Biomedical subjects
Publications and source records attributed to C Locke.
Numerous case reports have documented an enhanced hypoprothrombinemic effect caused by an interaction between fluoroquinolones (most notably, ciprofloxacin) and warfarin sodium. Conflicting data exist regarding the clinical significance of this interaction. Two patients who had elevated international normalized ratios after receiving concurrent levofloxacin and warfarin sodium are described.
BACKGROUND: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. METHODS: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. RESULTS: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavir-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. CONCLUSION: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.
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The effect of sertindole (a new selective antipsychotic compound) on the pharmacokinetic disposition of alprazolam was investigated. Fourteen subjects who completed the study received a single 1 mg dose of alprazolam without or with concomitant sertindole 12 mg daily. Coadministration of sertindole and alprazolam led to a half-hour decrease (P < 0.05) in mean Tmax value (alone: 1.2 h, in combination: 0.7 h) and a 1.6-h increase in the mean t1/2 value (12.5 +/- 3.2 versus 14.3 +/- 3.4 h, P < 0.05) of alprazolam. The mean Cmax (18.5 +/- 4.9 versus 18.5 +/- 4.8 ng/ml) and AUC (266 +/- 68 versus 275 +/- 57 ng x h/ml) values of alprazolam did not change statistically significantly in the presence of sertindole (P > 0.05). These pharmacokinetic changes are minor and not considered to be of clinical significance. Although both sertindole and alprazolam are substrate for CYP3A4 (cytochrome P-450 3A4), the results in this study suggest that sertindole is not an inhibitor of the metabolism of alprazolam.
PURPOSE: In two open-label long-term safety studies, we determined tiagabine (TGB) pharmacokinetics in patients with epilepsy. METHODS: In all, 2,147 plasma samples from 511 patients who participated in the studies were available. The total daily dose ranged from 2 mg administered once daily to 80 mg administered in four doses. A one-compartment model with first-order absorption and elimination was used to fit the TGB plasma concentration-time data, with a population pharmacokinetic approach. RESULTS: The patients' average (+/-SD) weight and age were 73.8+/-20.7 kg and 32.1+/-12.3 years. The most significantly factor affecting TGB pharmacokinetics was concomitant administration of other antiepileptic drugs (AEDs). The central clearance value in patients receiving AEDs known to induce hepatic drug metabolism was 21.4 L/h, a value 67% higher than the central clearance estimate obtained for the patients receiving AEDs not known to affect hepatic drug metabolism (12.8 L/h). There was no evidence of any dose or time effect, indicating that TGB pharmacokinetics are linear. TGB pharmacokinetics were not different in white, black, or Hispanic patients, although our ability to explore racial effects was limited since 90% of the patients were white. No other demographic variables (including age and smoking) or any clinical chemistry measurements (including bilirubin, SGOT, and SGPT) were important in explaining the variability in the clearance estimates. CONCLUSIONS: TGB pharmacokinetics are linear, influenced by enzyme-inducing AEDs, and largely unaffected by other demographic variables.
OBJECTIVE: The purpose of this study was to obtain preliminary data regarding the effects of cardiomyoplasty on health-related physical function and quality of well-being. EXPERIMENTAL DESIGN: Quasi-experimental with repeated measures. Patients were interviewed prior to surgery, with post-surgical follow-up interviews at 6 weeks, 6 months, and 12 months. SETTING: Interviews were usually conducted by telephone with patients who were at home at the time of data collection. PATIENTS OR PARTICIPANTS: Four patients receiving cardiomyoplasty at Allegheny General Hospital in Pittsburgh, Pennsylvania. INTERVENTIONS: Patients received cardiomyoplasty between November 1992 and April 1993. Cardiomyoplasty using the right latissimus dorsi muscle was performed on the first patient. A left muscle-wrap was performed on the subsequent three patients. MEASURES: Self-reported function and well-being were measured using the Sickness Impact Profile (SIP), the Quality of Well-Being Scale (QWB), and the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36). RESULTS: Patient responses on the SF-36 demonstrated general improvement in cardiomyoplasty survivors. Results on the QWB and SIP are mixed. CONCLUSIONS: Due to the small, incomplete sample and lack of any comparison group, extreme caution must be used in drawing any clinical conclusions from this preliminary data. Future randomized clinical trials of cardiomyoplasty need to include quality of life and health-related physical function as dependent variables. Further psychometric study is necessary which compares the usefulness of these various methods for assessing the value of outcomes for patients with end-stage heart disease.
The diurnal variation in the pharmacokinetic parameters of zileuton were evaluated in 12 healthy male volunteers in a three-period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600-mg zileuton either at 7 AM or 11 PM. In period III all participants received 600-mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of zileuton administered at 7 AM and 11 PM were not statistically significant. Plasma concentration-time profiles of zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of zileuton after single and multiple doses.
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OBJECTIVE: To study the effect of renal impairment on the pharmacokinetics of sertindole. METHODS: A single 4 mg oral dose of sertindole was given to normal subjects (n = 6) and subjects with various degrees of impaired renal function (n = 18) classified into mild, moderate, and severe/hemodialysis based on their creatinine clearance). The relationships between the pharmacokinetic parameters and the degree of renal impairment were investigated using regression analysis with creatinine clearance as an explanatory variable along with body weight. Subjects were also genotyped for CYP2D6-A or 2D6-B mutations. RESULTS: The mean CL/f and t1/2 values of sertindole ranged from 14 to 31 1.h-1 and from 73 to 93 h, respectively, and were not significantly related to creatinine clearances. There was no indication of any influence of creatinine clearance on the fraction of sertindole (0.994-0.995) binding to plasma proteins. The total fraction of the sertindole dose removed by dialysis was less than 0.1% Subjects with B/B genotype (n = 2) for CYP2D6 were associated with a distinctly lower clearance of sertindole (6.3 vs 25.3 1.h-1) than subjects with wt/wt genotype for CYP2D6. CONCLUSIONS: Since the pharmacokinetics of sertindole are unchanged by renal impairment, dosage adjustment does not appear to be necessary for subjects with various degrees of renal insufficiency or subjects with renal failure requiring hemodialysis.
BACKGROUND: Seratrodast, a potent thromboxane receptor antagonist, is approved in Japan for the treatment of asthma and currently is being developed in the United States. METHODS: This was a phase II, randomized, double-blind, parallel-group, placebo-controlled 15-center study of seratrodast in patients with mild to moderate asthma. A total of 183 patients were randomly assigned to receive daily doses of either placebo, or 80 mg seratrodast, or 120 mg seratrodast for 8 weeks. Pharmacokinetic and pharmacodynamic modeling was carried out by means of the population approach. A two-compartment model with zero-order input and first-order elimination best fitted the plasma concentration-time data. RESULTS AND CONCLUSIONS: The pharmacokinetics of seratrodast were linear after single and multiple dosing for 8 weeks. The population estimates for oral clearance and apparent volume of distribution were 8.5 ml/hr/kg and 43.3 ml/kg, respectively. All pharmacokinetic parameters (the oral central compartment clearance, the volumes of distribution of the central and peripheral compartments, and the intercompartmental clearance) were estimated with a precision of 10% or less and were found to be associated with body weight. The residual variability was 30%. The values of oral clearance estimated in this study in male patients were similar to those previously estimated in healthy male subjects. Seratrodast at a dose of 120 mg daily produced an increase in forced expiratory volume in 1 second (FEV1) from baseline that was linearly correlated with its plasma concentrations. The average slope of the concentration-effect relationship was 0.222% and 0.470% per microgram/ml after single and multiple dosing, respectively. Interpatient variability in response was mainly affected by the initial severity of the disease. A lower percentage of predicted FEV1 (i.e., more severe obstruction) was associated with higher slopes, and greater increases in FEV1.
To assess physician attitudes and practices in controversial areas of child abuse and neglect, anonymous questionnaires were mailed to pediatricians, family practitioners, and emergency medicine physicians in Pima County (Tucson) and Arizona (statewide). The effects of respondent characteristics on responses to each item were analyzed. Three hundred and ninety-three questionnaires (49.3%) were returned. Responses differed according to gender, age, specialty, and practice or training status. Females estimated a higher percentage of adult women had been sexually abused as children (26.6 vs. 21.6, p < .01) and a lower incidence of false accusations, when sexual abuse was alleged in custody disputes (48.1 vs. 56.1, p < .005) than did males. Older physicians were more likely to refer cases of sexual abuse to a specialist, were more concerned about false reports of child abuse, and gave higher estimates of the percentage of adolescent child sexual abuse offenders who could be rehabilitated (54.4 vs. 43.4, p < .05). Pediatricians expected a lower percentage of sexual abuse exams to be positive than did family practitioners (32.6 vs. 40.7, p < .05). Pediatricians were less likely to agree to involvement of Child Protective Services (CPS) in failure to thrive cases or to criminal prosecution of maternal drug use in pregnancy than either family practitioners or emergency physicians. Respondents were uncertain that reporting to CPS would lead to an improvement in the child's welfare. Exposition and explanation of physician attitudes may benefit medical education about child abuse.
The multiple-dose pharmacokinetics of ritonavir were investigated in four groups of human immunodeficiency virus-positive male subjects (with 16 subjects per group) under nonfasting conditions; a 3:1 ritonavir:placebo ratio was used. Ritonavir was given at 200 (group I), 300 (group II), 400 (group III), or 500 (group IV) mg every 12 h for 2 weeks. The multiple-dose pharmacokinetics of ritonavir were moderately dose dependent, with the clearance for group IV (6.8 +/- 2.7 liters/h) being an average of 32% lower than that for group I (10.0 +/- 3.2 liters/h). First-pass metabolism should be minimal for ritonavir. The functional half-life, estimated from peak and trough concentrations, were similar among the dosage groups, averaging 3.1 and 5.7 h after the morning and evening doses, respectively. The area under the concentration-time curve at 24 h (AUC24) and apparent terminal-phase elimination rate constant remained relatively time invariant, but predose concentrations decreased 30 to 70% over time. Concentration-dependent autoinduction is the most likely mechanism for the time-dependent pharmacokinetics. The Km and initial maximum rate of metabolism (Vmax) values estimated from population pharmacokinetic modeling (nonlinear mixed-effects models) were 3.43 microg/ml and 46.9 mg/h, respectively. The group IV Vmax increased to 68 mg/h after 2 weeks. The maximum concentration of ritonavir in serum (Cmax) and AUC after the evening doses were an average of 30 to 40% lower than the values after the morning doses, while the concentration at 12 h was an average of 32% lower than the predose concentration, probably due to protracted absorption. Less than 2% of the dose was eliminated unchanged in the urine. Triglyceride levels increased from the levels at the baseline, and the levels were correlated with baseline triglyceride levels and AUC, Cmax, or predose concentrations.
The pharmacokinetic-pharmacodynamic interaction between terazosin and finasteride was evaluated in an 18-day, parallel, open-label, randomized study. Forty-eight non-smoking, healthy, adult male volunteers entered the study. One third of the participants received terazosin alone, one third received terazosin and finasteride, and one third received finasteride alone. Multiple-dose coadministration of terazosin and finasteride did not alter the central values of steady-state pharmacokinetic parameters of either drug in a statistically significant manner. Compared with the single-agent groups, however, the group taking finasteride and terazosin had higher variability in the pharmacokinetic parameters of both drugs. Testosterone concentrations were not altered after administration of finasteride and terazosin alone or in combination. Terazosin administered alone did not affect the dihydrotestosterone concentrations. The significant reduction in dihydrotestosterone concentrations induced by administration of finasteride was not affected by coadministration of terazosin. Mean changes in blood pressure and pulse rate in these normotensive volunteers were generally slight; therefore, concurrent administration of multiple doses of terazosin and finasteride did not produce significant clinical concern.
Tetrahydro-2H-benz[b]azepin-2-ones as starting substances are synthesized by Beckmann rearrangement of Schmidt reaction. The tetrahydrobenzazepinones are transformed into the thiones, thiolactim ethers and phenylhydrazones. The compounds are tested as inhibitors of soja lipoxygenase.
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BACKGROUND: There is some evidence of a positive association between increased dietary salt consumption and both increased bronchial reactivity and mortality from asthma in men. This study assesses the effects of alterations in dietary salt consumption on the clinical severity of asthma in adult male asthmatic patients. METHODS: A randomised, double blind, placebo controlled, crossover design was employed. Twenty seven mild to moderate asthmatic patients were established on a low sodium diet (80 mmol/day) at the end of a 4-5 day run in period and then randomised to receive 200 mmol/day slow sodium or matching placebo for five weeks, crossing over to the alternative regime for a further five weeks. Patients used diary cards to record twice daily peak expiratory flow rates, daily symptom scores, and bronchodilator consumption. Spirometry and degree of bronchial responsiveness (methacholine challenge test) were measured at screening and at the end of each treatment period. Twenty four hour urinary sodium excretion was measured at screening and in duplicate for each treatment period. RESULTS: Twenty two patients completed the study. For these patients the mean (95% confidence interval (CI)) difference in 24 hour sodium excretion between treatments was 204 (175 to 235) mmol. Compared with placebo, sodium supplementation resulted in deleterious alterations of all measured parameters. Bronchial reactivity rose on slow sodium with a 0.73 (0.2 to 1.3) doubling dose methacholine difference compared with placebo. Estimated median (95% CI) difference in bronchodilator consumption was 1.3 (0.4 to 2.1) puffs per day, the estimated median difference in symptom score was 0.6 (0.2 to 0.9), and mean forced expiratory volume in one second fell by 0.21 (0.05 to 0.37) 1. The peak expiratory flow rate rose on placebo and fell on slow sodium. Median differences between treatments were 5.6% (2.2% to 9.8%) for morning and 7.8% (3.9% to 12.9%) for evening peak expiratory flow rate. CONCLUSIONS: Our results suggest that large increases in dietary sodium result in physiological deterioration and increased morbidity in male asthmatic patients.
To evaluate the effect of food on bioavailability, clarithromycin and 14-hydroxyclarithromycin (active metabolite) pharmacokinetics were assessed in 26 healthy adult volunteers after ingestion of a single oral 500-mg dose of clarithromycin in a fasting state (2 hours before breakfast after an overnight fast) and a nonfasting state (0.5 hours after the start of breakfast). Clarithromycin and 14-hydroxy metabolite plasma concentrations were measured using a high-performance liquid chromatographic technique. Food intake immediately before dosing increased the extent of absorption from the 500-mg tablet formulation by approximately 25%. The mean increase in metabolite area under the plasma concentration-time curve was approximately 9%. These results suggest that clarithromycin can be taken without regard to timing in relation to meals.
A multicentre study was conducted to determine whether liver impairment would alter the pharmacokinetics of temafloxacin, a new fluoroquinolone antimicrobial agent. 16 patients with cirrhosis and 12 healthy volunteers (the control group) received a single oral 600mg dose of temafloxacin. Blood and urine were sampled at frequent intervals after drug administration and assayed by high performance liquid chromatography. The mean age of patients with liver impairment was greater than that of the control group; they also had a lower creatinine clearance and urine output. There was no difference between the groups in either the peak plasma temafloxacin concentration or the time to reach peak concentration. However, the volume of distribution and elimination rate constant of temafloxacin were significantly lower in the group with liver impairment, as were total temafloxacin clearance, renal clearance, and the ratio of renal:creatinine clearance. Nonrenal clearance was similar in patients and controls. Creatinine clearance and urine output were found to account for most of the intersubject variability in total clearance as determined by multiple linear regression analysis. Because the altered temafloxacin pharmacokinetics appear to be primarily due to impaired renal function, this should be the main determinant of temafloxacin dosage in patients with liver disease.