Dramatic inhibition of amiodarone metabolism induced by grapefruit juice.

AIMS: Grapefruit juice increases blood concentrations of many drugs metabolized by CYP3A. Amiodarone is metabolized by CYP3A to N-desethylamiodarone (N-DEA). The aim of this study was to determine amiodarone kinetics when administrated with and without grapefruit juice. METHODS: Eleven healthy adult volunteers took part in a single sequence, repeated-measures design study. Each subject, who had been evaluated 6 months previously for amiodarone pharmacokinetics, was given a single oral dose of amiodarone (17 mg kg-1) with three glasses of 300 ml of grapefruit juice on the same day. RESULTS: Grapefruit juice completely inhibited the production of N-DEA, the major metabolite of amiodarone, in all subjects and increased the area-under-the-curve (AUC) and maximum concentration of amiodarone (Cmax) by 50% and 84%, respectively, as compared with the control period during which water had been administrated instead of grapefruit juice (AUC: 35.9 +/- 14.3 vs 23.9 +/- 11.2 microg ml-1 h, P < 0.005 and Cmax: 3.45 +/- 1.7 vs 1.87 +/- 0.6 microg ml-1, P < 0. 02, respectively) (means +/- s.d.). This inhibition of N-DEA production led to a decrease in the alterations caused by amiodarone on PR and QTc intervals. CONCLUSIONS: Grapefruit juice dramatically alters the metabolism of amiodarone with complete inhibition of N-DEA production. These results are in agreement with in vitro data pointing to the involvement of CYP3 A in the metabolism of amiodarone and suggests that this interaction should be taken into account when prescribing this antiarrhythmic drug.

Genotypic and phenotypic analysis of the polymorphic thiopurine S-methyltransferase gene (TPMT) in a European population.

1. Characterization of allelic variants of the TPMT gene (TPMT) responsible for changes in TPMT activity, and elucidation of the mechanism by which these alleles act, are required because of the clinical importance of this polymorphism for patients receiving thiopurine drugs. 2. We defined the mutational and allelic spectrum of TPMT in a group of 191 Europeans. Using PCR-SSCP, we screened for mutation the entire coding sequence, the exon-intron boundaries, the promoter region and the 3'-flanking region of the gene. Six mutations were detected throughout the ten exons and seven TPMT alleles were characterized. Four of them, TPMT*2, *3A, *3C and *7, harbouring the known mutations, G238C, G460A, A719G or T681G, were nonfunctional and accounted for 0.5, 5.7, 0.8 and 0.3% of the allele totality, respectively. 3. Within the promoter region, six alleles corresponding to a variable number of tandem repeats (VNTR), were identified. VNTR*V4 and *V5a which harbour four or five repeats of a 17-18 bp unit, were the most frequent (55% and 34%, respectively). The other VNTR alleles, having from five to eight repeats, were rarer. 4. The TPMT phenotype was correctly predicted by genotyping for 87% of individuals. A clear negative correlation between the total number of repeats from both alleles and the TPMT activity level was observed, indicating that VNTRs contribute to interindividual variations of TPMT activity. Therefore, additional analysis of the promoter region of TPMT can improve the phenotype prediction rate by genotyping.

Costs of HIV+/AIDS at CD4+ counts disease stages based on treatment protocols.

We report treatment protocols for HIV+/AIDS patients by CD4+ counts (T-lymphocyte cells/mm3: > or = 500, 499-200, 199-50, and < 50) as a tool to provide better definition and to project annual costs (total charges for services) and lifetimes costs for HIV+/AIDS. The treatment protocols, derived from the literature and an HIV+/AIDS Physician Panel, defined the resource use associated with antiretroviral therapy and opportunistic disease prophylaxis and treatment. Resource use costs were derived from the published literature, insurance database, Medicare fee schedules, surveys, and the Physician Panel. At CD4+ counts, the rates of opportunistic diseases were derived from the Physician Panel experience; the mean occupancy times were derived from the literature. The sensitivity analysis indicated stability of the lifetime costs to variation in mean occupancy times, rates of opportunistic diseases, rates of adverse events (AE), and costs. The total annual costs (1995 dollars) of HIV+/AIDS patients ranged from $1,934 (> or = 500), $6,015 (200-499), and $9,031 (50-199), to $25,239 ( < 50). The annual costs of opportunistic diseases are esophageal candidiasis (EC) ($2,194), tuberculosis (TB) ($2,924), cryptococcal meningitis (CM) ($17,264), toxoplasmosis ($17,631), Mycobacterium avium complex (MAC) (+20,153), Non-Hodgkin's lymphoma (NHL) ($22,329), wasting syndrome ($26,676), central nervous system (CNS) lymphoma ($27,333), Pneumocystis carinii pneumonia (PCP) [mild ($3,545), moderate ($4,889), and severe ($32,609)], Kaposi' sarcoma (KS) [mild/moderate ($5,902), and severe ($10,744)], and cytomegalovirus (CMV) retinitis ($100,337). The projected lifetime costs of HIV+/AIDS are $94,726 (annual costs $7,645). Our lower lifetime costs as compared with recent estimates may be due to including resources only for HIV+/AIDS-related treatment and not for non-HIV+/AIDS conditions, as well as reduced resource use resulting from more efficient diagnostic and therapeutic techniques and earlier prophylaxis provided by experienced HIV+/AIDS physicians. Nonetheless, our estimates are consistent with decreasing costs of HIV+/AIDS due to a reduction in the average length of stay and frequency of hospitalizations as well as to replacement of inpatient care by outpatient services.