Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin.

The oral bioavailability of two HMG-CoA reductase inhibitors, pravastatin and lovastatin, was investigated in this randomized, two-way crossover study. Twenty healthy men were randomly assigned to treatment with a 40-mg dose of pravastatin or lovastatin once daily for 1 week; steady state kinetics were assessed after the last dose. After 1 week of washout, each subject received the alternate treatment. Serum specimens were assayed by gas chromatography/mass spectrometry (GC/MS) for intact pravastatin or lovastatin acid and by bioassay for active inhibitor concentration and, after hydrolysis of lactones, for total inhibitor concentration. The systemic bioavailabilities of total (active plus potentially active) inhibitors for the two drugs were different, with the mean AUC value for lovastatin being 50% higher than that of pravastatin (mean +/- SEM AUC0-24 values of 285 +/- 25 and 189 +/- 13 ng-equiv x hr/mL, respectively, P less than .0001). Pravastatin, which is administered as the monosodium salt, is present in the systemic circulation as the open acid; lovastatin, which is administered as the lactone, is present as both open-acid active metabolites (62%) and closed-ring lactone metabolites (38%), which are potentially active. Based on mean AUC values, pravastatin accounted for 75% of the active inhibitors from a pravastatin dose. Lovastatin acid accounted for just 25% of the active inhibitors from a lovastatin dose, with the remainder due to other active metabolites. Significant decreases from baseline in total and low-density lipoprotein (LDL) cholesterol were observed during the first treatment leg for both pravastatin and lovastatin.(ABSTRACT TRUNCATED AT 250 WORDS)

An application of an MMPI classification system for predicting outcome in a small clinical sample of alcoholics.

The purpose of this study was to apply Conley and Prioleau's MMPI classification system to predict drinking and adjustment outcome for a sample of 113 inpatient alcoholics. Although a dual grouping (termed "reactive" and "essential") of the original six MMPI subtypes was found to be more useful for this sample size, the findings, nevertheless, supported the predictive value of this MMPI classification system. The "essential" group, derived from a triad of Psychopathic and Schizoform MMPI types was rated as drinking significantly more often during 4 years after treatment than the "reactive" group, derived from a triad of Neurotic and Classic MMPI types (Fisher's p = .02). Females classified as the "essential" MMPI group were rated as having significantly poorer adjustment (Fisher's p = .007) than females classified as the "reactive" MMPI group.

Pharmacokinetics of captopril in elderly healthy male volunteers.

The pharmacokinetics of captopril were studied in 12 healthy male volunteers aged 65 to 76 years, who each received a single 100-mg oral dose. Blood and urine samples were collected over a 24-hour period, and assayed for unchanged captopril (CAP), S-methylcaptopril (Me-CAP, plasma concentrations from 2 subjects only), and total captopril levels (TOT, a mixture of CAP and its dimer and mixed disulfides with endogenous thiol-containing compounds such as glutathione and cysteine). Mean values for the maximum concentration (Cmax) were 803 and 66.3 ng/mL for CAP and Me-CAP, respectively. Mean time to maximum concentration (tmax) was determined as 1.0, 1.4, and 1.0 for CAP, TOT, and Me-CAP, respectively. Mean areas under the plasma concentration-time curve (AUC) were 1,394 hr-ng/mL (CAP, 0-8 hr) and 17,316 hr-ng/mL (TOT, 0-24 hr). The mean estimated half-life (t 1/2) for CAP was 1.4 hr, and its renal clearance was 187 mL/hr/kg. Mean urinary excretion over 24 hr was 20.8 and 53.1 for CAP and TOT, respectively. Cmax, and AUC for CAP were 9% less and 13% greater, respectively, than in a historical control group of 18-35-year-old men, treated in the same clinic, by the same personnel, using the same analytic procedures, whereas the 24-hour urinary excretion was 25% lower and eight-hour renal clearance 36% lower in the older population. Since the values for Cmax, AUC, and t 1/2 were similar in the two populations, it does not appear that the pharmacokinetics of CAP are altered markedly with age alone.

Comparing bilateral to unilateral electroconvulsive therapy in a randomized study with EEG monitoring.

In a double-blind study, 48 DSM-III depressed patients were randomly assigned to either the bilateral or nondominant unilateral electroconvulsive therapy (ECT) group. Seizure length was monitored by electroencephalography (EEG). When seizures were less than 25 s, ECT was immediately readministered. When length of seizure and pretreatment depression scores were controlled between the two groups, there were no differences in treatment effectiveness, as measured by the Hamilton Rating Scale for Depression and the Beck Depression Inventory, or in the number of treatments required. This was true after five ECT treatments as well as after completing all ECT treatments. Thus, when ECT is monitored via EEG to assure the presence of an adequate seizure, bilateral and nondominant unilateral placement yield equivalent responses. If ECT had not been readministered immediately following a missed seizure, unilateral patients would have had significantly more missed seizures. Significant difficulties in both short- and long-term memory were found 24 hours after the fifth ECT in bilateral but not in nondominant unilateral patients. No apparent memory loss could be documented in nondominant unilateral ECT.

Pharmacokinetics of aztreonam in elderly male volunteers.

The pharmacokinetics of aztreonam were studied in 12 healthy male volunteers aged 65 to 75 years who received 1 g of the antibiotic intravenously. Data were fitted to a two-compartment open model to yield the following parameters: t 1/2, lambda 1, 0.15 h; t 1/2,z, 2.06 h; area under the 24-h serum concentration-time curve, 231.8 micrograms ml-1 h; Cmax, 120.1 micrograms/ml; V1 area, 0.16 l/kg; and serum clearance, 0.94 ml min-1 kg. Twenty-four hour urinary elimination reached 63.1% of dose as aztreonam and 3.1% as the open ring metabolite SQ 26,992. These data were similar to those obtained for healthy males aged 18 to 35 years. Thus, age per se is not a major therapeutic consideration in treating elderly patients, and other factors, primarily the parameters of renal function, should serve as the basis for any dose reduction.

Pharmacokinetic interaction of aztreonam with other antibiotics.

The pharmacokinetic interaction of the monobactam antibiotic aztreonam with cephradine, clindamycin, gentamicin, metronidazole, and nafcillin was investigated in five separate studies in 48 healthy male volunteers. All drugs were administered by 30-minute intravenous infusions in single-dose, three-way balanced cross-over studies. Drug levels were measured in serum, protein-free filtrate of serum, and urine. Small changes of no clinical significance were seen when aztreonam was given simultaneously with another antibiotic as compared with each drug alone. Maximum serum concentrations of aztreonam were reduced by 12.6 and 9.8 per cent when it was given with gentamicin and metronidazole, respectively. The percentage of serum aztreonam bound to protein fell by a maximum of 5.0 per cent when the monobactam was given in conjunction with nafcillin and rose by 5.1 per cent when accompanied by cephradine. Twenty-four-hour cumulative urinary excretion of aztreonam and clindamycin rose by 5.2 and 10.9 per cent, respectively, when they were administered simultaneously.

Dexamethasone in electroconvulsive therapy: efficacy for depression and post-ECT amnesia.

Dexamethasone, compared to placebo in a double-blind study, failed to prevent the memory deficiency that typically accompanies electroconvulsive therapy (ECT) (n = 48 patients treated for DSM-III diagnosed major depressive disorder). Rather, the administration of the drug was associated with attention (p less than 0.02) and short-term memory (p less than 0.0003) difficulties in both bilateral and unilateral ECT patients. Bilateral ECT plus dexamethasone patients had significantly less improvement (p less than 0.05) in their depression (measured by the Hamilton Depression Scale) compared to bilateral ECT plus placebo patients. These depression differences were not seen among unilateral ECT patients.

Immunology of the monobactam aztreonam.

To assess the immunological cross-reactivity of the monobactam antibiotic aztreonam (AZ), rabbits were immunized with protein conjugates of benzylpenicillin, cephalothin (CEPH), and AZ. The resulting antibenzylpenicilloyl (BPO) and anti-CEPH rabbit antibodies showed negligible cross-reactivity with AZ conjugated to human serum albumin (AZ-HSA), whereas anti-AZ showed negligible cross-reactivity with BPO-HSA and CEPH-HSA. Unlike benzylpenicillin and CEPH, unconjugated AZ was as effective as AZ conjugated to epsilon aminocaproic acid (AZ-EACA) in inhibiting the binding of homologous antibody. Studies with various analogs of AZ confirmed that immunoglobulin G (IgG) anti-AZ was entirely side-chain specific. The inhibition of the binding of human IgE anti-penicilloyl to BPO-HSA was studied in the presence of AZ-EACA, BPO-formyl lysine, and CEPH-EACA. Whereas CEPH-EACA displayed 3% cross-reactivity with BPO-lysine, AZ-EACA showed little or no cross-reactivity (much less than 0.9%). To assess the immunogenicity of AZ in humans, IgE and IgG antibodies were measured in sera from 36 healthy male volunteers receiving 0.5 or 1 g intravenously or intramuscularly every 8 h for 7 days. None of the subjects had detectable preexisting IgE reactive with AZ or demonstrated an IgE response to antibiotic administration. Four subjects gave evidence for naturally occurring IgG cross-reactive with AZ, but only one subject demonstrated a rise in IgG levels after exposure to AZ. This anti-AZ IgG did not cross-react with BPO or CEPH conjugates of bovine thyroglobulin and was completely side-chain specific. These studies suggest that AZ displays very low immunological cross-reactivity with other beta-lactam antibiotics and may be only weakly immunogenic in humans.

Renal handling of the monobactam azthreonam in healthy subjects.

Azthreonam is a new completely synthetic, monocyclic beta-lactam antibiotic with potent activity in vitro against most gram-negative aerobic bacteria. Its renal handling was studied in six healthy men after an intravenous loading dose of 1200 mg over 2 min followed by a continuous infusion of 500 mg/hr for 4 hr with and without oral probenecid (1 gm b.i.d. for 2 days before azthreonam infusion and during the day of infusion). To assess glomerular filtration, each subject also received an intravenous loading dose and continuous infusion of inulin. Azthreonam was excreted in the urine by glomerular filtration and tubular secretion in essentially equal proportions. Probenecid reduced plasma clearance of azthreonam bY suppressing renal tubular secretion, without altering glomerular filtration rate or nonrenal elimination. Probenecid increased total and free azthreonam levels and the azthreonam plasma t1/2 while reducing plasma protein binding and the apparent steady-state volume of distribution.

Oral bioavailability of the monobactam aztreonam (SQ 26,776) in healthy subjects.

To investigate the oral bioavailability of aztreonam (SQ 26,776), we administered single 500-mg doses of this monobactam as an oral solution, as two 250-mg capsules, and as a 3-min intravenous infusion to 15 healthy male subjects at 1-week intervals according to a three-way crossover study design. Serum and urine samples were assayed by microbiological methods. The absolute systemic bioavailability of each oral formulation, defined as the ratio of areas under the serum concentration-time curves after oral and intravenous administration, was less than 1%. Peak serum levels achieved with oral solution, capsule, and intravenous infusion were 0.15, 0.14, and 56.7 micrograms/ml, respectively, and cumulative urinary excretion was 0.7, 0.6, and 68% of the administered dose, respectively.

Review of single- and multiple-dose pharmacokinetics of the monobactam, aztreonam (SQ 26,776) in healthy subjects.

Aztreonam (SQ 26,776) is a new, completely synthetic, monocyclic beta-lactam antibiotic with potent activity against most aerobic gram-negative bacteria. The pharmacokinetics of single intravenous doses of 125-4,000 mg, single intramuscular doses of 250-1,000 mg, and multiple intravenous and intramuscular doses of 500 and 1,000 mg q.8 h during 7 days, were studied in 90 healthy male subjects. The half-life was 1.7, apparent volume of distribution 0.2 liters/kg, serum protein binding 56%, and urinary excretion 60-70% of the dose. No significant accumulation or change in pharmacokinetics of aztreonam was found during q.8 h dosing. Small amounts of the biologically inactive open beta-lactam ring metabolite, SQ 26,992, were found in the urine. Aztreonam level in serum and urine after 500- to 2,000-mg doses were potentially therapeutic for most Enterobacteriaceae and Pseudomonas aeruginosa.

Multiple-dose pharmacokinetics of the monobactam azthreonam (SQ 26,776) in healthy subjects.

Azthreonam, a monocyclic beta-lactam highly active against aerobic gram-negative bacteria in vitro, was administered to four groups of nine healthy male volunteers in the following four regimens: 500 mg intravenously (i.v.) over 2 min every 8 h, 1,000 mg i.v. over 2 min every 8 h, 500 mg intramuscularly (i.m.) every 8 h, and 1,000 mg i.m. every 8 h for 7 days. Serial samples of serum and urine were assayed by microbiological methods, and urine samples collected during the high-dose i.m. regimen were assayed by a high-pressure liquid chromatographic procedure. Mean peak serum levels were 39 and 99 micrograms/ml after the initial i.v. doses and 18 and 39 micrograms/ml after the initial i.m. doses. There was no evidence of drug accumulation. Mean serum trough levels were 1.0 and 2.5 micrograms/ml during the two i.v. regimens and 1.8 and 3.8 micrograms/ml during the two i.m. regimens. The mean difference among Cmax, area under the curve from 0 to 8 h, and urinary recovery at 0 to 8 h on days 1 and 8 was less than 13% for each regimen. From the i.v. study, the mean steady-state volume of distribution was 0.21 liter/kg, the terminal half-life was 1.6 h, serum clearance was 1.7 ml min-1 kg-1, urinary recovery was 60%, and serum protein binding was 56%. An average of about 6% of a 1,000-mg i.m. dose was excreted in the 8-h urine collection on day 8 as the open beta-lactam ring hydrolysis product of azthreonam. The concentrations of azthreonam in serum were within the range required to inhibit growth of susceptible organisms in vitro.

Single-dose pharmacokinetics of the monobactam azthreonam (SQ 26,776) in healthy subjects.

Azthreonam (SQ 26,776) is a new, completely synthetic, monocyclic beta-lactam antimicrobial agent that is highly active in vitro against most gram-negative bacteria. The pharmacokinetics of single intravenous doses of 125 to 4,000 mg, studied in 36 healthy male subjects, were best described by an open, linear, two-compartment kinetic model. The mean peak serum levels at 5 min after completion of 3-min infusions of 500-, 1,000- and 2,000-mg doses were 58, 125, and 242 micrograms/ml, respectively. The mean terminal serum half-life for all doses was 1.66 h, and the apparent volume of distribution was 0.18 liter/kg. The mean serum clearance was 1.27 ml min-1 kg-1, and urinary excretion averaged 68% of the doses administered. The pharmacokinetics of single intramuscular doses of 250 to 1,000 mg, studied in 18 subjects, were best described by a linear, one-compartment model, with first-order absorption and elimination. The mean peak serum levels occurring at 1 h after doses of 250, 500, and 1,000 mg were 12, 22, and 46 micrograms/ml, respectively. Other kinetic parameters were similar to those for intravenous administration. Tolerance of azthreonam was good, with only a mild rash in one subject and with mild to moderate transient elevations in serum transaminases and lactate dehydrogenase in two subjects.

A study of antibody levels in alcoholic, depressive and schizophrenic patients.

A study was undertaken to compare IgG, IgA, IgM, IgE and IgD antibodies in adult alcoholic, depressive and schizophrenic patients with healthy, adult controls. Total IgG, -IgA, -IgM, -IgE, and -IgD and specific-IgE antibodies were assessed using 33 allergens: 12 inhalant and 21 foods. There was no significant difference observed in the total immunoglobulin results between the patients and controls. There were, however, significant differences between the groups for allergen specific-IgE with the depressive patients exhibiting the greatest number of positive test results. The depressives had an over-all t-test value of 10.080 (5% = 1.960), the alcoholics t = 6.800 and the schizophrenics t = 6.015. The most often positive allergens were those from the perennial/mold group, although the most frequently positive single allergen was egg white and 100% of the depressives were sensitive to it. The data in this investigation suggest that psychiatric patients with alcohol dependence, depression and schizophrenia be studied further so that information on a causal relationship between allergen specific-IgE antibodies and these mental disorders can be evaluated.

Four year MMPI changes in abstinent and drinking alcoholics.

Alcoholic patients completed the Minnesota Multiphasic Personality Inventory (MMPI) while hospitalized for treatment and again after 4 years of follow-up. Those who remained abstinent and functioned well in the community for the 4-yr period were characterized during treatment by a significant elevation on the Depression (D) scale which decreased to normal ranges at follow-up. Those who continued to drink periodically over the 4-yr period had initial peaks on Psychopathy (Pd) and Hypomania (Ma) which were still elevated at follow-up. An intermediate group who were usually abstinent during the 4-yr period but had occasional relapses showed elevations on D and Pd during treatment with return to normal levels at follow-up.

The effect of codeine on involutional and senile depression.

The authors studied the effect of codeine on 12 severely depressed patients who failed to respond to tricyclic antidepressants. They all were in involution. Eight patients received codeine in combination with other tricyclic antidepressants and only one of them showed improvement. Four depressed patients received codeine alone and none of them improved. The patients were kept on codeine up to three weeks. The dose was gradually increased from 90 mg/day to 180 mg/day. All patients suffered from severe constipation--more than what they had on tricyclic antidepressant medication. All of the patients experienced a sedative effect. None of them had euphoria and none of them developed dependence. After the failure of codeine, the patients finally accepted electroconvulsive therapy or monoamine oxidase inhibitors, and with one exception, all improved.