Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin.

The long-term safety profile of simvastatin, established over 10 years of clinical use, is excellent. The principal adverse effect of all inhibitors of hydroxymethylglutarate co-enzyme A (HMG-CoA) reductase, myopathy, is infrequent. Simvastatin is a substrate for cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors can elevate the plasma concentration of HMG-CoA reductase inhibitory activity derived from simvastatin. Clinical experience has shown that concomitant use of potent inhibitors of CYP3A4 increase the risk for myopathy. Evaluation of data from clinical trials and postmarketing surveillance allows assessment of whether concomitant use of weaker CYP3A4 inhibitors, as represented by calcium channel blockers, has any effect on the risk of myopathy. Cases of myopathy in long-term clinical megatrials and in analyses of postmarketing adverse event reports have been surveyed. In megatrials with simvastatin, the overall incidence of myopathy was 0.025%. The proportion of patients developing myopathy who were taking a calcium channel blocker with simvastatin (1 of 3) was similar to the proportion of patients taking a calcium channel blocker overall. Among marketed-use adverse event reports, concomitant medication with a potent CYP3A4 inhibitor was more frequent among reports of myopathy than among reports of nonmusculoskeletal adverse events. No excess use of calcium channel blockers among myopathy reports was observed. We conclude that the overall risk of myopathy during treatment with simvastatin is very low. Potent CYP3A4 inhibitors, especially cyclosporine, significantly increase the risk. There is no evidence that weaker CYP3A4 inhibitors such as calcium channel blockers increase the risk.

Assessment of an immunoassay for interferon-alpha in cerebrospinal fluid as a diagnostic aid in infections of the central nervous system.

A highly sensitive and specific immunoradiometric assay, based upon a monoclonal antibody, was used to measure interferon-alpha (IFN-alpha) in the cerebrospinal fluid (CSF) of patients with central nervous system infections and in controls with non-infectious neurological disorders. IFN-alpha was detected in all 21 patients with viral meningitis but in only one of four patients with non-viral aseptic meningitis. It was also present in the CSF of three of four patients with herpes encephalitis and five of seven patients with acute bacterial meningitis. By contrast, IFN-alpha was present in the CSF in low concentrations in only five (7%) of 71 neurological controls. This rapid test is positive in viral meningitis and may help in distinguishing viral infection from other causes of aseptic meningitis. It is usually negative in non-infective disorders but will not distinguish between viral and bacterial infections.

The anatomical distribution of single leprosy lesions in an African population, and its implications for the pathogenesis of leprosy.

Data on the anatomical sites of single leprosy lesions found in 635 newly diagnosed and biopsy-confirmed leprosy patients are presented. These patients were found during total population surveys carried out by the Lepra Evaluation Project, a prospective longitudinal study of the epidemiology of leprosy in Karonga District, Northern Malawi. There was a striking excess of single lesions on the face and the back of the arms, compared to the distribution of skin surface area, and a deficit on the legs, regardless of age. There is some evidence for a sex difference in lesion distribution among adults, with facial and arm lesions being relatively more common in females and back lesions being more common in males. The excess of lesions on the face compared to the lower limbs is similar to data from Uganda, but very unlike data from Burma and elsewhere in Asia. Overall, the distribution of lesions does not suggest a pattern reflecting entry of Mycobacterium leprae, nor does it suggest an association with anatomical distribution of the nervous or vascular system. It is argued that the distribution reflects the influence of some 'local' environmental or behavioural factors.

The Karonga Prevention Trial: a leprosy and tuberculosis vaccine trial in northern Malawi. I. Methods of the vaccination phase.

In this report the methods of the Karonga Prevention Trial, a double-blind leprosy and tuberculosis vaccine trial in Karonga District, Northern Malawi, are described in detail. During a total population house-to-house survey, which lasted from November 1985 until August 1989, 121,008 people (57,892 males and 63,116 females) were vaccinated. A further 5835 people refused vaccination and 5757 were ineligible for vaccination, 2652 of them because they had a history or signs of leprosy, or because they were suspected to have early leprosy. A total of 66,145 individuals, without evidence of prior BCG vaccination, received one of the following: BCG, BCG + 5 x 10(7) killed Mycobacterium leprae, or BCG + 6 x 10(8) killed M. leprae; 54,863 individuals found with a typical or a doubtful BCG scar received either placebo or BCG, or (from mid-1987 onwards) BCG + 6 x 10(8) killed M. leprae. Side-effects were not looked for systematically, but 4 individuals self-reported with glandular abscesses, 9 with large post-vaccination ulcers (> 25 mm in diameter) and 2 with ulcers which persisted for more than 1 year. BCG vials collected from paraffin refrigerators in the field showed satisfactory concentrations of viable BCG throughout the trial. Post-vaccination skin test (RT23 and M. leprae soluble antigen) results and post-vaccination ulcer rates indicate that few mistakes were made in the field when recording the vaccine codes.

A comparison of the blood levels and urinary excretion of ethionamide and prothionamide in man.

The blood levels and urinary excretion of the anti-mycobacterial drugs ethionamide and prothionamide have been compared after oral dosage in man. High pressure liquid chromatographic methods were used to determine the two closely related thioamides and their microbiologically active sulphoxide metabolites after the ingestion of both single and combined doses of the two drugs. Both drugs were rapidly eliminated from the body, the half-life for the urinary excretion and removal from the plasma of prothionamide being slightly less than that of ethionamide. Less than 0.1% of the orally administered doses were excreted unchanged in the faeces. Plasma concentrations of ethionamide and its sulphoxide metabolite were substantially higher than those of prothionamide and prothionamide sulphoxide. The implications of these findings for the use of ethionamide or prothionamide in the treatment of lepromatous leprosy are discussed.

Immunoreactive IFN-gamma in CSF in neurological disorders.

Interferon gamma (IFN-gamma) was measured in the CSF of neurological patients using a highly specific and sensitive immunoradiometric assay. It was detected in 52% of patients presenting as suspected meningitis or encephalitis and in 83% with proven viral meningitis. In contrast IFN-gamma was detected in only 26% of patients who did not have an acute infection at the time of presentation. Only 15% of patients with multiple sclerosis had detectable CSF IFN-gamma. The presence of IFN-gamma in CSF in response to acute viral infections of the central nervous system may be of importance in relation to the pathophysiology of immunologically mediated neurological disorders.

Failure of Mycobacterium leprae soluble antigens to suppress delayed-type hypersensitivity reaction to tuberculin.

In order to test a published claim that the inclusion of Mycobacterium leprae antigens with a tuberculin skin test reagent can suppress delayed-type hypersensitivity (DTH) to tuberculin in both paucibacillary and multibacillary leprosy cases, 109 leprosy cases and 104 non-leprosy controls were skin-tested simultaneously with tuberculin with and without M. leprae soluble antigens. Tests were randomized between arms and carried out double-blind. There was a clear tendency for larger DTH responses with the combined tuberculin plus M. leprae antigen than with tuberculin alone in paucibacillary leprosy cases and in non-leprosy controls. No evidence for M. leprae antigen-mediated suppression of DTH was observed in any group. It is unclear whether the difference between the results reported here, which were obtained in Malawi, and those in the published literature which were obtained in India, is attributable to geographic differences in important biological variables or to differences in the experimental protocols. The need for methodological rigour in skin-test studies is stressed.

Efficacy of BCG vaccine against leprosy and tuberculosis in northern Malawi.

Protection afforded by BCG (bacillus Calmette-Guérin) vaccines against tuberculosis and leprosy varies widely between different populations. In the only controlled trial which assessed protective efficacy of BCG (Danish and Pasteur strains) against both diseases, there was slightly more protection against leprosy than against tuberculosis. We have studied the protective efficacy of BCG (Glaxo, freeze dried) vaccine against these two diseases in Karonga District, northern Malawi. BCG vaccination was introduced into this population in 1974. Prior information about BCG scar status was available for 83,455 individuals followed up between 1979 and 1989. 414 new cases of leprosy and 180 new cases of tuberculosis were found in this population over that period. Protection was estimated at 50% or greater against leprosy, and there was no evidence for lower protection against multibacillary (84%; 95% confidence interval 26% to 97%) than against paucibacillary (51%; 30% to 66%) disease. There was no statistically significant protection by BCG against tuberculosis in this population. These findings add to the evidence that BCG vaccines afford greater protection against leprosy than against tuberculosis.