Hepatomegaly with severe steatosis in HIV-seropositive patients.

OBJECTIVE: To describe death attributed to severe hepatomegaly and macrovesicular steatosis without inflammation or necrosis in HIV-seropositive patients without AIDS. PATIENTS: Patients from the AIDS Clinical Trials Group (ACTG) Adverse Reactions and the Food and Drug Administration's (FDA) Spontaneous Report databases. RESULTS: Six fatal and two non-fatal cases in which no known cause of hepatic steatosis could be found were identified. With one possible exception, none of the six fatal cases had a diagnosis of AIDS and all were in reasonable nutritional status (as indicated by weight and/or serum albumin); the majority were mildly to moderately overweight. All had received at least 6 months of antiretroviral therapy, and all had gastrointestinal complaints without other non-hepatic abdominal pathology. At least three out of the six had no history of progressively abnormal liver function tests until a few weeks prior to the onset of symptoms and subsequent death. Further investigation of the FDA and ACTG databases identified two similar but non-fatal cases in which abnormalities resolved after cessation of antiretroviral therapy. CONCLUSIONS: The cases described represent a degree of hepatic abnormalities that has not been reported previously in HIV-seropositive patients, and are probably an underestimate of actual incidence, since patients with possible etiologies of liver disease were excluded from the clinical history, laboratory, microbiologic, or histologic examination. The etiology of hepatic disease may be associated with antiretroviral therapy, HIV, or an unidentifiable infection, and requires further investigation.

Bioequivalence of generic thioridazine drug products--the FDA viewpoint.

The phenothiazines are among the most widely used drugs to treat symptoms commonly associated with acute and chronic psychoses. One of the commonly prescribed compounds within this class of drugs is thioridazine, available both as a generic product as well as the innovator product, Mellaril. Each of these products is coded as bioequivalent and consequently therapeutically equivalent by the Food and Drug Administration (FDA). A recent issue of this journal contained an article that raised a number of questions concerning the bioequivalence of the generic versions of thioridazine that have been approved by the FDA. Their article was based in part on information obtained from the FDA as well as information supplied to the authors by Sandoz, Inc., the manufacturer of the original thioridazine drug product Mellaril. The FDA has reviewed its original decision of bioequivalence. Based on this reassessment, the FDA strongly rejects the assertion by the authors that several of the approved generic thioridazine products are not bioequivalent. The rationale behind the FDA decisions and the FDA's viewpoint on the bioequivalence of generic thioridazine drug products is discussed in detail.

The history of the United States Food, Drug and Cosmetic Act and the development of medicine.

The future role of pharmacologists in the evaluation of drugs will increase as scientific knowledge and our understanding of drugs and disease processes increase. In addition, political issues and public fears will place further demands on the scientific community to try to influence the drug regulatory process. The FDA continually issues directives which guide all phases of drug development, from the identification of a chemical as being of potential interest on therapy, through all animal tests and clinical phases (4).

Inhibition of dihydrofolate reductase and cell growth by antifolates in a methotrexate-resistant cell line.

The structural features and lipid solubility of four different classes of antifolate compounds were compared for their inhibition of dihydrofolate reductase (DHFR) and growth in a normal and methotrexate (MTX)-resistant 3T6 mouse cell line. All of the compounds have been shown previously to have antifolate activity. The resistant cell line has a 7-fold increase in DHFR activity with normal transport, but an altered affinity for MTX. All the antifolates were equally effective in inhibiting DHFR and growth in the parent cell line. Inhibition of partially purified DHFR from the resistant cells increased with changes in lipid solubility and structure of the compounds, compared to the parent DHFR. These data demonstrate that the resistant cells may be more sensitive to the structurally dissimilar antifolates than to MTX and lend importance to further development of this type of antifolate. These results suggest that these compounds may be useful in circumventing antifolate resistance due to alterations in target enzyme concentration and drug-enzyme affinity, as well as drug transport.

Leukocyte hexose monophosphate shunt activity during phagocytosis in vitamin B12 and folic acid deficiencies.

Little information exists about leukocytic function in megaloblastic anemia. A report of abnormal hexose monophosphate shunt and phagocytic activity only in vitamin B12 deficiency and not in folate deficiency prompted us to examine latex-stimulated hexose monophosphate shunt activity in the two conditions. Only two of our five patients with pernicious anemia demonstrated defective activation, while one of the two folate-deficient patients also had this defect. These findings clearly indicate that hexose monophosphate shunt activity is neither consistently impaired in vitamin B12 deficiency nor consistently unaffected in folate deficiency.