/min/kg), midazolam (9.6 vs 7.1 ml/min/kg), or lorazepam (0.96 vs 1.08 ml/min/kg). Thus, differences in pharmacokinetics are unlikely to account for altered sensitivity to benzodiazepines that may occur in cigarette smokers.

Single 25 mg intravenous and 50 mg oral doses of trazodone were given to 43 healthy subjects, divided into young men and women (aged 18 to 40 years) and elderly men and women (aged 60 to 76 years). Among men, trazodone volume of distribution (Varea) was increased in elderly vs. young subjects (1.15 vs. 0.89 L/kg; P less than 0.05), and clearance decreased (1.65 vs. 2.31 ml/min/kg; P less than 0.05), thereby increasing elimination half-life (t1/2) in elderly men (8.2 vs. 4.7 hours; P less than 0.001). Varea in women was also increased in the elderly (1.5 vs. 1.27 L/kg; P less than 0.02), causing increased t1/2 (7.6 vs. 5.9 hours; P less than 0.05), but clearance was unrelated to age. Absolute bioavailability of oral trazodone averaged 70% to 90% and was unrelated to age or sex. In 23 obese subjects (mean weight 112 kg) vs. 23 matched control subjects of normal weight (mean 65 kg), Varea was greatly increased (162 vs. 67 L; 1.43 vs. 1.04 L/kg; P less than 0.001) and was highly correlated with body weight (r = 0.91). Clearance was unchanged between groups (146 vs. 136 ml/min), but the increased Varea caused prolonged t1/2 in obese subjects (13.3 vs. 5.9 hours; P less than 0.001). Reduced clearance of trazodone among elderly men may indicate a need for dosage reduction during chronic therapy. In obese individuals, choice of dosage during chronic treatment should be based on ideal rather than total body weight.

The pharmacokinetics of oral quinidine sulfate and quinidine gluconate were compared in seven healthy volunteers In a two part pharmacokinetic study. Part I was a single dose crossover trial assessing absorption and elimination of quinidine sulfate (400 mg, equivalent to 331 mg of quinidine base) and quinidine gluconate (495 mg, equivalent to 309 mg of quinidine base). Mean kinetic values for the sulfate and gluconate preparations, respectively, were: peak serum quinidine level 2.07 versus 1.24 μg/ml (P Part II evaluated steady state kinetics of both preparations in a cross-over trial in the same subjects. Maintenance dosing schedules were 200 mg of quinidine sulfate every 6 hours versus 495 mg of quinidine gluconate every 12 hours. Systemic availability of the gluconate at the steady state level was 10 percent less (based upon area under the serum concentration curve) or 7 percent less (based upon urinary excretion of quinidine) than that of the sulfate, but the differences were not significant. Interdose fluctuation in serum quinidine concentrations during the gluconate trial averaged 70 percent, which was not significantly different from the average of 67 percent during the sulfate trial. However, variation within and between subjects in minimal steady state levels with quinidine gluconate (15.6 and 16.0 percent, respectively) was greater than with quinidine sulfate (7.2 and 9.9 percent, respectively). Steady state concentrations during the multiple dose trial were not accurately predicted from single dose pharmacokinetics, either for quinidine sulfate (r = 0.45) or quinidine gluconate (r = −0.12), but deviation of observed from predicted concentrations tended to be greater with quinidine gluconate. The slow absorption of quinidine from the gluconate preparation allows maintenance therapy on a 12 hourly dosage schedule with acceptable interdose fluctuation in serum levels. Variability within and between subjects in absorption kinetics tends to be greater with quinidine gluconate than with the more rapidly absorbed sulfate salt.

Normally menstruating young female volunteers with no evidence of cardiovascular disease participated in a controlled study of digoxin effects on serum thyroid stimulating hormone (TSH) and prolactin levels in the basal state and after stimulation with thyrotropin releasing hormone (TRH). In the first study, subjects received oral digoxin, 0.5 mg daily, or matching placebo, on days 10 through 22 of a menstrual cycle, then crossed over to placebo or digoxin for days 10 through 22 of the next cycle. Basal serum TSH and prolactin on days 7 through 9 and 20 through 22 did not differ significantly between placebo and digoxin cycles. Levels of both hormones rose after a 200-micrograms intravenous dose of TRH given on days 8 and 21, but the response to TRH did not differ between placebo and digoxin cycles. In the second study, subjects received 0.5 mg intravenous digoxin daily for days 7 through 21 of a menstrual cycle. Basal serum TRH and prolactin did not change significantly in response to digoxin. The findings suggest that hormonal changes associated with digoxin therapy, if they exist, are more likely to reflect direct effects on the target organ rather than indirect effects on the hypothalamic-pituitary axis.

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.

Twelve normal subjects aged 24-41 years, and 12 subjects aged 62-79 years, received single 50-mg doses of chlordiazepoxide hydrochloride by mouth and by intravenous injection on two occasions. Chlordiazepoxide volume of distribution was significantly correlated with body weight (r = 0.63, p less than 0.001), but was not related to age or sex. Among male subjects, elimination half-life was prolonged (20 vs. 8 h, p less than 0.025) and clearance reduced (20 vs. 43 ml/min, p less than 0.05) in elderly as opposed to young volunteers. Among women, there was no significant difference between elderly and young subjects in elimination half-life (12 vs. 13 h) or clearance (29 vs. 22 ml/min). Absolute bioavailability of oral chlordiazepoxide was not less than 100%, and was unrelated to age or sex. Among 20 subjects who received a single 1.0- to 1.2-gram intravenous dose of antipyrine on another occasion, clearance of chlordiazepoxide and of antipyrine were significantly correlated (r = 0.62, p less than 0.01). Like many other low-clearance oxidatively metabolized compounds, chlordiazepoxide clearance is reduced and half-life prolonged in elderly men, but not elderly women. Individual variations in chlordiazepoxide clearance are significantly correlated with those of antipyrine, a drug commonly used as an index of hepatic oxidizing capacity.

Benzodiazepines are widely prescribed, and in 1979 almost 10% of the adult population was taking them. Prior studies of outpatient usage of benzodiazepines have relied on survey or prescription data, which may be confounded by noncompliance. To determine the actual use of benzodiazepines, plasma benzodiazepine concentrations were measured in 225 consecutive outpatients from a university cardiology outpatient service. Self reports indicated that the great majority of the patients (191) were taking at least one medicine, and 70 reported being on a psychotropic drug. Seventy-seven patients reported taking benzodiazepines, the majority being on bromazepam (20), diazepam (26) or oxazepam (19). In 25 of those 77 patients, the reported drug could not be detected in plasma. Conversely, in 10 of the 225 patients, benzodiazepines which were not reported were detected (diazepam or flurazepam). Of those taking benzodiazepines, many had a low concentration, suggesting intermittent rather than regular use. Thus, many patients for whom benzodiazepines are prescribed take them irregularly, and a small group uses them without reporting their prescription. These findings have implications for the clinical presentation of illness and for the possibility of drug interactions.

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.

The bioavalability of digoxin tablets and solution has been studied during maintenance therapy in a cross over study. Each preparation was given over a period of at least 7 days to patients with compensated congestive heart failure. Urine concentrations and plasma levels were analysed for digitoxin. There was no significant difference between the two preparations. Determination of steady state serum concentrations and urinary excretion during maintenance therapy as an index of bioavalability are more cumbersome than a single dose study. From a pharmacokinetic point of view however, analyses of steady-state conditions are preferable to a single dose study. In addition, steady state of drug input and output resembles the usual digitalis therapy.

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.

LIDOCAINE is commonly administered parenterally for the treatment of cardiac arrhythmias. The use of this drug is complicated by its narrow therapeutic index.1 Any reduction in its metabolic cleara...

Pharmacokinetic drug-drug interactions which involve currently available benzodiazepines may be classified into two major categories: interactions which affect benzodiazepine rate of absorption, and interactions which affect clearance and, therefore, elimination half-life. Ethanol is the prototype for absorptive interactions. Concurrent ethanol use and oral ingestion of benzodiazepine derivatives uniformly slows the rate but does not change the extent of benzodiazepine absorption. Interactions which affect benzodiazepine clearance affect only those derivatives which are oxidatively metabolized or cleared as a function of hepatic blood flow (high first-pass clearance). Conjugated benzodiazepines are not implicated in such interactions. Rifampin and chronic ethanol use induce benzodiazepine oxidation, while cimetidine, oral contraceptives, ethanol (acute ingestion), disulfiram, isoniazid, and propranolol inhibit benzodiazepine oxidation. In addition, ethanol, cimetidine and isoniazid decrease first-pass hepatic extraction of triazolam, enhancing its systemic availability and decreasing oral clearance. The pharmacokinetic consequence of induction of benzodiazepine oxidation is higher clearance and decreased steady-state concentrations during chronic dosing. Conversely, inhibition of benzodiazepine oxidation decreases clearance and increases steady-state benzodiazepine concentrations during chronic dosing. Because a correlation of benzodiazepine plasma concentration and pharmacological effect is not established, the pharmacodynamic consequences of these interactions are not currently well characterized.Pharmacokinetic drug-drug interactions which involve currently available benzodiazepines may be classified into 2 major categories: interactions which affect benzodiazepine rate of absorption, and interactions which affect clearance and, therefore, elimination 1/2-life. Ethanol is the prototype for absorptive interactions. Concurrent ethanol use and oral ingestion of benzodiazepine derivatives uniformly slows the rate but does not change the extent of benzodiazepine absorption. Interactions which affect benzodiazepine clearance affect only those derivatives which are oxidatively metabolized or cleared as a function of hepatic blood flow (high 1st pass clearance). Conjugated benzodiazepines are not implicated in such interactions. Rifampicin and chronic ethanol use induce benzodiazepine oxidation, while cimetidine, oral contraceptives, ethanol (acute ingestion), disulfiram, isoniazid, and propranolol inhibit benzodiazepine oxidation. In addition, ethanol, cimetidine and isoniazid decrease 1st pass hepatic extraction of triazolam, enhancing its systemic availability and decreasing oral clearance. The pharmacokinetic consequence of induction of benzodiazepine oxidation is higher clearance and decreased steady state concentrations during chronnic dosing. Conversely, inhibition of benzodiazepine oxidation decreases clearance and increases steady state benzodiazepine plasma concentration and pharmacological effect is not established, the pharmacodynamic consequences of these interactions are not currently well characterized. (author's)

Twelve healthy volunteers received single oral doses of propranolol (80 mg), metoprolol (100 mg), L-bunolol (2 mg), and placebo in a four-way crossover study. Blood pressure, ventricular rate, and echocardiographically determined ejection fraction, ejection time, and mean rate of circumferential fiber shortening (mVcf) were measured before dosing and at multiple time points during 10 hours after each dose, with subjects maintained in the supine position. Reductions in systolic and diastolic blood pressure following administration of each of the beta blockers were greater than those observed with placebo, but differences among the four treatments were not significant. Heart rate reductions with the beta blockers differed significantly from placebo (P less than .001), but differences among the three beta blockers were not significant. Differences among the four treatments in mVcf decrement did not attain significance at the 5% level (.05 less than P less than .1), and there were no significant differences in ejection-time prolongation or ejection-fraction reduction. Thus, reduced blood pressure, heart rate slowing, and reduced cardiac contractility may be associated with placebo treatment and may indicate the need for placebo controls in studies of the cardiovascular effects of beta blockers. Despite differing secondary pharmacologic properties, the three beta blockers reduced heart rate to a similar extent. Other effects of the beta blockers on blood pressure and cardiac contractility could not be consistently distinguished from those associated with placebo.

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self-rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half-life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half-life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P less than .05). Self-ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

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.

The pharmacokinetics of a single 30-mg oral dose of oxazepam was evaluated in seven patients with chronic renal failure on maintenance hemodialysis and in seven healthy controls matched for age and sex. Based on total (free plus bound) serum oxazepam concentrations, elimination half-life was prolonged in renal patients compared to controls (22 vs 8 h, p less than 0.001) and volume of distribution increased (3.0 vs 1.4 1/kg, p less than 0.02). However, total clearance was similar between groups (1.8 vs 1.9 ml/min per kilogram). These findings were confounded by the increased oxazepam free fraction in serum of renal failure patients (10.3%) as compared to healthy controls (4.3%). Correction for differences in binding indicates similar distribution of unbound oxazepam between groups, but reduced clearance of pharmacologically active unbound oxazepam in renal patients (18 vs 45 ml/min per kilogram). Oxazepam dosage, therefore, may require downward adjustment for renal failure patients on hemodialysis.

Bei 6 gesunden Versuchspersonen wurde die biologische Verfugbarkeit von Digoxin und von zwei Digoxin-Kombinationspraparaten (Theophyllin- Theobromin-Digoxin, Carbochromen-Digoxin) nach einer einmaligen oralen Dosis, die 1 mg Digoxin entsprach, untersucht. Uber 18 Std wurden die Digoxin-Serumspiegel radioimmunologisch bestimmt, die varianzanalytisch bei den drei gepruften Medikamenten keine signifikanten Unterschiede aufwiesen. Von diesen Ergebnissen wird in Kenntnis der Pharmakokinetik von Digoxin beim Menschen auf eine gleiche biologische Verfugbarkeit des Digoxins aller drei untersuchter Medikamente geschlossen.

In 12 patients undergoing coloscopy, 0.5 mg digoxin in aqueous alcoholic solution was injected into the transverse colon. The late maximum of the blood level curve at about 2 hours after the administration suggested delayed absorption of the glycoside. However, the 24 hour urinary excretion of 17 +/- 3.4% in 8 patients with normal colonic mucosa demonstrated extensive absorption in the distal part of the bowel. The results have been contrasted with the findings in 4 patients with ulcerative colitis who excreted only 1.66 +/- 0.6% of the given dose in 24 hours.

Acetaminophen is a widely prescribed analgesic/antipyretic metabolized by hepatic glucuronide and sulfate conjugation. Twelve patients, 30-66 years of age, with stable Class III or IV congestive heart failure (CHF) and 12 healthy controls matched for age, sex, and weight received single 650-mg intravenous doses of acetaminophen. Pharmacokinetic variables were determined from multiple plasma acetaminophen concentrations measured by liquid chromatography during 12 h after the dose. Compared with controls, mean total clearance of acetaminophen was reduced in CHF patients (3.56 vs. 4.59 ml/min/kg, p less than 0.025), indicating reduced biotransformation capacity in this disease. Volume of distribution was also significantly reduced in CHF patients (0.85 vs. 1.02 L/kg, p less than 0.05). Since elimination half-life depends on both volume of distribution and clearance (both of which were reduced), the half-life was similar between groups (2.87 vs. 2.34 h, NS). Thus, hepatic conjugation of acetaminophen is impaired in CHF. The finding may also apply to other drugs biotransformed by conjugation.

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.

infarction is not known. Moreover, the diagnosis of this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agents which potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable.

A LARGE and clinically important interaction between digoxin and quinidine is now well documented.1 2 3 4 5 The cardiac glycoside digitoxin is extensively used in clinical practice, but its interaction with quinidine has not been definitively evaluated.6 , 7 In this study, which assessed the pharmacokinetic interaction of digitoxin with quinidine, we found that simultaneous administration of quinidine had no statistically significant effect on the distribution or clearance of intravenously administered digitoxin. Methods Ten healthy male and female volunteers participated after giving informed consent (Table 1). Their ages ranged from 23 to 32 years. None had evidence of medical disease, and none were taking medications . . .

8 healthy volunteers (age 25±4 years) received in randomized sequence 50, 100, 200, 400, and 600 mg Atenolol orally and 50 mg Atenolol intravenously during 5 minutes under continuous ECG monitoring. On 3 consecutive days prior to the first application of Atenolol the volunteers were exercised on the treadmill under continuous measurement of the blood-pressure until a heart rate of 150 min was achieved. This individually determined load was used on the treadmill 3 h after oral and 1 hour after i.v.-application of Atenolol. Systolic and diastolic blood pressure and heart rate was measured at rest and after 1.5 min and 3 min of exercise. The results are expressed as difference between rest (=0) and exercise in blood pressure (Δs=systolic2 1Δd=diastolic RR in mm Hg) and heart rate (HR in min).

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.

Alterations in drug metabolizing capacity associated with the aging process can be elucidated using analgesic-antipyretic agents as model compounds. Antipyrine serves to profile drug oxidizing capacity. Drug oxidation is significantly impaired in old age, but agerelated changes are far greater in men than in women. Acetaminophen analogously serves to profile conjugating capacity, which is minimally influenced by age both in men and in women. Changes in the capacity to biotransform these model compounds are reasonably well predictive of parallel changes in the same person's ability to metabolize other drugs transformed by the same pathway.

The relation of serum digoxin concentrations (SDC) to subjective manifestations of toxicity was evaluated in 300 patients with permanent transvenous pacemakers. All had been receiving the same daily d

Ten healthy volunteers received 300 mg. of quinidine base as the gluconate salt by 15-minute intravenous infusion. Physiologic variables monitored before, during, and for 24 hours after the infusion were: electrocardiogram, systolic and diastolic blood pressure, echocardiogram, and carotid pulse tracing. During quinidine infusion, mean ventricular rate increased by 18% (67.1 to 79.5 beats per minute) and corrected QT interval increased by 54% (0.44 to 0.68 sec.). QRS duration did not change significantly, nor did systolic or diastolic blood pressure. Ejection fraction (EF) measured by echocardiography did not decrease during quinidine infusion, but rather increased by 12% (0.58 to 0.65). Mean rate of circumferential fiber shortening (Vcf) likewise increased by 22%, from 1.15 to 1.40 per second. Over the 24-hours post-infusion, all monitored physiologic variables fluctuated considerably; in the case of EF and Vcf, apparently random variations over time were as great as those attributable to quinidine infusion. Mean (and range) kinetic variables for quinidine were: volume of distribution, 2.03 (1.47 to 3.00) liter/Kg.; elimination half-life, 6.3 (4.8 to 7.9) hours; total clearance, 3.8 (2.8 to 5.2) ml./min./Kg. Neither total nor unbound serum quinidine concentrations were significantly correlated with physiologic changes. Thus, intravenous quinidine in the doses studied did not have negative inotropic effects in a series of healthy humans.

Serum nifedipine concentrations and hemodynamic changes were evaluated in ten healthy volunteers after a single 40-mg oral dose of nifedipine. Peak serum concentrations averaged 45 micrograms/l, attained 2.7 h after dosage. The mean elimination half-life was 5.9 h (range: 3-12 h). Blood pressure, ventricular rate, and echocardiographically-determined rate of circumferential fiber shortening did not differ between placebo and nifedipine trials. Five additional subjects ingested nifedipine once in the control state and on a second occasion with a standard breakfast. Coingestion of food delayed the peak serum nifedipine concentration but did not alter the area under the serum concentration curve. Thus the pharmacokinetic profile of nifedipine indicates that a three- or four-times-daily dose is, in general, appropriate in clinical practice. Completeness of absorption is not altered by coadministration with food. Adverse hemodynamic effects of single oral doses in healthy persons are not evident.

5 patients with chronic renal failure on maintenance hemodialysis and 5 healthy matched controls received single 20-mg intravenous doses of clorazepate dipotassium. Clearance of pharmacologically active unbound desmethyldiazepam was reduced in renal failure patients as opposed to controls, and free fraction in serum was greater. Since desmethyldiazepam distribution was reduced in renal patients, elimination half-life was actually shorter than in controls (36 vs. 57 h). In 10 dialysis patients receiving chronic diazepam treatment (5-15 mg/day), steady-state concentrations of diazepam (56 ng/ml) and desmethyldiazepam (77 ng/ml) were significantly lower than in age- and weight-matched controls receiving similar doses (189 and 216 ng/ml, respectively). However after correction for the higher free fractions of both compounds in renal patients as opposed to controls, steady-state concentrations of unbound drug were found to be similar between groups. Interpretation of kinetic variables and steady-state serum concentrations of extensively protein-bound drugs requires consideration of alterations in protein binding that may occur in disease states.

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.

Pharmacokinetics of the benzodiazepine bromazepam were evaluated in volunteer subjects who received single 6 mg oral doses followed by blood sampling during the next 48 hours. Age and gender effects were studied in 32 subjects, divided into young (aged 21 to 29 years) and elderly (aged 60 to 81 years) groups. Compared with young subjects, the elderly had significantly higher peak serum bromazepam concentrations (132 vs. 82 ng/ml), smaller volume of distribution (0.88 vs. 1.44 L/kg), lower oral clearance (0.41 vs. 0.76 ml/min/kg), and increased serum free fraction (34.8% vs. 28.8% unbound). However, gender had no significant influence on bromazepam kinetics. In 11 young female users of oral contraceptive steroids, compared with seven age- and weight-matched control women not using oral contraceptives, no differences in bromazepam kinetics were observed. Coadministration of cimetidine (1.2 gm daily) significantly reduced bromazepam clearance (0.41 vs. 0.82 ml/min/kg) and prolonged elimination half-life (29 vs. 23 hours). Propranolol (160 mg daily) significantly prolonged bromazepam half-life (28 vs. 23 hours), but the reduction in clearance associated with propranolol (0.65 vs. 0.82 ml/min/kg) did not reach significance. Bromazepam has the pharmacokinetic characteristics of benzodiazepines with half-life values between 20 and 30 hours. Consistent with its biotransformation pathway by hepatic microsomal oxidation, bromazepam clearance is significantly impaired in elderly individuals, by coadministration of cimetidine and possibly propranolol.