[The first to go--physicians who experimented on themselves]. / De gikk først--leger som eksperimenterte på seg selv.

Since ancient times, there have been rules for experiments on humans. Some have claimed that if one thinks an experiment might involve danger, it should first be tried out on oneself. There are, in fact, numerous examples of doctors who have undergone daring experiments on themselves. Among them are Max von Pettenkofer, who drank cholera bacteria, Werner Forssmann who catheterized his own heart, John Paul Stapp, who sat in a rocket sled at almost the speed of sound, and then made an abrupt stop. Doctors from Walter Reed's research team infected themselves with yellow fever, Erik Jacobsen demonstrated the effect of antabuse and alcohol on himself, Barry J. Marshall drank helicobacter pylori bacteria, Klaus Hansen drank heavy water, and Ole Jakob Malm transplanted foreign tissue onto his own skin in order to discern among different tissue types. This article describes these various experiments, why they were done, and their consequences. The perspective of ethics in such experimental research is briefly discussed.

Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype.

OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.

[Individualized pharmacotherapy based on cytochrome P-450 (CYP) genotyping]. / Individualisert farmakoterapi basert på cytokrom P-450 (CYP)-genotyping.

BACKGROUND: Genetic polymorphisms of the drug-metabolising cytochrome P-450 (CYP) enzymes CYP2C9, CYP2C19 and CYP2D6 have been characterized, and several of these variants lead to reduced or absent activity. This is of clinical importance mainly in patients having two non-functional alleles, phenotypically characterised as "poor metabolisers" (1-10% of Caucasians). Since most drugs are transformed into inactive or less active metabolites, "poor metabolisers" are at increased risk of developing drug induced adverse reactions. MATERIAL AND METHODS: Studies of relevant literature (MedLine search) in addition to our own experiences, show that CYP genotyping can predict the phenotype and thereby explain some abnormal drug responses and may be used to individualize pharmacotherapy. RESULTS: At present, CYP genotyping (CYP2C9/2C19/2D6) is most frequently requested in psychiatry and anticoagulant therapy, but the field is expanding. Important factors for implementation of pharmacogenetic methods are accuracy of diagnosis, quality of reports, response time, and cost. INTERPRETATION: Pharmacogenetic analyses will significantly contribute to reducing treatment costs for drug-induced adverse reactions and costs of sick leave, by predicting the best drug and the most effective and safest dosage. The expenses of full genotyping (CYP2C9/2C19/2D6) are equivalent to one day of sick leave. One might ask: Are pharmacogenetic analyses coming to the point where they drive down costs incurred by illness?