Micha Levy

Drugs in the aetiology of agranulocytosis and aplastic anaemia

Abstract:u2002 Agranulocytosis and aplastic anaemia are rare but serious conditions known to be caused by numerous drugs. Most of what is known or suspected about the aetiology is based on case reports, with only a few formal epidemiological studies that provide quantitative estimates of risk. Updated results have been obtained from a combined analysis of data from 3 case‐control studies that used similar methods: the International Agranulocytosis and Aplastic Anemia Study (IAAAS), conducted in Israel and Europe; a study conducted in the northeast US; and a study conducted in Thailand. Totals of 362 cases of agranulocytosis, 454 cases of aplastic anaemia and 6458 controls were included in the analyses. The IAAAS and Thai study were population‐based, providing estimates of the incidence of the 2 dyscrasias. The overall annual incidence of agranulocytosis in the ambulatory population was 3.4/106 in the IAAAS and 0.8/106 in Thailand; by contrast the incidence of aplastic anaemia was 2.0/106 in the IAAAS and 4.1/106 in Thailand. A total of 21 compounds were significantly associated with an increased risk of agranulocytosis in the IAAAS and US studies. Excess risks ranged from 0.06 to 13 cases/106 users/wk; the most strongly associated drugs were procainamide, anti‐thyroid drugs and sulphasalazine. An association with drugs that had previously been suspected was also seen in Thailand. The overall aetiologic fractions of agranulocytosis due to drug use were 62% in the IAAAS, 72% in the US and 70% in Thailand. Eleven drugs were significantly associated with an increased risk of aplastic anaemia, with excess risks ranging from 1.4 to 60 cases/106 users in a 5‐month period. The most strongly associated drugs were penicillamine, gold and carbamazepine. Aetiologic fractions were 27% in the IAAAS, 17% in the US and 2% in Thailand, which paralleled the prevalence of use of associated drugs in the 3 populations. The present results confirm that agranulocytosis is largely a drug‐induced disease, with similar proportions accounted for in 3 disparate geographic regions. By contrast, although many of the expected associations were observed for aplastic anaemia, most of the aetiology is not explained by drugs. For all associated drugs, the excess risks are sufficiently low that blood dyscrasias should not figure prominently in the balancing of risks and benefits.

BREAST CANCER AND ALCOHOLIC-BEVERAGE CONSUMPTION

The relation between breast cancer and alcoholic-beverage consumption was evaluated in a case-control study of 1152 women with breast cancer and two groups of control women-519 with endometrial or ovarian cancer, and 2702 with non-malignant disorders. The relative-risk estimate of breast cancer, with allowance for all potential distorting factors, for women who had ever drunk alcoholic beverages relative to those who had never drunk was 1.4 (95% confidence interval, 1.0-2.0) when the comparison group was the group with endometrial or ovarian cancer and 1.9 (1.5-2.4) when the controls who had non-malignant disorders were the comparison group. The association was evident for beer, wine, and spirits. The association was not explained by any of the major known risk factors for breast cancer, but we had no information on dietary factors. The findings support the hypothesis that alcohol consumption, or related dietary factors, increases the risk of breast cancer.

Colchicine prophylaxis in familial Mediterranean fever: reappraisal after 15 years.

As determined in this study of 45 patients, the prolonged use of colchicine therapy in familial Mediterranean fever (FMF) is safe and effective in preventing flares of FMF and amyloidosis. It has acceptable adverse effect profile and can be used in children and pregnant women. Its discontinuation predisposes patients to acute FMF attacks and the development of amyloidosis. Articular involvement is less responsive to colchicine and may require therapy with nonsteroidal antiinflammatory drugs.

Relation of aplastic anaemia to use of chloramphenicol eye drops in two international case-control studies

Although the use of chloramphenicol eye drops is thought to cause aplastic anaemia,1 this side effect has not been studied critically. We examined the use of ocular chloramphenicol in two population based case-control studies conducted with the same methods. 2 3nnThe data from the international granulocytosis and aplastic anaemia study were collected over varying times from 1980 to 1986 in Israel and in Ulm and Berlin (Germany), Milan (Italy), Budapest (Hungary), Sofia (Bulgaria), and Stockholm and Uppsala (Sweden); the total base population was about 19 million.2 Data collection continued independently in Sweden until 1992. The Thai study was conducted from 1989 to 1994 in Bangkok and from 1990 to 1994 in Khonkaen and Songkla; the total population was about 21 million.3nnIn both studies patients with aplastic anaemia were identified by regular telephone contacts with all hospitals in the study …

DIAZEPAM AND THE RISK OF BREAST CANCER

The relation of breast cancer to diazepam use was evaluated in a case-control study of 1236 women with breast cancer and 728 control subjects with other malignancies. Compared to women who never used diazepam, the relative risk for women who used the drug at least 4 days per week for at least 6 months was estimated to be 0.9, with 95% confidence limits of 0.5 and 1.6. There was no apparent association for recent use, or for use in the distant past, although confidence intervals were fairly wide in these categories. The results were not explained by various potential confounding factors, including the major risk factors for breast cancer. The findings suggest that regular diazepam use does not increase the risk of breast cancer relative to other cancers.