Cancer risk in people with epilepsy using valproate-sodium.

OBJECTIVES: Based on reports of antitumour properties of sodium-valproate, we hypothesised that valproate has a cancer-protective effect in people with epilepsy. We aimed to determine cancer risk in people with epilepsy using sodium-valproate. MATERIALS AND METHODS: Continuous data for 2997 people with epilepsy who had been prescribed valproate for at least two years, and for 11,988 unexposed people were provided by the UK General Practice Research Database. Hazard ratios (HRs) for all cancers and individual cancers between the exposed and unexposed groups, with smoking and alcohol consumption and age as covariates, were calculated using the Cox proportional hazards method. RESULTS: Exposure to valproate had no influence on the incidence of the composite of all cancers [HR: 1.19, 95% CI: 0.97-1.47, P = 0.10]; there was, however, a significant excess of colon cancers [HR: 3.95, 95% CI: 1.97-7.92, P = 0.001] and a trend towards an excess of prostate neoplasms [HR: 2.15, 95% CI: 0.92-5.02, P = 0.08] and in addition, a trend towards reduced incidence of breast cancer [HR: 0.40, 95% CI: 0.14-1.30, P = 0.08] in the exposed group. CONCLUSIONS: The lack of an inverse association between valproate use and hazard ratios for all cancers and several individual cancer sites does not lend support for a cancer-protective role for valproate.

Premature mortality in refractory partial epilepsy: does surgical treatment make a difference?

BACKGROUND: Epilepsy carries an increased risk of premature death. For some people with intractable focal epilepsy, surgery offers hope for a seizure-free life. The authors aimed to see whether epilepsy surgery influenced mortality in people with intractable epilepsy. METHODS: The authors audited survival status in two cohorts (those who had surgery and those who had presurgical assessment but did not have surgery). RESULTS: There were 40 known deaths in the non-surgical group (3365 person years of follow-up) and 19 in the surgical group (3905 person-years of follow-up). Non-operated patients were 2.4 times (95% CI 1.4 to 4.2) as likely to die as those who had surgery. They were 4.5 times (95% CI 1.9 to 10.9) as likely to die a probable epilepsy-related death. In the surgical group, those with ongoing seizures 1 year after surgery were 4.0 (95% CI 1.2 to 13.7) times as likely to die as those who were seizure-free or who had only simple partial seizures. Time-dependent Cox analysis showed that the yearly outcome group did not significantly affect mortality (HR 1.3, 95% CI 0.9 to 1.8). CONCLUSION: Successful epilepsy surgery was associated with a reduced risk of premature mortality, compared with those with refractory focal epilepsy who did not have surgical treatment. To some extent, the reduced mortality is likely to be conferred by inducing freedom from seizures. It is not certain whether better survival is attributable only to surgery, as treatment decisions were not randomised, and there may be inherent differences between the groups.

Gross and histopathological observations of long-term catheterized vessels in experimental sheep.

Chronic indwelling central vessel catheters provide vascular access for compartmental infusion or sampling. However, complications with catheter patency during the postoperative and/or experimental period often arise. In order to identify physiological occurrences common with such complications, 10 multicatheterized sheep (61.8 +/- 7.8 kg BW), obtained from a previous nutrient flux study were used for gross and histopathological investigation. Catheters had been surgically placed in a hepatic portal vein (PVC), a hepatic vein (HVC), a distal mesenteric vein (MVC) and a mesenteric artery (MAC). In the previous study, catheters (PVC, HVC and MAC) were used to collect blood samples or infuse (MVC) p-aminohippurate. Catheters were maintained for a total of 58 days prior to necropsy. Histopathological findings indicated that catheter failures were associated with the following tissue responses: (i) thromboses with frequent focal vasculitis; (ii) euplastic tissues associated with extensive fibrosis; (iii) granulomas; (iv) neo-vascularization of the media; (v) calcification processes; and (vi) micro-abscesses. Additional studies are needed that address and incorporate improvement of catheter design and placement to minimize irritation of endothelium, improvement of catheter treatments and therapeutic regimes, and development and use of alternative anti-coagulants. A greater understanding of the mechanisms leading to failure will help researchers improve catheter performance and patency.

Effect of the 5-lipoxygenase inhibitor ZD2138 on aspirin-induced asthma.

BACKGROUND: The cysteinyl leukotrienes may play a central part in the mechanisms of aspirin-sensitive asthma. Previous work has shown that individuals with aspirin-sensitive asthma have high basal urinary LTE4 levels which increase further upon aspirin ingestion, and that sulphidopeptide leukotriene receptor antagonists attenuate aspirin-induced airflow obstruction. If the cysteinyl leukotrienes cause aspirin-induced asthmatic reactions, inhibition of the 5-lipoxygenase pathway should prevent aspirin-induced bronchospasm. This hypothesis has been tested with ZD2138, a specific non-redox 5-lipoxygenase inhibitor. METHODS: Seven subjects (four men) with aspirin-sensitive asthma with baseline FEV1 values > 67% were studied. ZD2138 (350 mg) or placebo was given on two separate occasions two weeks apart in a randomised double blind fashion. A single dose of aspirin was administered four hours after dosing and FEV1 was measured for six hours. Inhibition of the 5-lipoxygenase pathway by ZD2138 was assessed by measurements of urinary LTE4 levels and ex vivo calcium ionophore stimulated LTB4 generation in whole blood, before administration of drug or placebo and at regular time intervals after dosing and aspirin administration. RESULTS: ZD2138 protected against the aspirin-induced reduction in FEV1 with a 20.3 (4.9)% fall in FEV1 following placebo compared with 4.9 (2.9)% following ZD2138. This was associated with 72% inhibition of ex vivo LTB4 generation in whole blood at 12 hours and a 74% inhibition of the rise in urinary LTE4 excretion at six hours after aspirin ingestion. CONCLUSIONS: In aspirin-sensitive asthma the 5-lipoxygenase inhibitor ZD2138 inhibits the fall in FEV1 induced by aspirin and this is associated with substantial inhibition of 5-lipoxygenase.