Phase I dose-escalation study of the thioxanthone SR271425 administered intravenously once every 3 weeks in patients with advanced malignancies.

This study was performed to determine the dose limiting toxicity (DLT), the recommended phase II dose and the pharmacokinetic profile for SR271425, given over 1 h every 3 weeks. The initial starting dose of SR271425 was 17 mg/m(2). Patient selection was based on common phase I criteria as well as additional cardiac criteria. Thirty-eight patients were accrued to 16 dose levels from 17 to 1,320 mg/m(2). Patient characteristics included 24 males and 14 females ages 35-78 with an Eastern Cooperative Oncology Group performance status of 0 (ten patients), 1 (27) and 2 (1). Tumor types were typical for a phase I study. The maximum administered dose was 1,320 mg/m(2) with two DLTs, both QTc grade 3 prolongation. No drug related hematological toxicity was noted. Grade 1 toxicities included rash, flushing, pruritus, weight loss, diarrhea, hypertension and fatigue. Grade 2 toxicities included yellow discoloration of the skin, nausea and vomiting. QTc prolongation and hyperbilirubinemia were the only grade 3 toxicities noted. No confirmed tumor response was observed; however, two patients had prolonged stable disease. Both C(end) and area under the plasma concentration-time curve increased in a dose related manner. Plasma drug concentrations declined in a biphasic manner with a mean terminal elimination half-life (t (1/2)) of 7.1 h (+/-1.3). There was no change in clearance or volume of distribution over the dose range studied. Due to cardiac toxicity occurring with both the parent compound, SR233377, as well as this analog, this series of agents was abandoned from further clinical development.

Phase I dose-escalation study of a novel antitumor agent, SR271425, administered intravenously in split doses (d1-d2-d3) in patients with refractory solid tumors.

BACKGROUND: SR271425 is a novel DNA-binding cytotoxic agent with a broad spectrum of antitumor activity in preclinical models,across a variety of the schedule of administration. In toxicological studies, it has been reported to prolong QTc proportionally to C (max). In order to circumvent this C (max)-related QTc prolongation, 5 phase I studies were initiated to investigate 1-h, 24-h, weekly, and split iv infusions. This phase I study assessed a split-dose regimen (a 1-h infusion on each of Days 1 to 3, repeated every 3 weeks) to establish the dose limiting toxicities (DLT), to recommended a phase II dose, and to characterize PK/PD. METHODS: Patient with advanced solid tumors, adequate bone marrow, hepatic, renal function and on specific cardiac criteria were eligible and "3 + 3" design was used for dose escalation. That dose escalation was guided by PK data, toxicities observed and information from other ongoing phase I studies with SR271425. SR271425 plasma levels (PK samples) were measured using a validated LC-MS/MS method. Careful monitoring of ECGs was done, and ECGs were read centrally. RESULTS: Three centers enrolled 19 heavily pretreated patients to six dose levels, from 75 to 450 mg/m(2)/day (i.e., 225-1,350 mg/m(2)/cycle): 12 males and 7 females. Median age 56. Median ECOG, PS = 1. Main tumor types were brain, breast, gynecological, and urological. Patients received a median of 2 cycles (range: 1-6). NCI-CTC Grade 1-2 toxicities included nausea, vomiting, asthenia, rash, and yellow skin discoloration. No DLTs were reported, and there were no dose-limiting prolongations of QTc. Both C (end) and AUC increased in a dose-related manner, with no evidence of accumulation between Day 1 and Day 3, consistent with the mean (+/-SD) terminal elimination half-life of 5.11 +/- 1.21 h. Stable disease was observed in five cases. CONCLUSION: Split doses allow high cumulative exposure to SR271425 without significant toxicity, especially without QTc prolongation. MTD was not reached due to the early termination of the SR271425 program by the sponsor.

Neuroleptics and mortality in schizophrenia: prospective analysis of deaths in a French cohort of schizophrenic patients.

OBJECTIVE: The putative role of neuroleptics in the known excess mortality of subjects with schizophrenia remains disputed. The aim of this study was to assess the link between mortality and the class of neuroleptic. METHOD: Causes of death (suicide, cardiovascular, etc.) and exposure to neuroleptics were studied in a cohort of 3474 patients with schizophrenia followed from 1993 to 1997. RESULTS: From 1993 to 1997, 178 patients died. The risk of all-cause death (OR=1.59; 95% CI 1.02-2.50; p=0.04), and suicide (OR=2.22; 95% CI 1.24-3.97; p=0.006) were increased in users of thioxanthenes (alone or associated with other drugs), and increased risk of "other causes" of death was associated with use of atypical neuroleptics (OR=2.06; 95% CI 1.15-3.70; p=0.0016). CONCLUSION: Our findings suggest the existence of association between certain classes of neuroleptics and death, all cause or specific. This could be related to the drug itself or to patient selection.

Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.

BACKGROUND: Antipsychotic drugs have been associated with an increased risk of adverse events such as venous thromboembolism. Our aim was to assess this risk in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous thromboembolism. METHODS: From a baseline population of 29,952 recipients of conventional and atypical antipsychotic drugs aged younger than 60 years, we identified 42 individuals with idiopathic venous thromboembolism and 172 matched controls. We compared risk of current and recent use of antipsychotic drugs with non-use before the index date in cases and controls. FINDINGS: Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use (adjusted odds ratio 7.1 [95% CI 2.3-21.97]). Although we found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism (odds ratio 24.1 [3.3-172.7]) than were high potency antipsychotic drugs such as haloperidol (3.3 [0.8-13.2]). The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use. INTERPRETATION: Current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.

Phase I pharmacokinetic study of the novel antitumor agent SR233377.

SR233377 is a novel thioxanthenone analogue that demonstrated solid tumor selectivity in vitro with activity confirmed in vivo against several murine tumors including those of colon, pancreas, and mammary origin. Its primary preclinical dose-limiting toxicities included myelosuppression and neurological toxicity. The neurological toxicity was acute and could be ameliorated in mice when the drug was administered as a 1-h infusion instead of rapid i.v. injection. As a result of its preclinical efficacy profile, SR233377 entered Phase I clinical investigation. The compound was administered i.v. over 2 h on day 1 repeated every 28 days. The starting dose was 33 mg/m2 (one-tenth the mouse LD10). Escalations continued to 445 mg/m2 (six escalations), where dose-limiting toxicity was observed. At this dose, acute ventricular arrhythmias, including one patient with torsades de pointes and transient cardiac arrest, occurred. Because this toxicity might have been related to the plasma peak, the protocol was amended to a 24-h infusion beginning at 225 mg/m2. With this dose, prolongation of the corrected QT interval (QTc) over the pretreatment levels resulted. Because prolonged QTc is a known forerunner to acute ventricular arrhythmias, clinical development of SR233377 was stopped. However, preclinical antitumor and toxicity studies with analogues are underway with hopes of identifying a new clinical candidate with similar antitumor effects that is devoid of cardiac toxic effects.

Phase I/pharmacokinetic trial of the novel thioxanthone SR233377 (WIN33377) on a 5-day schedule.

PURPOSE: SR233377 (WIN33377) is a novel 4-aminomethyl thioxanthone derivative with promising preclinical activity against solid tumors at doses substantially below the MTD. We performed a phase I trial to determine a suitable phase II dose of SR233377 when administered as a 2-h intravenous infusion for five consecutive days. METHODS: A group of 25 patients with a range of solid tumor diagnoses and good performance status received SR233377 at eight dose levels ranging from 4.8 mg/m2 per day to 74.7 mg/m2 per day. Cycles were repeated every 35 days and patients were evaluated for response following two cycles of treatment. Doses were escalated in cohorts of three using a modified Fibonacci scheme. Pharmacokinetic sampling was performed during the first cycle in all patients. RESULTS: Toxicities of SR233377 on this schedule included neutropenia, fever, nausea, and dyspnea but all were mild and not dose-limiting. Asymptomatic prolongation of the corrected QT (QTc) interval during infusion in all patients monitored at the 74.7 mg/m2 dose level prompted closure of the study. QT lengthening correlated with increasing plasma concentrations of SR233377. SR233377 Cmax values increased linearly with dose, but substantial interpatient variability in SR233377 AUC, clearance, and half-life was noted. There was no evidence of drug accumulation when day 1 and day 5 AUC and Cmax values were compared. Seven patients displayed tumor growth inhibition lasting for 4 months or more. CONCLUSIONS: We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.

Zuclopenthixol-induced neuroleptic malignant syndrome at rechallenge and its extrapyramidal effects.

This is the first report of a zuclopenthixol-induced NMS. The lack of previous reports may be because the receptor-binding profile of thioxanthenes give rise to fewer extrapyramidal effects than comparable neuroleptics. It is important to know more of the relationship between the potential for induction of extrapyramidal effects and success in NMS rechallenge.

Early years of the Salmonella mutagen tester strains: lessons from hycanthone.

The 1960s witnessed detailed studies on the genetic properties of a large number of histidine-requiring mutants of Salmonella typhimurium. The early 1970s saw development of selected strains, the Ames strains, for use in rapid, cheap, sensitive, and manipulable tests of chemicals and chemical mixtures for genotoxic activities. Our contribution during this latter period was an investigation into the mutagenicity of hycanthone and some of its analogues. Some lessons that this study provided are enumerated. Hycanthone is definitely a liver carcinogen in rodents predisposed by hepatic hyperplasia. Between 1969 and 1975, an estimated total of 100 kg of hycanthone was injected into some 1,000,000 humans with liver hyperplasia caused by infections with parasites. It may now be possible to assess directly the long-term impacts of hycanthone in man.

A possible variant of the neuroleptic malignant syndrome.

A 20-year-old man developed generalised rigidity and signs of autonomic instability following the introduction of therapy with zuclopenthixol decanoate. A diagnosis of NMS was made, despite the absence of hyperthermia. He recovered on treatment with thiamine, dantrolene, and bromocriptine.

The neuroleptic malignant syndrome. Case report with a review of the literature.

Following the administration of fluphenthixol (a depot phenothiazine) for a psychotic illness, a 44-year-old woman developed weakness, rhabdomyolysis and renal failure, together with hyperthermia (42 degrees C) and signs of both autonomic and central nervous system dysfunction. She died following massive intestinal haemorrhage, intra-abdominal sepsis and probable disseminated intravascular coagulation. A diagnosis of neuroleptic malignant syndrome had been made, but treatment with dantrolene sodium was probably instituted too late to prevent the progress of the complications she had developed. This syndrome, which follows the use of phenothiazines or butyrophenones, is rare, potentially fatal and probably underdiagnosed. It has been likened to malignant hyperthermia, but a review of the literature points to many differences. Both dantrolene sodium and dopaminergic drugs (bromocriptine, amantidine and L-dopa) have been shown to be efficacious and their continued use, despite a failure in this case, is advocated until more is known about this syndrome.

Schizophrenic relapse after drug withdrawal is predictable.

Thirty-two patients in remission were followed by regular ratings during a prospective neuroleptic withdrawal study. They were outpatients who fulfilled the DSM-III criteria of schizophrenia and who were motivated for drug withdrawal. The relapse rate was 81%. The results from the rating scales confirm the hypothesis that a symptom increase occurs before psychotic relapse. In the order statistical differences occurred, the factors predicting relapse were those concerned with positive psychopathology, motor dysfunction, impaired affects and sleep disturbances. The corresponding symptoms and signs were mainly concerned with thought disorders, paranoid ideation, overactivity, depression and insomnia middle, all of nonpsychotic degree of severity. If prodromes appear, the patient should resume his neuroleptic treatment, or other preventive measures should be taken. By such therapeutic interactions, psychotic relapse may be prevented, or can be dealt with in an outpatient setting.