Carbamazepine-nefazodone interaction in healthy subjects.

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated in 12 healthy male volunteers. Subjects received nefazodone 200 mg twice daily for 5 days, and blood sample collection was performed on day 5 for 0- to 48-hour pharmacokinetic analysis. A 4-day wash-out phase then followed from days 6 to 9. Carbamazepine 200 mg was administered once daily from days 10 to 12, and then 200 mg was given twice daily from days 13 to 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 200 mg twice daily was added to the dosing regimen from days 40 to 44, and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, and triazoledione) decreased significantly as well (p < 0.001). Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg twice daily was found to be safe and well tolerated; however, the increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

Pharmacokinetic evaluation of co-administration of nefazodone and lithium in healthy subjects.

OBJECTIVES: To evaluate the possible pharmacokinetic interaction between nefazodone and lithium. METHODS: Twelve healthy volunteers received nefazodone 200 mg b.i.d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to day 20, escalating doses of lithium 250 mg b.i.d. to 500 mg b.i.d. were given; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i.d. was added to the lithium dosing regimen. Venous blood sampling was performed on days 5, 15 and 20 for 0- to 48-h-pharmacokinetic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and triazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by flame photometry. RESULTS: Co-administration of nefazodone did not modify pharmacokinetic parameters of lithium at steady-state. Comparison of the area under the plasma or serum concentration-versus-time curve calculated from 0-12 h (AUC0-12) of nefazodone and hydroxynefazodone revealed no significant differences when nefazodone was administered alone or with lithium. The mean maximum peak plasma concentration Cmax and AUC0-12 of meta-chlorophenyl-piperazine (mCPP) were significantly reduced by 27% (P < 0.001) and 16% (P < 0.001) with the co-administration. The mean Cmax and AUC0-12 of triazoledione were reduced by 23% (P < 0.005) and 16% (P < 0.01) by the co-administration. CONCLUSION: Since there were no clinically significant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered.

Efficacy and safety of d-sotalol, a pure class III antiarrhythmic compound, in patients with symptomatic complex ventricular ectopy. Results of a multicenter, randomized, double-blind, placebo-controlled dose-finding study. The d-Sotalol PVC Study Group.

BACKGROUND: There is increasing interest in pure class III antiarrhythmic compounds, ie, drugs in which the electrophysiological effect is confined to the propensity for producing an isolated lengthening of action potential duration. d-Sotalol represents the prototype of such pure class III agents. This double-blind, placebo-controlled, randomized dose-finding study evaluated the antiarrhythmic efficacy and safety of d-sotalol in patients with symptomatic chronic ventricular ectopy. METHODS AND RESULTS: A total of 233 patients presenting with > or = 30 premature ventricular contractions (PVCs) per hour during drug-free Holter monitoring randomly received placebo or d-sotalol at dosages of 50, 100, or 200 mg BID. Drug efficacy was assessed by repeat Holter monitoring at the end of double-blind therapy. There was a dose-dependent increase in QT and QTc duration, indicating class III activity. A dose-related decrease in hourly PVC counts was observed, reaching statistical significance for patients receiving 200 mg d-sotalol BID (311 PVCs/h during baseline compared with 135 PVCs/h during active treatment, P < .05). Analysis of the primary efficacy criterion (ie, > or = 75% reduction in total PVCs/h) revealed a significant treatment effect only for the highest d-sotalol dose, with 8 patients (14%) meeting this criterion. Eighteen patients reported side effects, which led to drug discontinuation in 5. One sudden death and one nonfatal cardiac arrest occurred in patients with dilative cardiomyopathy receiving 200 mg d-sotalol BID. No incidence of torsade de pointes was reported. CONCLUSIONS: d-Sotalol exerts dose-dependent class III activity in patients with symptomatic ventricular ectopy. Its PVC-suppressing activity is modest and becomes evident predominantly at dosages of 200 mg administered BID. The observation of drug-associated serious adverse arrhythmic events emphasizes the need for individualized careful dose titration, particularly in patients with advanced organic heart disease.

Adjuvant chemotherapy of recurrent superficial transitional cell carcinoma: results of a European organization for research on treatment of cancer randomized trial comparing intravesical instillation of thiotepa, doxorubicin and cisplatin. The European Organization for Research on Treatment of Cancer Genitourinary Group.

A total of 356 patients with recurrent superficial transitional cell carcinoma of the bladder was entered in a randomized clinical trial to compare intravesical thiotepa, doxorubicin and cisplatin with respect to the recurrence rate and disease-free interval. After complete transurethral resection of all visible lesions, the drugs were administered weekly for 4 weeks and monthly for 11 months. The recurrence rates per year were 0.50 for thiotepa, 0.54 for doxorubicin and 0.58 for cisplatin. Of 266 patients (mean followup 41 months) 35 reported an increase in T category and 19 of them had distant metastases. No association between treatment and progression was noted. Thus, there is no difference among treatments with respect to efficacy. However, severe anaphylactic reactions were observed in the cisplatin arm and chemical cystitis was more frequently reported in patients who received doxorubicin.

Hexamethylmelamine and low or moderate dose cisplatin with or without pyridoxine for treatment of advanced ovarian carcinoma: a study of the Eastern Cooperative Oncology Group.

A total of 248 analyzable patients with Stages III-IV ovarian epithelial cancer (114 with and 134 without prior chemotherapy) were randomized to one of four cisplatin (DDP)-hexamethylmelamine (HMM) regimens. In each, HMM, 200 mg/m2 was given orally daily on days 8-21 of each 21-day cycle. DDP was given i.v. on Day 1 at a dose of 37.5 mg/m2 (regimens A and B) or 75 mg/m2 (regimens C and D). In addition, since pyridoxine administration has been reported to reduce the neurotoxicity of HMM, that agent was given at a dose of 300 mg/m2 orally on Days 1-21 in regimens B and D. Randomization was stratified for performance status (0-1, 2-3) and largest tumor diameter at entry (greater than 2- less than or equal to 10 cm, greater than 10 cm) for previously untreated patients, and for performance status and time from initial diagnosis to entry on study (less than or equal to 1 year, greater than 1 year) for previously treated patients. The overall response rate (PR + CR) was 54%, with 25% of patients achieving a complete response. The 61% response rate with the higher dose DDP regimens was significantly greater than the 47% response rate with the lower dose regimens (p = 0.031). Multivariate analysis identified higher DDP dose, age less than 60 years, no prior chemotherapy, small tumor bulk and favorable tumor grade as significant prognosticators for response. The overall median response duration was 8.3 months (range 1-70 months). Prior chemotherapy, pyridoxine administration, recent diagnosis, and large tumor size were identified by multivariate analysis as factors adversely affecting response duration. Patients treated with the higher dose DDP regimens had more severe nausea, vomiting, and neurotoxicity. This study demonstrates that the combination of DDP + HMM is an effective regimen for advanced ovarian carcinoma that yields response rates comparable to other more complex regimens, and that there is a dose-response relationship for DDP in ovarian cancer. Although pyridoxine administration significantly reduced neurotoxicity, its adverse effect on response duration suggests that the agent should not be administered with DDP or HMM. The mechanism by which pyridoxine may unfavorably affect response duration deserves further investigation.

Pentostatin induces durable remissions in hairy cell leukemia.

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

Adjusting for age-related competing mortality in long-term cancer clinical trials.

Mortality related to causes other than the treated disease may have a significant impact on overall survival in long-term clinical trials. We present a model that adjusts for age-related competing mortality when cause of death is missing or only partially available. Through use of a piecewise exponential survival model, we extend relative survival methods to continuous follow-up data, allowing the competing mortality to differ from that of the general population by a scale parameter. An EM algorithm provides a simple way to compute the maximum likelihood estimators (MLEs) and to test hypotheses using widely available software. We compare the bias and relative efficiency of this model to a piecewise exponential Cox model for overall survival. Theoretical results are confirmed by simulations and illustrated with data from a clinical trial in colorectal cancer. This example also shows how age-related and disease-related mortality can be confounded in an analysis of overall survival. We conclude with a discussion of the advantages and disadvantages of the model.

Phase II trial of carboplatin in soft-tissue sarcoma.

As part of the Eastern Cooperative Oncology Group program for the assessment of new drugs in sarcomas, a Phase II trial of carboplatin was performed in patients who had received no more than one prior chemotherapy regimen. A total of 50 patients received either 400 mg/m2 or 320 mg/m2 depending on whether they had received prior radiotherapy. A response rate of 16% (95% confidence interval 6-32%) occurred in the 37 patients who had received doxorubicin as their only prior systemic therapy. Three of the six responses were complete and persisted for 7 to 34 months. In contrast none of the 13 patients who received carboplatin after initial progression on doxorubicin and subsequent progression on interferon alpha responded. The overall response rate was therefore 12% (95% confidence interval 5-24%). Toxicity was primarily hematologic, with 14 patients having Eastern Cooperative Oncology Group (ECOG) grade 3 toxicity and no grade 4 or 5 toxicities. In view of the number of complete responses, carboplatin should be studied further in untreated patients with advanced soft tissue sarcoma.