Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy.

BACKGROUND: Azodicarbonamide (ADA), a HIV-1 zinc finger inhibitor, targets a new step in viral replication and cell infectivity. OBJECTIVE: A first phase I/II clinical study of ADA. METHODS: ADA was administered at escalating doses concomitantly with current antiviral therapy during a 3-month open-label period in patients with advanced AIDS and documented virological failure. After 3 months, patients were randomized in a double-blind placebo-controlled withdrawal, ADA being given at the highest tolerated dosage. RESULTS: Fifteen patients with advanced disease failing on combined antiretroviral therapy, 75% of them with proven phenotypic resistance, had a median baseline CD4 cell count of 85 x 10(6) cells/l, CD4/CD8 cell ratio of 0.09 and median plasma RNA viral load of 4.2 log10 copies/ml. Tolerance to ADA was dose dependent and some patients developed nephrolithiasis, glucose intolerance or showed an ADA-related cytotoxicity towards CD4 cells at higher dosages. No patient died during the study period. ADA increased CD4 cell percentage, increased the CD4/CD8 cell ratio and decreased plasma RNA viral load from baseline. At the end of the double-blind period, the ADA group, but not the placebo group, showed a significant response (P < 0.05). No phenotypic resistance to ADA was observed. Overall, 3/11 patients (27%) had consistent viral load reductions > 0.5 log10 copies/ml compared with baseline and 5/ 11 (45%) showed a CD4 cell recovery from baseline > 33%. In responders, ADA induced a median peak increase in CD4 cell percentage change from baseline of 65% (range 47-243%), and viral load decrease of 1.04 log10 copies/ml (range 0.52-1.23). CONCLUSIONS: The maximal tolerated dosage of ADA appears to be 2 g (three times daily). This study provides safety results that will allow larger clinical trials to confirm the preliminary efficacy data.

Genetic toxicology in industrial practice: general introduction.

During the past decade, important position statements on mutagenicity testing have been issued by industrial organizations such as CEFIC (the European Council of Chemical Industry Federations) and ECETOC (the European Chemical Industry Ecology and Toxicology Centre). Mutagenicity testing is of potential value as a research tool for screening new compounds, as a probe for the identification of harmful substances and as a diagnostic tool for monitoring the health of individuals exposed to certain chemicals. The problems inherent in mutagenicity testing include specificity and sensitivity, and meaningful interpretation of test data will depend on the strict maintenance of accepted quality standards.

Cytogenetic investigation on leukocytes of workers exposed to metallic mercury.

A cytogenetic analysis was performed in 28 mercury-exposed subjects as well as eight control subjects from the same chloralkali plant and in 12 healthy controls from the "general population." No chromosomal effects could be demonstrated in the mercury-exposed population in comparison with both control groups. Also no effect of smoking was observed. From the study it seems obvious that mercury, although it is capable of producing chromosomal damage even at low exposure levels, will not be harmful in this respect when adequate protection measures are taken.

Mortality in an european cohort occupationally exposed to epichlorohydrin (ECH).

A study was undertaken on the mortality of workers exposed to ECH at four European sites with plants producing epichlorohydrin (ECH), epoxy resins, glycerin, and other specialty chemicals derived from ECH. The vital status of 606 individuals with at least one year of exposure to ECH, starting at least 10 years before the final date of the study on 31 December, 1978, were collected. Mortality was analysed for a subgroup with 10 or fewer years of exposure, and another subgroup with more than 10 years of exposure. Four deaths from different cancers were observed against five expected. No excess mortality from cancer was observed in either subgroup or the complete cohort, which could be related to ECH exposure. The small size of the cohort and the limited number of deaths due to low average age (42 years), as well as the short duration of the observation period, do not allow a firm conclusion to be reached regarding the potential carcinogenicity of ECH in man. Current exposure levels are low, but exposure in the early days of production occasionally reached levels high enough to be irritating. We recommend updating the study 5 years from the final date of the present study, i.e. on 31 December, 1983. Within their limitations this and other epidemiological studies so far provide no evidence for an association between occupational exposure to ECH and the occurrence of malignant neoplasms in man.