Search

The relationship between plasma drug level of venlafaxine and daily intake was studied in 89 major depressive inpatients. In addition, changes over time in severity were assessed weekly in a subgroup of 22 depressed patients using the Montgomery and Asberg Depression Rating Scale (MADRS) and the Clinical Global Impression improvement scale. The results indicate a moderate correlation between daily doses and plasma concentrations, together with a higher relationship between improvement on the MADRS scale and concentration. Moreover, plasma concentrations (for venlafaxine and its predominant metabolite, O-desmethylvenlafaxine) up to 400 microg/l can be considered as effective, as already suggested in a previous study. No case of venlafaxine discontinuation occurred during the longitudinal study, and the incidence of adverse event, as estimated by the Target Emergent Symptoms and Side-effects scale, was low, suggesting that the drug is well tolerated for such plasma concentrations. [ABSTRACT FROM AUTHOR]

The generic term "dioxin" covers more than 400 chemicals of which less than 30 prove to be toxic. Such compounds are involved in environmental pollutions and in food contaminations. Some selected dioxins have also been used as a non-lethal chemical weapon. The assessment of the impact on health needs a precise toxicological identification. Without that basic assessment, a discrepancy may appear between the real risk linked to the exposure and the concerns and fear generated in the population, particularly because in animals the toxic concentrations of dioxins can interfere with some hormonal systems, alter immunity, induce chloracne, and participate in the development of sarcomas, lymphomas and some carcinomas. They may be responsible for some birth defects.

The carcinogenic potential of environmental xenoestrogens (i.e., organochlorines) is a matter of controversy. Their pathogenic role as promoters in breast cancer has been previously suggested. In Europe, despite their prohibition since the '70s, residues persist in soil and rivers resulting in a widespread contamination of the general population. In this study, we have compared the serum levels of p,p'-1,1-dichloro-2, 2-bis (4-chlorophenyl) ethylene (DDE) and hexachlorobenzene (HCB) in 231 women at the time of breast cancer discovery and in 290 age-matched healthy controls. p,p'-DDE was found in 76.2% of cases and in 71.1% of controls but HCB was present only in 12.6% of cases (29 from 231) and in 8.9% of controls (26 from 290). Even if taking all undetectable results (recorded as "0") into consideration, mean values were significantly different in cases when compared to controls. The serum level of p,p'-DDE was 3.46 +/- 3.48 ppb (0.58 +/- 0.58 microg/g lipid) in patients and 1.85 +/- 2.09 ppb (0.31 +/- 0.35 microg/g lipid) in controls (p < 0.0001). The HCB serum level was 0.66 +/-.25 ppb (0.11 +/- 0.21 microg/g lipid) in patients and 0.20 +/- 1.02 ppb (0.03 +/- 0.17 microg/g lipid) in controls (p < 0.0001). When considering p,p'-DDE and HCB as binary variables (1 if higher than the limit of quantification, 0 if lower), the presence of both residues was significantly associated with an increased risk of breast cancer development (OR 2.21, 95% CI 1.41-3.48 for p,p'-DDE and OR 4.99, 95% CI 2.95-8.43 for HCB). No excess was observed among parous women or when familial history of breast cancer was considered. In the cancer group, no differences in serum levels of p,p'-DDE or HCB were found in relation with estrogen-receptor (ER) status, Bloom stage or lymph node metastasis, but the HCB level was moderately correlated with tumor size (p = 0.026).

Most antidepressants are metabolized by cytochrome P450 (CYP) 2D6, and it is well known that there may be significant interindividual variation in the capacity to metabolize xenobiotics. About 7 to 10% of whites are poor metabolisers (PM), and, on the contrary, about 5% are ultrarapid metabolizers (UM), inducing very different rates in the transformation of antidepressants extensively metabolized by CYP 2D6. CYP 2D6 polymorphism can be a potential risk factor for the development of side effects or a reason for the poor efficacy of the treatment. Various probe drugs may be used for phenotyping CYP 2D6, but genotyping is now available using leukocyte DNA and is independent of concomitant drug use. In this study, we used PCR-based methods for the identification of CYP 2D6 genotypes in 49 patients receiving standard doses of fluoxetine or paroxetine and found that plasma concentration of the antidepressant drugs was significantly correlated with genetic status. In one patient who displayed CYP 2D6 gene duplication (UM), paroxetine plasma concentration was extremely low. In PM fluoxetine-treated patients, drug plasma concentration was significantly higher than that seen in extensive metabolizers.

Xenoestrogens such organochlorine pesticides are known to induce changes in reproductive development, function or behaviour in wildlife. Because these compounds are able to modify the estrogens metabolism, or to compete with estradiol for binding to the estrogen receptor, it may be possible that these products affect the risk of developing impaired fertility, precocious puberty or some kinds of cancer in man.

There is an increasing concern about environmental exposure to multiple chemicals and adverse changes in reproductive development, function, or behaviour in wildlife. The major group of environmental chemicals, such as organochlorine pesticides, polychlorinated biphenyls (PCBs) and other xenoestrogens are currently known to have estrogenic effects in vertebrates or fishes. Recent studies suggest that past exposure to such estrogenic compounds may affects the risk of developing breast cancer, precocious puberty, or impaired fertility in man.

Controversy still exists concerning the proper daily dose of methadone to be used in opiate dependency treatment. Because it is admitted that serum methadone concentration may be significantly correlated with the amount of drug available at the receptor level, it could be interesting to predict the methadone daily doses necessary to reach such a serum concentration. The authors have attempted to correlate the serum methadone level with the daily intake, considering the metabolic activity of the patients. A poor correlation was found between methadone doses and methadone serum concentrations (r2 = 0.0409, p = 0.048). The test used to determine the metabolic activity of patients is the 6-OH cortisol/17-OH corticosteroids ratio in urine. This urinary 6-OH cortisol/17-OH corticosteroids ratio was tested because cortisol is metabolized through the same P450 cytochromes as methadone, namely cytochrome P450 3A4. This determination could be of interest because it could be tested before methadone administration to predict optimal doses. But when the authors tried to correlate the methadone serum concentration with the steroid ratio, they failed to find a significant correlation (r2 = 0.0046, N.S.), even when they took into account the daily doses (r2 = 0.0015, N.S.), most probably because of some limitations of the cortisol ratio.

We evaluated the performance of the Emit tox benzodiazepine and barbiturate assays (Dade Behring) and fluorescence polarisation immunoassay (FPIA) (Abbott) for use with serum determinations in preliminary therapeutic drug monitoring or acute drug intoxication detection. Performance, as indicated by CVs, of the Emit tox benzodiazepine and barbiturate assays and FPIA showed that both immunochemical techniques are precise and have good reproducibility. For within-run studies, results from benzodiazepine determinations showed maximum CV values of 1.91% for the Emit method and 2.65% for FPIA; results from barbiturate determinations showed maximum CV values of 2.01% for the Emit method and 1.89% for FPIA. For between-run studies, results from benzodiazepine determinations showed maximum CV values of 1.79% for the Emit method and 1.12% for FPIA; results from barbiturate determinations showed maximum CV values of 2.09% for the Emit method and 2.02% for FPIA.

Depression is a pathology frequently observed in general medicine (10%). Treatment of depression makes great use of drugs from different pharmacological classes. The optimal posology is difficult to establish, and clinicians prefer to avoid side effects by prescribing low regimen. This study is related to an evaluation of seric antidepressant concentrations in comparison with the daily doses in a large psychiatric population. Side effects of drugs are appreciated by enzymatic determinations.

Reduced vitamins K are acting as cofactors of glutamic carboxylation of procoagulant factors (II, VII, IX and X). The reduction of these vitamins is inhibited by oral anticoagulants. The response to antivitamins K is individual and may change during the treatment of a patient. The determinations of plasmatic vitamin K and acenocoumarol may help to explain the mechanism of a resistance to the anticoagulant therapy. Quantifications of vitamin K1 are realized after liquid-liquid extraction with liquid chromatography and fluorescence detection after post-column reduction. For acenocoumarol, plasma concentration is measured, after liquid-liquid extraction, by liquid chromatograph, with ion trap mass spectrometer detector.

Pesticides are widely used to control any pest, including vectors of diseases, unwanted species of plants or animals. They are ubiquitous contaninants of our environment and have been found in water, vegetables, human and animal tissues. Acute or chronic intoxications are well documented. Some pesticides seem to have additive or synergistic effects of oestrogenic compounds, influencing the endocrine functions in several animal species. Moreover, pesticides can induce mutagenesis, carcinogenesis and immunotoxicity.

The objectives of the therapeutic drug monitoring are to assume the efficacy and inocuity of a medical treatment and the patient's observance. The administration of a drug to a patient is not always performed in the same conditions and therefore treatment has to be adapted. When necessary, this one is very often based on empiric or very approximative notions and, more seldom, on results of plasmatic concentrations of the drug. The CAPCIL program allows the possibility to objectivate the medical decision and adapt the posology on the basis of two kinetic parameters: the biological half-life and the distribution volume. Indeed, most of pharmacokinetics modifications (drug interactions, diseases, ...) are affecting the two parameters. With basic informations so as height and weight, posology, treatment objectives and peak/trough plasmatic concentrations of the drug, the program is proposing several posology adaptation schemes. The example of a once-a-day administration of amikacin is discussed.

The BTTS study (Belgian Toxicology and Trauma Study) was performed in Belgium between January 15th 1995 and June 15th 1996. The purpose was to investigate how frequently the drivers involved in road accidents were driving under the influence of psychotropic drugs. Two thousand fifty-three blood tests were performed of which 207 in the Liège region. The results obtained at the national level are compared to those obtained at the level of the Liège region. In both cases, the BTTS study allows the conclusion that a considerable proportion of drivers involved in road accidents resulting in significant traumatic consequences were driving under the influence of substances with psychotropic properties.

The in vivo ability of the specific PAF-antagonist WEB 2086, a thienotriazolodiazepine, to inhibit platelet-activating factor (PAF) in cattle was investigated by in vitro determination of platelet aggregation curves. WEB 2086 was infused intravenously into a group of 5 healthy male Friesian calves in a dose of 3 mg/kg over 1 min. The resultant inhibition peaked between 30 min and 1 h after administration of WEB 2086. The inhibition was significantly reduced after 3 h and became non-significant after 6 h, but maximal pre-treatment aggregation had not been restored by 24 h after the injection of WEB 2086. These results confirm previous results obtained in vitro and suggest that WEB 2086 is a potent antagonist of PAF activity in calves. They also suggest that further clinical studies with WEB 2086 in cattle are desirable.

Immunotoxicity of drugs represents an important problem for 10 to 12% of the overall population. There are 4 types immunotoxicological manifestations of drugs: immediate hypersensitivity, cytotoxic reactions, immune complexes reactions and delayed-type hypersensitivity. The most frequently concerned drugs are penicillins, cephalosporins, anesthetics (type I), erythromycin estolate, nitrofurantoin, sulfonamids, antitubercular agents (type II), quinidine, ticarcillin, valproate, pyramidon (type III) and finally for type IV, topical drugs (antihistaminic products, oestradiol, s.c. heparin).

Tamoxifen is the most often prescribed non steroidal antioestrogenic agent in the world for breast cancer. Worldwide collaboration. has centralized the results, of different trials throughout the world on oral adjuvant therapy in the early stages of breast cancer. A significative regression of the tumour was observed in most cases. Moreover, recent epidemiological studies suggest that tamoxifen could prevent new contralateral primary tumours. The risk of the disease should thus be reduced by the prophylactic use of antioestrogens such as tamoxifen. Investigations using a variety of models have evaluated the effect of tamoxifen on tumour promotion and cell growth. Tamoxifen-induced growth inhibition is associated with major changes in biochemical events in cultured human breast cancer cells including cell proliferation or growth factor production. Growth inhibition of oestrogen-responsive human breast cancer cells is associated with an induced secretion of autoinhibitory polypeptides (TGF beta) and an antagonistic effect on the synthesis of proliferative proteins (TGF alpha,...). The first step in the mechanism of action of the drug is binding of tamoxifen to the oestrogen receptors. Development of resistance to tamoxifen treatment is a great problem in treatment of breast cancer patients and the mechanism of resistance will require further study: under the influence of the drug, tumours could become remodelled as selected subpopulations emerge resistant-tamoxifen. The fact that some breast cancers which are oestrogen receptor-negative respond to antioestrogen suggests that parallel but separate pathways for oestrogen and antioestrogen action may exist. This paper summarizes the results of the most recent studies concerning this promising drug.