P Frick

Seven cases of agranulocytosis and two of liver damage that were probably due to amodiaquine treatment were studied. In five cases agranulocytosis was combined with liver damage, and in one case of primary liver damage moderate neutropenia was present. Three patients died. High total doses or prolonged duration of treatment, or both, appear to favour the occurrence of these reactions. The clustering of five of the seven cases of agranulocytosis within six months in one medical centre indicates that the risk to benefit ratio of amodiaquine for malaria prophylaxis should be re-evaluated.

The potential of ketoconazole prophylaxis to antagonize the activity of amphotericin B against aspergilli was investigated in vitro and in neutropenic mice. Exposure of Aspergillus fumigatus (six strains) and of Aspergillus flavus or Aspergillus niger to ketoconazole resulted in a uniform increase of the minimal fungicidal activity of amphotericin B, from 0.15-0.63 mg/liter to greater than 2.5 mg/liter in a microwell assay. To test the relevance of this antagonism in vivo, we challenged neutropenic mice iv with a lethal dose of conidia from two strains of A. fumigatus and then treated the mice first with ketoconazole and then with amphotericin B or amphotericin B plus ketoconazole. Pretreatment with ketoconazole for 48 hr completely abolished the protective effect of a subsequent therapy with amphotericin B, whether ketoconazole therapy was stopped (P less than .001) or not (P less than .001). Ketoconazole given alone had no significant effect on survival. Our data show that ketoconazole not only antagonized the fungicidal activity of amphotericin B in vitro but also abolished in vivo the protective effect of the only drug shown to be useful in the therapy of aspergillosis. The clinical importance of this antagonism, which is not limited to Aspergilli in vitro, requires careful consideration before ketoconazole prophylaxis can be recommended for patients at high risk of developing invasive opportunistic fungal infections.

Abstract 1. A circulating anticoagulant was demonstrated in three patients with "collagen disease." In all cases it was associated with a false positive blood serology and a four plus cephalin cholesterol flocculation. 2. In one instance, the anticoagulant was transferred to a newborn infant where it persisted for seven weeks. The infant also demonstrated the abnormal serologic and turbidimetric tests during the first six months of life. 3. The anticoagulant probably acted as anti-thromboplastin. 4. The occurrence of a clotting inhibitor in association with other manifestations of hypersensitivity and its transplacental transfer strongly suggest that the mechanism of development is immunologic in type. 5. This study included a total of thirty patients with lupus erythematosus disseminatus and associated conditions conventionally grouped under the term "collagen disease." The incidence of circulating anticoagulants was 10 per cent.

Abstract A new abnormal hemoglobin was observed in 15 members over four generations of a large Swiss family and has been termed "Hemoglobin Zürich." The discovery of this hemoglobin was prompted by a severe hemolytic crisis in two members of the family after sulfonamide therapy. During this episode, virtually all erythrocytes and reticulocytes contained a single large inclusion body which was visible with Giemsa and brilliant cresyl blue stains. Outside the hemolytic episode, the erythrocytes revealed no morphologic abnormalities. The results of enzyme studies were all within normal limits. The association of a hemoglobinopathy with a drug-induced inclusion body anemia without any demonstrable enzyme defect is a new entity. The anomalous hemoglobin is inherited as a dominant character and affects both sexes. Thus far, only the heterozygous form has been observed.