Clinical pharmacokinetics and pharmacodynamics of ifosfamide and its metabolites

This review discusses several issues in the clinical pharmacology of the antitumour agent ifosfamide and its metabolites. Ifosfamide is effective in a large number of malignant diseases. Its use, however, can be accompanied by haematological toxicity, neurotoxicity and nephrotoxicity. Since its development in the middle of the 1960s, most of the extensive metabolism of ifosfamide has been elucidated. Identification of specific isoenzymes responsible for ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways. Whether ifosfamide is specifically transported by erythrocytes and which activated ifosfamide metabolites play a key role in this transport is currently being debated. In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood. Assessment of the pharmacokinetics of ifosfamide and metabolites has long been impaired by the lack of reliable bioanalytical assays. The recent development of improved bioanalytical assays has changed this dramatically, allowing extensive pharmacokinetic assessment, identifying key issues such as population differences in pharmacokinetic parameters, differences in elimination dependent upon route and schedule of administration, implications of the chirality pf the drug and interpatient pharmacokinetic variability. The mechanisms of action of cytotoxicity, neurotoxicity, urotoxicity and nephrotoxicity have been pivotal issues in the assessment of the pharmacodynamics of ifosfamide. Correlations between the new insights into ifosfamide metabolism, pharmacokinetics and pharmacodynamics will rationalise the further development of therapeutic drug monitoring and dose individualisation of ifosfamide treatment

Alcohol use, cigarette consumption and chronic post-traumatic stress disorder

Aims: The relationship between alcohol consumption, cigarette smoking and post-traumatic stress disorder (PTSD) was studied in 147 male former members of the civilian resistance against the Nazi occupation of Holland during World War II. Methods: The subjects were interviewed at home. Measures included rating of current PTSD and a self-report measure of smoking and alcohol use. Results: The weekly alcohol consumption reported by veterans was substantially below that of the general population. Furthermore, there was no significant difference in self-reported alcohol consumption between veterans with and without current PTSD. Cigarette smoking, however, was more prevalent in those with current PTSD. Conclusions: The absence in these veterans of a correlation between PTSD and alcohol consumption is contrary to the results of most studies on this subject. It may be related to the exclusion from organized resistance activities of people prone to the over-consumption of alcohol. It is hypothesized that, in trauma survivors, current substance use is associated with peri-traumatic patterns of psychological tension-reduction modes