Phase I study of the novel Cdc2/CDK1 and AKT inhibitor terameprocol in patients with advanced leukemias.

PURPOSE: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial. PATIENTS AND METHODS: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days. RESULTS: Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression. CONCLUSION: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

Remifentanil reduces auditory and somatosensory evoked responses during isoflurane anaesthesia in a dose-dependent manner.

We studied 60 patients during stable isoflurane anaesthesia (0.4 MAC) after premedication with temazepam. Patients were allocated randomly to one of three dose regimens of remifentanil: 1 microgram kg-1 i.v. over 1 min and an infusion of 0.2 microgram kg-1 min-1 (low dose); 2.5 micrograms kg-1 and 0.5 microgram kg-1 min-1 (medium dose); and 5 micrograms kg-1 and 1 microgram kg-1 min-1 (high dose). The auditory (AER) and median nerve somatosensory (SER) responses were elicited throughout, and recorded before and after tracheal intubation, and surgical incision, together with systolic and diastolic arterial pressure and heart rate. Venous blood concentrations of remifentanil were measured at the above times. After administration of remifentanil, Pa and Nb amplitudes of the AER increased at the low dose, remained constant at the medium dose and decreased at the high dose. This dose-related effect was linear and significant (P = 0.012, P = 0.05). Pa amplitude correlated inversely with remifentanil blood concentrations before and after intubation and incision (P = 0.002, P < 0.001, P < 0.001 and P < 0.001). In the SER, P15-N20 amplitudes decreased after administration of remifentanil (P < 0.001), whereas P25-N35 and N35-P45 amplitudes increased at all dose concentrations (P < 0.001 and P < 0.001). After intubation, P15-N20 and N35-P45 amplitudes increased at the low dose, did not change at the medium dose and decreased at the high dose (P = 0.001, P = 0.027). After remifentanil, systolic and diastolic arterial pressure and heart rate decreased in a linearly dose-related manner (P = 0.033, P < 0.001, P < 0.001). At all doses the three variables increased after intubation (P = 0.001, P < 0.001, P < 0.01), and systolic and diastolic arterial pressure increased after incision (P = 0.027, P = 0.039).

Clinical pharmacology of ondansetron in postoperative nausea and vomiting.

Ondansetron is a 5-HT3 receptor antagonist which is effective and well tolerated as an antiemetic for emesis induced by cancer chemotherapy and radiation therapy, and in the prevention and treatment of postoperative nausea and vomiting. Ondansetron is rapidly absorbed after oral administration (tmax 1.9 h) with an absolute bioavailability of around 60%. Its terminal elimination half-life is 3.5 h and it is extensively hepatically metabolized. Plasma clearance is 0.38 litre h-1 kg-1 and volume of distribution is 1.8 litre kg-1. Plasma clearance is reduced by age (31% reduction) and hepatic failure (80% reduction in severe failure). In patients undergoing general anaesthesia there is a slight prolongation of terminal half-life, which is not of clinical significance. Ondansetron is very well tolerated in volunteer studies. Headache, mild abdominal pain, and constipation occur infrequently. There is no evidence for effects of ondansetron on cardiac function (electrocardiogram, cardiac output, blood pressure and heart rate), and haemostatic function in volunteers and patients. Respiratory depression induced during general anaesthesia is not potentiated by ondansetron. No drug interactions have been noted with temazepam, atracurium, alfentanil and alcohol in man. There are also no interactions seen in animal studies using pentobarbitone, morphine, neostigmine, prednisolone and diazepam.

The Chief Scientist reports.... Voluntary agency support for people with mental health problems.

The development of a cohesive support system is vital to the success of community based services and day care is an essential component of any system of support. McCreadie et al in a Scottish study of psychiatric hospital provision showed that while there was wide variation around Scotland in the provision of hospital based care, there was a general dearth of health service and local authority community-based services. Philip and Stuckey in a survey of NHS long term non-resident patients of the Royal Edinburgh Hospital found that hospital staff felt that such patients would have benefited from additional daytime activity different from that provided in the health service. These authors found that some patients did make significant use of voluntary agencies, but were unable to elicit any systematic reasons for using or not using these agencies. Surveys in the statutory and voluntary sectors completed to date have tended to concentrate on the opinions of staff groups about the requirements and needs of clients. There has been no systematic survey of the facilities and opportunities most desired by users of voluntary sector support agencies. This survey, which received support from the Chief Scientist Organisation Mini-Project Scheme, aims to remedy this lack and to provide a factual basis from which the NHS, local authorities and voluntary agencies can draw, in their mutual aim of helping people with mental health problems. The results of the survey, while carried out in Edinburgh, may have relevance to planners and providers further afield in Scotland.