Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.     

Hazard-Rate Analysis and Patterns of Recurrence in Early Stage Melanoma: Moving towards a Rationally Designed Surveillance Strategy

Background

While curable at early stages, few treatment options exist for advanced melanoma. Currently, no consensus exists regarding the optimal surveillance strategy for patients after resection. The objectives of this study were to identify patterns of metastatic recurrence, to determine the influence of metastatic site on survival, and to identify high-risk periods for recurrence.

Methods

A retrospective review of the Duke Melanoma Database from 1970 to 2004 was conducted that focused on patients who were initially diagnosed without metastatic disease. The time to first recurrence was computed from the date of diagnosis, and the associated hazard function was examined to determine the peak risk period of recurrence. Metastatic sites were coded by the American Joint Committee on Cancer (AJCC) system including local skin, distant skin and nodes (M1a), lung (M1b), and other distant (M1c).

Results

Of 11,615 patients initially diagnosed without metastatic disease, 4616 (40%) had at least one recurrence. Overall the risk of initial recurrence peaked at 12 months. The risk of initial recurrence at the local skin, distant skin, and nodes peaked at 8 months, and the risk at lung and other distant sites peaked at 24 months. Patients with a cutaneous or nodal recurrence had improved survival compared to other recurrence types.

Conclusions

The risk of developing recurrent melanoma peaked at one year, and the site of first recurrence had a significant impact on survival. Defining the timing and expected patterns of recurrence will be important in creating an optimized surveillance strategy for this patient population.     

Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992

BACKGROUND: By 2016, the proportion of Canadians older than 65 years of age will increase to 16%, and there will be an increase in the absolute number of cases of cardiovascular disease in older Canadians. The Canadian Heart Health Surveys database provides information about this population upon which health policy related to cardiovascular disease can be based. This paper presents for the first time population-based data on the risk factors for cardiovascular disease in older Canadians. METHODS: Canadians from all 10 provinces participated in surveys of cardiovascular risk factors; health insurance registries were used as sampling frames. In each province, probability samples of 2200 adults 18 to 74 years old not living in institutions, on reserves or in military camps were asked to participate in interviews and to undergo testing at clinics for major risk factors for cardiovascular disease. RESULTS: A total of 2739 men (response rate 70%) and 2617 women (response rate 66%) aged 55 to 74 years participated in the survey and also provided follow-up clinical measurements at the clinic. Overall, 52% of participants were hypertensive, 26% had isolated systolic hypertension, and 30% had a total blood cholesterol level of 6.2 mmol/L or greater. Rates of current smoking were lower in women than men (17% v. 22%). Overall, 87% of men and 78% of women who were current smokers smoked at least 10 cigarettes per day. Only slightly more than half of participants exercised at least once a week for at least 15 minutes, and almost half had a body mass index of 27 or greater. In only 4% was no major risk factor for cardiovascular disease detected. INTERPRETATION: Significant numbers of older Canadians have one or more major risk factors for cardiovascular disease. Many of these risk factors are amenable to modification.     

Change in Criteria for USP Dissolution Performance Verification Tests

The US Pharmacopeial Convention has been evaluating its performance verification tests (PVT) for several years. These tests help ensure the integrity of the US Pharmacopeia performance test when a dissolution procedure, as described in General Chapter Dissolution <711>, is relied upon to test a nonsolution orally administered dosage form. One result of the evaluation is a change in the PVT criterion from one based on individual tablet results to one based on the mean and variability of a set of tablets. This paper describes the new PVT and its criterion and how its acceptance limits are derived from results of a collaborative study, explains a two-stage option for the test, and presents operating characteristics.