Pharmacodynamic evaluation of the benzodiazepine-oral contraceptive interaction.

The sedative, psychomotor, and memory effects of single oral doses of alprazolam (ALP), lorazepam (LOR), temazepam (TMP), and triazolam (TRZ) were evaluated in women taking oral contraceptives (OCs) and a comparable group of control women. Nine women taking OCs and 11 control women took doses of 1 mg ALP and 2 mg LOR and 10 OC users and 10 control women took 30 mg TMP and 0.5 mg TRZ on two occasions separated by 28 days. Minimal psychomotor impairment was noted after TMP. ALP, LOR, and TRZ produced greater performance impairment in the OC users. Correcting the maximum observed performance decrement for plasma concentration did not account for the differences between OC users and controls. After TMP, there was less sedation during the first 2 hours in OC users, who also had higher plasma TMP clearance. There were no differences in sedation between OC users and controls after ALP, LOR, and TRZ; however, there was less than 50% power to detect a 30% difference. Amnestic effects in OC users and controls did not differ after any of the four drugs. The observed patterns of anterograde amnesia were different, with the earliest and most pronounced recognition failure after TRZ (50% at 1.5 hours), while the LOR effect increased to a maximum (30%) 4 hours after dosing. Our data suggest that differences in benzodiazepine pharmacokinetics between OC users and control women do not account for observed differences in psychomotor impairment. Women taking OCs are more sensitive to the psychomotor effects of single oral doses of benzodiazepines.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibuprofen and sulindac kinetics in alcoholic liver disease.

Ibuprofen and sulindac kinetics after oral doses were compared in 15 patients with alcoholic liver disease and 29 normal subjects. The patients with alcoholic liver disease were divided into a group with fair hepatic function (FHF) and a group with poor hepatic function (PHF) based on elimination rates of indocyanine green. The effects of alcoholic liver disease on the ibuprofen kinetics were minimal. The absorption of the drug appeared to be delayed in some of the PHF patients, and slight differences were noted in the serum AUC and the elimination rate constant for ibuprofen. The absorption of sulindac was delayed in both PHF and FHF groups of patients, as was the appearance of the active metabolite, sulindac sulfide, and the inactive metabolite, sulindac sulfone. The plasma AUC for sulindac sulfide in patients with poor hepatic function was four times that in normal subjects. The kinetics of sulindac, a pro-drug that relies on the liver for conversion to an active metabolite, were markedly affected by alcoholic liver disease.

Effects of end-stage renal disease and aluminum hydroxide on temazepam kinetics.

The kinetics of temazepam, 30 mg, were evaluated in 11 patients with end-stage renal disease. Age ranged from 18 to 65 years. On two occasions separated by 1 week, single oral 30 mg doses of temazepam were given once with water (TM) and once with 3600 mg aluminum hydroxide gel (TM + AHG). There were no significant differences in the maximum plasma concentration, the time to reach maximum concentration, or elimination rates between TM and TM + AHG dosing. In approximately half the subjects there were secondary temazepam peak concentrations. In the remaining subjects, temazepam elimination was biphasic, with the terminal t1/2 ranging from 11 to 77 hours. There was a lag time before absorption in all subjects. The percent free temazepam in plasma from dialysis subjects ranged from 4.4% to 8.8% (mean = 5.9%). Compared with literature reports of subjects with normal renal function, the maximum plasma concentration was lower and the percent free temazepam was higher in dialysis subjects. When sedation score was plotted against plasma temazepam concentration, there was clockwise hysteresis consistent with tolerance or adaptation to effects of the drug. Thus aluminum hydroxide gel does not affect temazepam absorption. The clinical significance of the low plasma concentrations and high free temazepam fraction in dialysis subjects is uncertain.

Effect of oral contraceptives on triazolam, temazepam, alprazolam, and lorazepam kinetics.

The effects of low-dose estrogen oral contraceptives (OC) on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprazolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR) were studied in two parallel crossover studies of 20 women each. Women taking OC steroids containing low doses of estrogen and women matched for age, weight, and cigarette smoking received single oral doses of TRZ (0.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Kinetics were determined as plasma concentrations during 48 hr after dosing. OCs inhibited the metabolism of ALP: The AUC increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. In contrast, OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. Low-dose estrogen OCs may therefore inhibit the metabolism of some oxidized benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines.

PIP: Because benzodiazepines and oral contraceptives (OCs) are among the most widely prescribed drugs and have a potential for interaction, 2 parallel crossover studies were conducted to determine the effects of OCs on the elimination of the oxidized benzodiazepines triazolam (TRZ) and alprozolam (ALP) and the conjugated benzodiazepines temazepam (TMZ) and lorazepam (LOR). 20 healthy women taking OCs containing does of under 35 mcg of ethinyl estradiol for 3 months or more and 20 women matched for age, weight, and cigarette smoking received single oral doses of TRZ (.5 mg) and TMZ (30 mg) or ALP (1 mg) and LOR (2 mg). Treatments were seperated by 28 days to control for effects of menstural cycle on drug metabolism. Kinetics were determined as plasma concentrations during 48 hours after dosing. The data indicated that OCs differentially affect the elimination of the benzodiazepines studied. OCs inhibited the metabolism of ALP: the area under the curve (AUC) increased and the elimination rate constant was greater in users of OCs. For TRZ, which has an intermediate extraction ratio, the AUC was increased by OCs but not significantly so. OCs decreased the AUC for TMZ and the elimination rate constants for LOR and TMZ. The AUC of LOR was not affected by OCs. It was concluded that low-dose estrogen OCs may inhibit the metabolism of some conjugated benzodiazepines and accelerate the metabolism of some conjugated benzodiazepines, but the clinical implications are unclear. The relationship between plasma concentration and effect has not been determined for most benzodiazepines, but the results suggest that the time required to achieve steady-state concentrations would be longer and that there would be higher steady state concentrations of ALP in OC users. Because both TMZ and LOR are eliminated more rapidly by OC users, women taking OCs should achieve steady-state concentrations more rapidly than nonusers. Because TMZ clearance is increased by OCs, mean plasma concentration may be decreased. The usual 30 mg dose of TMZ may therefore be less effective as a hypnotic in OC users.

Triazolam protein binding and correlation with alpha-1 acid glycoprotein concentration.

On two occasions separated by a minimum of 1 wk, plasma was obtained from 12 patients (aged 18 to 73 yr) on dialysis after an overnight fast. Samples were assayed for albumin and alpha 1-acid glycoprotein (AGP) concentrations. 14C-Triazolam was added to each sample to a final concentration of 5 ng/ml. Protein binding was determined by equilibrium dialysis. Unbound triazolam ranged from 6.4% to 15.4% (mean = 10.0%). AGP concentrations ranged from 71.8 to 205.1 mg% (mean = 123.4 mg%). Triazolam binding ratio (bound/unbound concentration) correlated with AGP concentration (r2 = 0.69) but not with albumin concentration, age, or sex. This correlation was verified by adding AGP in varying amounts to control plasma.

Effect of sulfasalazine on digoxin bioavailability.

Low levels of digoxin were noted in a patient receiving digoxin and sulfasalazine (SSA). Discontinuation of SSA resulted in a significant increase in serum digoxin levels. To determine whether or not SSA consistently interfered with the therapeutic effect of digoxin, both drugs were administered to 10 normal subjects in a crossover study. Each received 2 doses of digoxin (0.5 mg, elixir): one dose given alone, and a second dose after 6 days of treatment with SSA. When digoxin was given with SSA, the average area under the serum digoxin curve fell from the control value of 8.79 ng-hr-ml(-1) to 6.66 ng-hr-ml(-1) (p less than 0.05), fell and total urinary excretion decreased from 278 mcg/10 days to 228 mcg/10 days (p less than 0.025). These changes suggest interference with the bioavailability of digoxin by SSA. Studies were conducted to determine whether SSA inhibited digoxin absorption by physically absorbing the glycoside from solution. In vitro tests failed to reveal any significant adsorptive properties for SSA.

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration.

Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.

Nighttime dosing of triazolam in patients with liver disease and normal subjects: kinetics and daytime effects.

This study was designed to determine whether the severity of liver dysfunction in cirrhosis affects the kinetics and next-day effects of triazolam after bedtime administration of a single oral dose. Eight patients with biopsy-proven cirrhosis and seven normal subjects matched for age, weight, and sex participated as paid volunteers. The first night was the control night, when no nighttime sedative was administered. The next day, psychomotor testing was performed at 8:30 AM, 2 PM, and 5 PM. Triazolam 0.25 mg was administered at 10:30 PM that evening. Psychomotor testing was repeated on the posttriazolam day in the same manner as on the control day. Blood samples were obtained from a venous catheter at 11 predetermined times in the 14 hours after triazolam administration. Memory testing was also performed. Apparent oral clearance of triazolam was directly related to albumin concentration and indocyanine-green elimination rate constant, and inversely related to partial thromboplastin time expressed as seconds over control. Clearance was 6.69 +/- 2.52 mL/min/kg in the normal subjects and 4.99 +/- 3.14 in the subjects with cirrhosis. There were no significant differences in Cmax between normal subjects (1.43 +/- 0.44 ng/mL) and subjects with cirrhosis (1.62 +/- 0.31 ng/mL) or in tmax (2.0 +/- 1.0 vs 2.5 +/- 1.9 hr) between normal and cirrhosis subjects, respectively. Posttriazolam, cirrhotic subjects took significantly longer to sort cards at 8:30 AM than on the control day. There was a significant correlation between extent of impairment on 8:30 AM card sorting by suit and AUC0-8 (r = 0.687; P = 0.0046).(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam pharmacokinetics in alcoholic liver disease.

Alprazolam, a triazolobenzodiazepine, was administered to 17 patients with alcoholic liver disease. The pharmacokinetic parameters derived from plasma alprazolam concentrations were compared with data obtained from 17 normal subjects who were matched for age and sex. The rate of absorption of alprazolam was slower in patients with alcoholic liver disease. The time of maximum serum concentration was 3.3 hours, compared with 1.5 hour in normals (P less than 0.02). The maximum concentrations, however, did not differ (18.4 vs. 17.2 micrograms/ml). The elimination half-life of drug was longer in the patients (19.7 hours) than in the normal subjects (11.4 hours), while the clearance of the drug was slower in the patients with alcoholic liver disease (0.6 vs 1.2 ml/min/kg). The volumes of distribution (area) did not differ between the two groups (1.1 vs. 1.2 liter/kg). The changes in elimination half-life and clearance indicate that the metabolism of the drug is slowed in patients with alcoholic liver disease.

The excretion of rosaramicin in breast milk.

The excretion of rosaramicin, a macrolide antibiotic, was studied in the breast milk of ten lactating women. Breast milk and serum samples were collected for 48 hours after a single 250-mg oral dose of rosaramicin. Mean serum half-life, apparent volume of distribution, and oral clearance were 4.4 hours, 3.41 L/kg, and 6.34 mL/min/kg, respectively. Mean milk/serum ratio was 0.12 and the total amount of drug recovered over the first ten hours was 6.25 micrograms, approximately 0.0025% of the dose. A positive correlation between breast milk volume and breast milk clearance was found, suggesting that the amount of drug received by a nursing infant will depend on the volume of milk produced by the mother. Drug-induced toxicity from the parent drug is unlikely to occur in nursing infants since the amount of rosaramicin that a nursing infant could ingest is small.

Prescription to over-the-counter switch: a regulatory perspective.

This paper discusses the origins of the over-the-counter (OTC) drug category and presents information about the process of switching a drug from prescription (Rx) to OTC status. It also reviews past and current drug laws in terms of how they relate to OTC drugs.

Comparison of kaolin-pectin and activated charcoal for inhibition of aspirin absorption.

The effects of kaolin-pectin suspension and of activated charcoal on aspirin absorption were compared. Ten fasting volunteers each received on five separate occasions three 325-mg aspirin tablets with: (1) 240 ml of water, (2) 10 g of activated charcoal in a slurry with 240 ml of water, (3) 30 ml of kaolin-pectin suspension with 210 ml of water, (4) 60 ml of kaolin-pectin with 180 ml of water, and (5) 90 ml of kaolin-pectin with 150 ml of water. Aspirin bioavailability was estimated from spectrophotometric assay of total 48-hour urinary salicylate recovery. The mean urine salicylate recovery following administration of activated charcoal (69.5%) was significantly less (p less than 0.01) than that following administration of 30, 60 or 90 ml of kaolin-pectin (90.6, 94.6 and 95.3%, respectively) or of water only (98.6%). The mean percent aspirin recoveries for the 30-ml and 60-ml kaolin-pectin treatments were significantly less than that for water only (p less than 0.05). Neither activated charcoal nor kaolin-pectin delayed the rate of aspirin absorption. Although kaolin-pectin reduces the absorption of aspirin, the effect would be of marginal clinical importance. Kaolin-pectin suspension is not recommended as a treatment for aspirin poisoning.

Oral malignant and premalignant changes in 'Shammah'-users from the Gizan region, Saudi Arabia.

A survey of the oral mucosa in 661 of the people living in various geographical locations of the Gizan region has been carried out. Mucosal lesions compatible with 'oral leukoplakia' have been found to affect approximately 68% of the users of the native snuff known as 'Shammah'. The lesions were almost always at the site where 'Shammah' was habitually held. Histological examination of biopsy specimens obtained from 29 different individuals revealed squamous cell carcinoma in 7 cases and carcinoma in situ in 2 cases, whereas the remaining specimens showed ortho- and para-hyperkeratosis, some of which also had premalignant changes. The results of this study point to a possible causal relationship between the use of 'Shammah' and the development of oral premalignant and malignant lesions among snuff-dippers in the Gizan region.

Amphetamine psychosis.

A case report of amphetamine psychosis in a 16-year-old female that closely resembled paranoid schizophrenia following the possible ingestion of a large quantity of amphetamine tablets is presented. The symptoms associated with amphetamine psychoses, the criteria used for differentiating amphetamine psychoses from schizophrenia, and the treatment of this drug-induced reaction are discussed. Treatment recommendation include the use of a dopamine antagonist such as haloperidol and the use of ascorbic acid to accelerate the renal elimination of amphetamines.

New drug evaluations. Triazolam.

Triazolam is a sedative/hypnotic triazolobenzodiazepine, structurally related to alprazolam. Recently, it has been approved for the short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Triazolam is metabolized with a half-life of 1.5-5.0 hours. Its one active metabolite, which appears in low concentrations and is inactivated rapidly, is not thought to contribute to its pharmacologic activity. Triazolam has been shown to decrease sleep latency and the number of nocturnal awakenings while increasing total sleep time in patients with insomnia. Sleep electroencephalogram studies show that triazolam has no effect on delta-sleep (Stages 3 and 4) and has variable effects on rapid-eye-movement sleep. Nighttime administration of triazolam increases daytime alertness in insomniacs and improves or has no effect on performance. The reported side effects are similar to those of other benzodiazepines and include drowsiness, dizziness, and dry mouth. The recommended dosage of triazolam is 0.25-0.5 mg hs. A reduced initial dose of 0.125 mg should be used in geriatric patients.