Reversible adsorption (desorption) of aspirin from activated charcoal.

The potential desorption of aspirin from activated charcoal was investigated in eight patients in a randomized cross-over study. Despite prebinding of aspirin, systemic absorption did occur. Desorption from activated charcoal was characterized by a peak salicylate concentration that was 16% of control and a time to peak salicylate concentration that was delayed in the study group. Bioavailability of aspirin from activated charcoal described by area under the curve was 19% of control. Elimination half-lives were similar in both groups until 12 hours after ingestion, but after 12 hours the half-life of the study group was prolonged while salicylate concentrations were undetectable in the control group. Fifteen percent to 20% of aspirin prebound to charcoal may desorb leading to systemic absorption. Furthermore, release from activated charcoal is initially delayed then sustained through 30 hours.

Cognitive effects of beta-adrenergic antagonists after single doses: pharmacokinetics and pharmacodynamics of propranolol, atenolol, lorazepam, and placebo.

The behavioral effects of two beta-adrenergic receptor antagonists, selected to represent differing lipophilicity, were evaluated in a double-blind, single-dose, parallel-group study. A group of 55 healthy volunteers (mean age, 28 years) received single oral doses of placebo, atenolol (50 mg), propranolol (40 mg), or lorazepam (2 mg). Plasma drug concentrations, self-ratings of sedation and mood, observer ratings of sedation, and performance on the Digit Symbol Substitution Test (DSST) were assessed at multiple times during 24 hours after drug administration. Information acquisition and recall were tested at 3 and 24 hours after drug administration. Lorazepam significantly increased sedation and fatigue, impaired DSST performance, and impaired memory. The time course of these changes was highly consistent with plasma lorazepam concentrations. In contrast, atenolol and propranolol produced at most small changes in self-ratings and observer ratings and did not alter DSST performance or memory. Under experimental conditions that are sensitive to the depressant effects of a typical benzodiazepine, single doses of atenolol and propranolol produced no meaningful changes, compared with placebo.

Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo.

Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).

Trazodone kinetics: effect of age, gender, and obesity.

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.

Lack of effect of influenza vaccine on the pharmacokinetics of antipyrine, alprazolam, paracetamol (acetaminophen) and lorazepam.

31 healthy male (n = 17) and female (n = 14) volunteers, aged 20 to 45 years, were divided into 4 groups and received on 3 separate occasions either: paracetamol (acetaminophen) 650mg intravenously (n = 9); alprazolam 1mg orally (n = 7); antipyrine (phenazone) 1g intravenously (n = 8); or lorazepam 2mg intravenously (n = 7). Doses were administered prior to influenza vaccine (0.5ml, intramuscularly) and at 7 and 21 days post-vaccination. The overall differences among the 3 trials in clearance of antipyrine were of borderline significance (p less than 0.0611), with a trend towards reduced clearance in both of the post-vaccination trials. There were no overall differences observed in the elimination half-life of antipyrine, nor were there significant differences between trials in cumulative urinary excretion or fractional recovery of intact antipyrine, 4-hydroxyantipyrine, norantipyrine, or 3-hydroxymethyl antipyrine. For paracetamol and alprazolam, there were no significant differences among the 3 trials in any of the kinetic variables. The elimination half-life of lorazepam varied significantly among trials, but differences were small and not systematic. Lorazepam clearance did not vary significantly among trials. Thus, clearance of drugs which undergo hepatic conjugative reactions such as glucuronidation and sulphation are unlikely to be affected by the coadministration of influenza vaccine. Furthermore, not all drugs which are biotransformed by hepatic microsomal oxidation necessarily have impaired clearance due to coadministration of influenza vaccine.

Clearance of the antihistamine doxylamine. Reduced in elderly men but not in elderly women.

A single oral dose of doxylamine succinate 25 mg was administered to 21 young (20 to 43 years) and 22 elderly (60 to 87 years) volunteers. Multiple plasma doxylamine concentrations were determined during a 30-hour period after each dose. Elderly and young women did not differ significantly in peak plasma doxylamine concentration (Cmax) [116 vs 103 micrograms/L], time to Cmax (tmax) [2.4 vs 2.4 h], elimination half-life (12.2 vs 10.1 h), volume of distribution (179 vs 176 L) or clearance (191 vs 218 ml/min). Cmax (107 vs 108 micrograms/L) and tmax (2.1 vs 1.6 h) also did not differ between elderly and young men. However, elderly men had reduced doxylamine clearance (174 vs 240 ml/min, p less than 0.02; 2.5 vs 3.2 ml/min/kg, p less than 0.07) and prolonged half-life (15.5 vs 10.2 h, p less than 0.05). The reduced doxylamine clearance and prolonged half-life in elderly men, but not in elderly women, is similar to results for many other drugs which are transformed by oxidation.

Alprazolam pharmacokinetics in women on low-dose oral contraceptives.

Sixteen women chronically using low-dose estrogen-containing oral contraceptive steroids (OCs) and 23 drug-free control women received a single 1-mg oral dose of alprazolam. Multiple plasma samples drawn during 48 hours after the dose were analyzed by electron-capture gas-liquid chromatography. There were no significant differences between controls and oral contraceptive users in alprazolam volume of distribution (1.27 versus 1.39 L/kg), elimination half-life (11.9 versus 12.3 hours), total clearance (1.36 versus 1.39 mL/min/kg), or total area under the plasma concentration versus time curve (227 versus 243 ng/mL X hr). Alprazolam free fraction in plasma was slightly but significantly greater in the oral contraceptive group as opposed to the control group (28.4 versus 27.0% unbound), respectively. However, comparison of free clearance between groups revealed no significant difference (4.61 versus 4.89 mL/min/kg, respectively). Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the metabolic clearance of alprazolam.

Antipyrine pharmacokinetics in women receiving conjugated estrogens.

The pharmacokinetics of a single 1.0 to 1.2-g intravenous dose of antipyrine was studied in 22 healthy female volunteers aged 28 to 70 years (mean, 45 years). Eleven subjects had been taking a conjugated estrogen preparation for at least 3 months; the other 11 subjects who were not taking conjugated estrogens and who were matched for age, weight, and smoking patterns, served as a control group. Plasma antipyrine concentrations were determined by high-pressure liquid chromatography (HPLC) in multiple plasma samples drawn 24 to 48 hours after dosage. Mean +/- SE pharmacokinetic variables in control and conjugated-estrogen groups were volume of distribution, 0.57 +/- 0.02 versus 0.56 +/- 0.02 L/kg; elimination half-life, 11.0 +/- 0.82 versus 12.6 +/- 0.89 hours; and clearance, 0.63 +/- 0.06 versus 0.54 +/- 0.03 mL/min/kg. None of the differences was significant. Although antipyrine clearance is significantly impaired by oral contraceptives, there is no evidence of altered antipyrine pharmacokinetics from treatment with conjugated estrogens.

Enhanced bioavailability of triazolam following sublingual versus oral administration.

The rate and extent of the absorption of triazolam following sublingual and oral administration were evaluated in this study. Eight healthy volunteers received triazolam 0.5 mg in a commercially available tablet, by sublingual and oral routes on two occasions in random sequence. Plasma triazolam concentrations during 24 hours after each dose were measured by electron-capture gas-liquid chromatography. The mean total area under the curve for sublingual administration was significantly larger than that following oral dosage (28.9 vs 22.6 ng-hr/mL, P less than .025). The peak plasma concentration after sublingual dosage was also higher than after oral administration (4.7 vs 3.9 ng/mL, P less than .1). No significant differences between sublingual and oral administration were found for the elimination half-life of triazolam (4.1 vs 3.7 hr) and the time of peak concentration (1.22 vs 1.25 hr) after dose. Thus, the bioavailability of triazolam after sublingual administration is increased by an average of 28% compared with oral administration of the same dose, possibly because first-pass extraction is bypassed. Clinical effects of triazolam may likewise be enhanced by sublingual dosage.

Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam.

Healthy volunteers received single doses of either phenytoin (300 mg IV), alprazolam (1 mg orally) or lorazepam (2 mg IV) on two occasions in random sequence. One of the two trials was a control; for the other trial, subjects ingested metronidazole, 250 mg three times daily beginning 4 days prior to and continuing for the duration of each kinetic study. Compared with control, metronidazole significantly prolonged phenytoin half-life (23 versus 16 hours, P less than .02) and reduced its clearance (.28 versus .33 mL/min/kg, P less than .005), known to depend on aromatic hydroxylation. However, metronidazole did not significantly alter kinetic variables for either alprazolam (metabolized by aliphatic hydroxylation) or lorazepam (metabolized by glucuronide conjugation). Thus, metronidazole has the capacity to impair the clearance of certain oxidatively metabolized drugs, but there is no apparent way to predict which drugs will be so influenced.

Reduced systemic absorption of intrabronchial lidocaine by high-frequency nebulization.

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.

Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives.

Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

Pharmacokinetics of diphenhydramine and a demethylated metabolite following intravenous and oral administration.

Ten healthy volunteers received a single 50-mg dose of diphenhydramine (DP) hydrochloride intravenously and orally on two separate occasions. Kinetics of DP and a major demethylated metabolite (DMDP) were determined from multiple plasma samples drawn during a 24- to 48-hour period after dosage. Modification of a gas chromatographic (GC) technique allowed simultaneous quantitation of DP and DMDP. Mean kinetic variables for DP after intravenous (IV) dosage were: volume of distribution, 4.5 L/kg; elimination half-life, 8.4 hours; clearance, 6.2 mL/min/kg. After oral DP administration, a peak plasma level of 66 ng/mL was reached 2.3 hours after dosage. Systemic availability was 72%, nearly identical to the predicted estimate (71%) based on clearance of IV DP relative to hepatic blood flow. Appearance of the metabolite, DMDP, mirrored disappearance of DP; the area under the plasma concentration-time curve (AUC) for DMDP was highly correlated (r = .79, P less than .05) with a clearance of IV DP. However, metabolite AUC was significantly higher after oral as opposed to IV DP (218 vs 145 hr-ng/mL, P less than .05). Because DP and DMDP elute nearly identically on standard GC systems, methodologic modifications are needed to resolve them. Coelution of the two compounds could bias kinetic data based on plasma concentration presumed to be specific for intact DP.

Pharmacokinetics and pharmacodynamics of diphenhydramine 25 mg in young and elderly volunteers.

Thirty-seven young and elderly male and female volunteers 21 to 76 years of age received a single 25-mg oral dose of diphenhydramine or matching placebo in a double-blind, randomized, two-way crossover study. Plasma diphenhydramine concentrations, self-ratings of sedation, mood, and autonomic effects, performance on the digit-symbol substitution test (DSST), and heart rate were determined for 24 hours after administration. Information acquisition and recall were tested at 2.5 and 24 hours after administration. Age and gender did not significantly influence diphenhydramine peak plasma concentration, time of peak concentration, elimination half-life, area under the plasma concentration curve, or apparent oral clearance. Effects on psychomotor performance, sedation, mood, and memory did not differ between diphenhydramine and placebo in either group. Thus, the pharmacokinetics of single 25-mg oral doses of diphenhydramine are not influenced by age or gender. This dose of diphenhydramine produces essentially undetectable pharmacodynamic effects in both the young and elderly.

Triazolam kinetics: interaction with cimetidine, propranolol, and the combination.

Nineteen healthy volunteers received a single 0.5-mg oral dose of triazolam on four occasions under the following conditions: (1) triazolam alone; (2) triazolam with cimetidine, 300 mg four times daily; (3) triazolam with propranolol, 40 mg four times daily; (4) triazolam with both cimetidine and propranolol. Triazolam kinetics were determined from multiple plasma concentrations measured during 24 hours after each dose. Compared with control, peak plasma triazolam concentration (Cmax) was significantly increased by cimetidine (5.4 versus 3.9 ng/mL), total area under the plasma concentration curve (AUC) increased (21.3 versus 16.1 ng/mL X hr), and oral clearance decreased (485 versus 668 mL/min). However triazolam half-life was not increased. During propranolol alone, triazolam Cmax (4.1 ng/mL), AUC (14.3 ng/mL X hr), and clearance (759 mL/min) did not differ significantly from control, whereas kinetic variables for triazolam with cimetidine plus propranolol were similar to those with cimetidine alone. Plasma free fraction for triazolam (17 to 18% unbound) did not differ significantly among the four treatment conditions. Mean steady-state plasma cimetidine concentrations during trials 2 and 4 were similar (1.04 versus .98 micrograms/mL), whereas plasma propranolol was significantly higher during cimetidine plus propranolol than with propranolol alone (47 versus 29 ng/ml, P less than .001). Thus cimetidine coadministration significantly inhibits triazolam clearance, causing increased triazolam AUC and Cmax, but without a prolongation in half-life. Propranolol itself does not impair triazolam clearance, nor does propranolol potentiate the inhibitory effect of cimetidine alone.

Influence of oral contraceptive use and cigarette smoking, alone and together, on antipyrine pharmacokinetics.

The pharmacokinetics of antipyrine following a single 1-g intravenous dose was determined in 63 healthy women. Subjects were divided into 4 groups as follows: 1) cigarette smokers using low-dose oral contraceptives (n = 15); 2) nonsmokers using low-dose oral contraceptives (n = 12); 3) cigarette smokers not using oral contraceptives (n = 10); and 4) controls, neither cigarette smokers nor oral contraceptive users. Plasma antipyrine concentrations during 24 to 48 hours after dosage were measured by high-performance liquid chromatography. Mean kinetic variables in the nonsmoking, non-oral contraceptive using control group were: volume of distribution, 37.7 L; elimination half-life, 13.2 hours; and clearance, 34.4 mL/min. In cigarette smoking, non-oral contraceptive users versus controls, elimination half-life was reduced (8.0 vs. 13.2 hours, P < 0.05) and clearance increased (56.0 vs. 34.4 mL/min, P < 0.05). In nonsmoker oral contraceptive users, the reverse was true (elimination half-life was significantly increased: 16.6 vs. 13.2 hours, P < 0.05; and clearance was significantly decreased: 24.8 vs. 34.4 mL/min, P < 0.05). In smokers who were using oral contraceptives, values were not significantly different from controls (elimination half-life, 11.2 hours; clearance, 39.5 mL/min). Volume of distribution did not differ among the four groups. Thus the opposing effects on antipyrine clearance of the induction of metabolism by cigarette smoking and the inhibition due to low dose oral contraceptive use in effect negate each other when combined in humans.

Cinoxacin: mechanism of action, spectrum of activity, pharmacokinetics, adverse reactions, and therapeutic indications.

Cinoxacin, a chemotherapeutic agent that inhibits bacterial DNA synthesis, has recently been approved for the treatment of initial and recurrent bacterial urinary tract infections. Although closely related to nalidixic acid, cinoxacin possesses some distinct characteristics: rapid attainment of therapeutic urinary concentrations and greater activity against strains of Enterobacteriaceae that cause urinary tract infections. Biopharmaceutical properties include serum protein binding of approximately 70%, 50-60% excretion of intact drug in the urine of patients with normal renal function, and an elimination half-life of approximately one hour. The elimination half-life is increased in patients with decreased renal function and when probenecid is coadministered. Adverse events occur infrequently and consist of nausea, vomiting, headache, dizziness, and hypersensitivity reactions. The drug compares favorably with standard therapies for the treatment of bacterial cystitis and recurrent urinary tract infections. Initial studies demonstrate that cinoxacin has substantial efficacy as a prophylactic agent for those women who experience recurrent, symptomatic urinary tract infections.

Quality control of extemporaneously prepared microdose captopril capsules: weight variation versus content uniformity.

Microdose (1 mg) captopril therapy is commonly used for the initial dose titration in patients with congestive heart failure. Since this dosage form is not commercially available, it has to be extemporaneously compounded. Quality control of each batch is commonly evaluated using the weight variation technique described in the USP. Despite careful titration with microdose, captopril capsules variability in patient's response has been observed. In order to explain this fluctuation, the actual content of extemporaneously compounded microdose captopril capsules was evaluated using a high pressure liquid chromatographic assay. Microdose captopril capsules were prepared by triturating 25 mg tablets with lactose in a mortar using standard geometric dilution technique and a Sharpe-Dohme hand-operated capsule filling machine. Forty-eight microdose captopril capsules were randomly selected from the compounded batch and were individually assayed for captopril amount. The mean +/- standard deviation (SD) amount of captopril in each capsule was 1.27 g +/- 0.31 mg with a range of 0.84 g to 1.96 mg. The coefficient of variation was 24.5%. Ten captopril capsules were randomly selected from the compounded batch and were individually weighed. The capsules had a mean weight +/- SD of 198.3 g +/- 21.2 mg and a coefficient of variation of 7.3%. Even though the extemporaneously prepared microdose captopril capsules were within acceptable limits for weight variation described in the USP, the actual dose administered to the patients could vary by as much as 24.5%.

Evaluation of the analgesic efficacy of EMLA cream in volunteers with differing skin pigmentation undergoing venipuncture.

BACKGROUND AND OBJECTIVES: Lidocaine/prilocaine cream (EMLA) applied to intact skin for 60 minutes has been shown to reduce venipuncture pain. Recent studies have suggested that lidocaine/prilocaine cream is less effective on heavily pigmented skin. The objective of this study was to evaluate the topical anesthetic efficacy of lidocaine/prilocaine cream in volunteers with varying skin pigmentation types. METHODS: Sixty volunteers were enrolled into each of three groups based on skin pigmentation history. Subjects were randomized to receive lidocaine/prilocaine cream onto the antecubital fossa of one arm and placebo cream on the comparable location of the other arm for either 60, 90, or 120 minutes prior to venipuncture. Assessments of perceived pain associated with each venipuncture were made by the subject using a visual analog scale. RESULTS: Lidocaine/prilocaine cream applied for 60 minutes significantly (P < .0001) reduced the pain of venipuncture compared to placebo regardless of the skin pigmentation type. Pain reduction did not differ significantly across skin types (P = .7986). Additional exposure up to 120 minutes did not change the efficacy of EMLA cream. CONCLUSIONS: Lidocaine/prilocaine cream is a safe and effective topical anesthetic for reducing pain associated with venipuncture in individuals, regardless of skin pigmentation.

Efficacy of fenoprofen in the treatment of primary dysmenorrhea.

We compared fenoprofen calcium, 200 mg; fenoprofen calcium, 400 mg; aspirin, 650 mg; and a placebo in 85 women for the relief of primary dysmenorrhea in a double-blind, clinical trial. The usefulness of these drugs was judged from data obtained over four consecutive menstrual periods on: restriction of daily activity, pain intensity scores, need for rescue analgesics, withdrawal due to lack of efficacy, and adverse events. Both fenoprofen, 200 mg, and fenoprofen, 400 mg, offered significant (P less than .01) pain relief when compared to placebo and aspirin. Analyses of data on 1, 2 and 3 indicated that aspirin was not significantly different from placebo. The aspirin-treated group reported the greatest number of adverse reactions, but the differences between the four groups were not statistically significant. Our study lends support to the concept of a "plateau analgesic effect" of nonsteroidal antiinflammatory drugs (NSAIDs): fenoprofen, 200 mg, appears to be as effective as fenoprofen, 400 mg. When this type of drug fails to provide relief for a woman suffering from primary dysmenorrhea, switching to another NSAID may be more appropriate than increasing the dosage and the probability of dosage-related side effects.