The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.     

Cost-effectiveness of a post-exposure HIV chemoprophylaxis program for blood exposures in health care workers.

We performed a cost-effectiveness analysis of a post-exposure chemoprophylaxis program for health care workers who sustained exposures to blood. We analyzed a program of (1) treatment with zidovudine alone versus no treatment and (2) treatment with three-drug therapy versus no treatment. Assuming that 35% of exposures were to HIV-positive sources, the zidovudine regimen prevented 53 HIV seroconversions per 100,000 exposures, at a societal cost of $2.0 million per case of HIV prevented. The cost per quality-adjusted life year saved was $175,222. A three-drug chemoprophylactic therapy program (postulating 100% effectiveness and 35% source HIV positivity), prevented 66 seroconversions per 100,000 exposures, at a cost of $2.1 million per case of HIV prevented and $190,392 per quality-adjusted life year saved. Treating sources known to be HIV-positive and treating severe exposures were the most cost-effective strategies.     

Lorazepam for chronic catatonia: a randomized, double-blind, placebo-controlled cross-over study

Acute catatonic syndromes occurring in the context of various medical and neuropsychiatric conditions, including schizophrenia, have been shown to respond well to benzodiazepines (BZD). However, there have been no studies specifically designed to address the BZD treatment response of persistent catatonic states. Eighteen patients with clinically stable chronic schizophrenia, who also displayed enduring catatonic features, underwent a 12-week long, random assignment, double-blind, placebo-controlled cross-over trial with lorazepam (6 mg/day). A comprehensive assessment, including the subjects’ clinical and motor (catatonic as well as drug-induced movement disorders) condition, was performed at baseline and four weekly intervals thereafter. Pre-existing medication was kept constant throughout the study. Lorazepam had no effect on the subjects’catatonic signs and symptoms, suggesting that acute and chronic catatonic syndromes associated with schizophrenic illness might have a different neurobiological basis. Received: 25 May 1998/Final version: 22 September 1998     

Linear model for visual-vestibular interaction.

The results of experiments are evaluated in terms of a simple model for the interaction of eye movement responses to simultaneous optokinetic and vestibular stimuli. The model predictions agree with the results of these experiments and explain many clinical observations concerning the effect of vision on nystagmus. The model accounts for the dominance of the visual system's response over the vestibular system's response at low frequencies. It also accounts for the inability of patients with decreased smooth pursuit system response to suppress the vestibulo-ocular reflex during simultaneous optokinetic and vestibular stimulations. The model provides useful information for the design of combined optokinetic and vestibular stimuli for test vestibulo-ocular reflexes.     

Thoughts about encounters between nondisabled and disabled peers: Situational constraints,states-of-mind,valenced thought categories

This study explores three issues: thoughts and feelings of individuals with and without physical disabilities concerning encounters in different situations, ways of grouping self-statements into valenced categories, and use of states-of-mind (SOM) ratios as an alternative to positive and negative thought frequencies. Data from 127 able-bodied and 46 physically disabled college students indicate that, in everyday social encounters, nondisabled individuals' thoughts and feelings were more negative, while those of disabled individuals were more negative when helping was involved and when encounters centered on the impairment. Thus, problematic encounters between people with and without disabilities may be due to the reactions of individuals with disabilities in situations which involve help, and to reactions of able-bodied persons in everyday contexts. The data also confirm the utility of SOM ratios as an alternative to valenced frequencies in cognitive assessment: SOM scores discriminated groups when situational demands were manipulated and scores were linearly related to criterion measures. However, SOM ratios differed dramatically, depending on the attentional focus of thoughts. The findings illustrate types of thoughts which occur during interaction between people with and without disabilities, demonstrate a simple technique for grouping thoughts into valenced categories on an empirical basis, and highlight the relative contribution of cognitive and affective elements to overall valenced scores. Implications for research on assessment of self-statements are discussed and recommendations are made concerning programming to facilitate the social integration of people with disabilities.This research was supported by grants to the first author from the Social Sciences and Humanities Research Council of Canada and from Fonds F.C.A.R. pour l'aide et le soutien à la recherche. Thanks are due to Meribah Aikens, Maria Barile, Leo Bissonette, Bosco Daude, Jim Dubois, Lillian Fox, Evelyn Gold, Naomi Goodz, Darlene Judd, André Leblanc, John Martos, Sue McKenzie, Irwin Slopak, and Joan Wolforth for their assistance with various stages of this investigation.     

Sinus node-atrioventricular node isolation: long-term results with the "corridor" operation for atrial fibrillation

The "corridor" operation is designed to restore sinus rhythm to patients with atrial fibrillation by electrically isolating the sinus node, a band of atrial tissue and the atrioventricular (AV) node from the remaining atrial tissue. Nine patients with drug-refractory atrial fibrillation underwent this operation; four patients had chronic atrial fibrillation and five had paroxysmal atrial fibrillation; the mean duration of symptoms was 12 +/- 8 years. Patient ages ranged from 25 to 68 years (mean 48 +/- 12). At preoperative electrophysiologic study, no patient had evidence of an accessory AV pathway or AV node reentry. Sinus node recovery time could not be determined in five patients because of recurrent atrial fibrillation during or before programmed stimulation. At operation the corridor of atrial tissue connecting the sinus and AV nodes was successfully isolated from the remaining left and right atrial tissue in all patients. One patient required early reoperation for recurrent atrial fibrillation before hospital discharge. At the predischarge electrophysiologic study, the corridor remained isolated in all patients except for one patient who had intermittent conduction between the corridor and excluded right atrium. One patient had nonsustained atrial fibrillation and one had atrial tachycardia evident in the corridor. Atypical AV node reentry of uncertain significance was induced in one other patient. Over a total follow-up of 191 patient months (mean 21 +/- 20), seven patients remained free of atrial fibrillation. Two patients had recurrent atrial fibrillation, which in one patient was effectively controlled by a single antiarrhythmic agent. A permanent pacemaker was implanted in four patients for sinus node dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cisplatin disposition in children and adolescents with cancer

Summary The disposition of cisplatin was evaluated in 28 children and adolescents with cancer, as part of a phase II clinical trial. Patients received either 30 mg/m² (11) or 90 mg/m² (17) of cisplatin as a 6-h IV infusion. Serum samples and divided urine collections were obtained over 48 h following completion of the cisplatin infusion, and were assayed in duplicate for total platinum by atomic absorption spectrophotometry. Serum samples obtained up to 4 h after three cisplatin infusions were assayed for parent (free) cisplatin following ultrafiltration. The mean (±SE) elimination half-life of free cisplatin in serum was 1.3 (±0.4) h. Serial serum concentrations of total platinum following 90 mg/m² dosages were adequately described by a biexponential equation. The mean (±SE) serum T_1/2 of total platinum was 0.42 (±0.10) h and the mean (±SE) T_1/2 was 44.43 (±8.24) h. The intercompartment distribution rate constants of a two-compartment kinetic model indicate extensive tissue accumulation of total platinum, with a rate of transport into tissue compartments (K₁₂) that is about six times the rate of transport out of tissues (K₂₁). The mean (±SE) renal clearance of total platinum from 0–3 h was 37.36 (±11.96) ml/min/m² and 35.8 (±13.6) ml/min/m² for the 30 mg/m² and 90 mg/m² groups, respectively. This value decreased to 3.25 (±0.94) and 2.16 (±0.4) ml/min/m² for the two groups by the 6–12 h interval, and remained between 1 and 3 ml/min/m² for the duration of the observation period. The ratio of total plantinum clearance to creatinine clearance decreased significantly(P<0.05) beginning 3 h post-infusion. The change in renal clearance of total platinum is apparently a function of two independent first-order processes for renal clearance of parent drug and cisplatin metabolites.