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Background:Intraperitoneal (IP) perioperative chemotherapy with cisplatin is an interesting option in ovarian cancer treatment. A combination of cisplatin with IP epinephrine (already shown to improve IP and decrease systemic platinum (Pt) exposure) was evaluated using a population pharmacokinetic analysis.Methods:Data from 55 patients treated with cisplatin-based IP perioperative chemotherapy with (n=26) or without (n=29) epinephrine were analysed using NONMEM.Results:Epinephrine halves clearance between peritoneum and serum (IPCL) and increases the Pt central volume of distribution, IP exposure and penetration in tissue. IPCL has a better predictive value than any other parameter with respect to renal toxicity.Conclusion:This confirms that IPCL could be useful in assessing renal toxicity. As IPCL is also linked to tissue penetration and IP exposure, it may be proposed as biomarker. In addition to a Bayesian estimation, we propose a single-sample calculation-way to assess it. Prospective studies are needed to validate IPCL as a biomarker in this context. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate whether endurance exercise in middle-aged men induces changes in plasma total homocysteine (tHcy) and total cysteine (tCys), and whether these changes depend on the diet especially on vitamin B6, folic acid and vitamin B12 intakes. Methods: Twelve trained subjects (52.33 ± 2.4 years) and twelve untrained subjects (56.23 ± 0.9 years) volunteered for the present study. tHcy and tCys were measured with high-pressure liquid chromatography at rest in both groups and during an incremental exercise performed on a cycle ergometer until exhaustion in the trained subjects. Results: At baseline homocysteinemia and cysteinemia were lower in trained subjects (7.48 ± 0.4 and 183.45 ± 13.6 μmol/l) compared with untrained subjects (9.79 ± 0.4 μmol/l, p < 0.001; 229.01 ±14.7 μmol/l, p < 0.05, respectively). Incremental exercise also induced a decrease in tHcy and tCys concentrations. Moreover, tHcy concentration was negatively related to the folic acid and B12 intakes in untrained (r = –0.589, p < 0.05; r = –0.580, p < 0.05, respectively) as well as in trained groups (r = –0.709, p < 0.01; r = –0.731, p < 0.01, respectively) whereas no correlation between tCys and vitamin in the diet was observed. Conclusion: This study demonstrates that the combined effects of a chronic physical exercise and a high folate and vitamin B12 intake could be responsible for the reduction of plasma tHcy and tCys concentrations that might be a key for the prevention of many diseases. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aims To evaluate the use of the Digene Hybrid Capture™ system, a chemituminescent hybridization assay for the analysis of low and intermediate/high risk human papillomavirus (HPV) DNA, on paraffin-embedded tissues and to investigate possible reasons for reaction failure. Methods Fifty cervical biopsies were tested by an in situ hybridization (ISH) method using probes for HPV 6/11, 16/18, 31/33/51 and by the Digene Hybrid Capture%trade; system. Results The ISH was able to detect HPV in 23 out of the 50 biopsies. Eight samples were positive with the HPV 6/11 probe. 4 with the 16/18 probe. 6 with the 31/33/51 probe and 5 had mixed infections. With the Hybrid Capture™ system. having taken the mixed infections into account, 40 samples gave concordant results. while total and partial discordances were observed in 6 and 4 samples respectively. The relative sensitivity of the new assay was 91.6% and specificity 84.2% for low risk HPVs; and 80% and 94,3% respectively for intermediate/high risk HPVs. Agreement rates on HPV positivity for either low risk or intermediate/high risk types were 86% and 94% respectively in comparison with ISH results. Conclusion The Hybrid Capture™ system is simple. reliable in use and suitable for routine discrimination of HPVs in tissue sections from paraffin-embedded blocks. It might thus be of clinical value in the diagnosis and prognosis of HPV infection. [ABSTRACT FROM AUTHOR]

Objectives. –Studies performed to assess the diagnostic value of tests for hymenoptera allergy are usually designed to validate the test whereas very few have evaluated these tests in routine diagnostic situations. In fact, the diagnostic value of such tests, especially skin prick-tests and basophil histamine release, has rarely been studied systematically in patients referred by their physician to an allergist for confirmation of the diagnosis and recommendations for immunotherapy. The aim of the present study was to assess the diagnostic value of skin prick-tests, specific IgE assay and basophil histamine release in patients referred to an allergy unit for suspected hymenoptera venom allergy. Patients and methods. – Diagnostic tests were done prospectively in 25 consecutive patients with allergic reactions to hymenoptera venom defined by clinical history and positive intradermal skin tests, including patients with a localized or a more extensive skin reaction associated with malaise and/or respiratory symptoms, and in 21 control subjects. The hymenoptera studied included yellow jacket (YJ) and honeybee (HB). The sensitivity, specificity, concordance and predictive values of the tests were calculated.Results. – The observed sensitivity, specificity, and positive and negatives predictive values of skin prick-tests with 100 μg/mL HB venom (in percent) 33.3; 100; 100; and 85.7, respectively, and with 100 μg/mL YJ venom 30; 100; 100 and 85, respectively. For skin prick-tests with 300 μg/mL HB venom the values were 75; 100; 100 and 94, respectively and for skin prick-tests with 300 μg/mL YJ venom 57; 100; 100 and 90.3, respectively. For specific IgE assays, the values for HB were 100; 95.2; 84 and 100, respectively and for YJ 100; 76.2; 51.2, and 100, respectively. For basophil histamine release the values for HB were 89; 100; 100 and 97.3 for YJ they were 94; 89, 6 and 98.4, respectively. Conclusions. – Skin prick-tests with venom concentrations under 300 μg/mL are not sensitive enough for an accurate diagnosis of hymenoptera allergy. Basophil histamine release appears to be a good complementary test but it needs better standardization. [Copyright &y& Elsevier]

The microdialysis expanded mainly in the field of the neuro- and the dermopharmacology with the study of the transmitters released in the central nervous system and derm. Since ten years, this tool gained other disciplines such as cardiology and cardiovascular surgery. Indeed, the collection and the study of the molecules released in the myocardic interstitial fluid without deteriorating it functioning made microdialysis a powerful tool in the study of the extracellular environment of the cardiomyocyte. The purpose of this study is to point out the principle of the microdialysis and to show its various uses in the field of cardiovascular pharmacology. [Copyright &y& Elsevier]

Previous studies indicate that adenosine supplementation or nitric oxide synthase (NOS) inhibition during reperfusion exert protective effects against myocardial ischemia-reperfusion (I/R) injury. We wanted to test the hypothesis that NOS inhibition before I/R also protects the myocardium against further injury and aimed to determine the involvement of adenosine receptors in a perfused rat heart model. Rats were injected with 10 mg/kg of L-NAME (N(omega)-nitro-L-arginine methyl ester) or L-NAME + SPT (8-(p-sulfophenyl)-theophylline)--an adenosine antagonist - at 2 x 25 mg/kg or with a saline buffer, 24 hrs prior to heart excision. The hearts, perfused retrogradely were subjected to 60 min of global ischemia followed by 120 min reperfusion. L-NAME decreased NOx (nitrite and nitrate) production (16.2 +/- 3.2 vs. 7.0 +/- 1.8 micromol/L; P<0.05) in vivo and increased the release of troponin I (0.04 +/- 0.01 vs. 0.02 +/- 0.01 microg/L; P<0.05) in the plasma, compared to controls. After 120 min of reperfusion, there was a higher release of adenosine (26.1 +/- 2.2 vs. 2.4 +/- 1.2 nmol/min; P<0.01) and a decrease in troponin I levels (0.19 +/-0.07 vs. 0.59 +/- 0.16 ng/min; P<0.05) in the L-NAME group compared to controls. These results were accompanied by a higher proportion of recovery of left ventricular developed pressure (72.0 +/- 4.0 vs. 60.0 +/- 4.0%; P<0.05) and coronary flow (72.0 +/- 5.0 vs. 51.0 +/- 4.0%; P<0.05) in the L-NAME group. These beneficial effects were not blocked by the adenosine receptor antagonist. The present study reveals that L-NAME protects against I/R injury when the inhibitor is administered 24 hrs before ischemia. The beneficial effects observed in this model appear to be independent of adenosine receptor stimulation.

Background: Reactive oxygen species generated by ultraviolet light result in photocarcinogenic and photoaging changes in the skin. Antioxidants protect the skin from these insults., Objective: The aim of this study was to determine the ex vivo ascorbic acid penetration and its degradation in the skin after its topical application from an 8% new formulation., Method: Ascorbic acid was applied to human skin fragments. Ascorbic acid and its metabolites were collected by microdialysis and assessed by gas chromatography mass spectrometry., Results: After topical application of the new formulation, the ascorbic acid level achieved was 8.5% higher than [corrected] times the normal tissue value. This high ascorbic acid dermal concentration remained constant if a topical application was made every 8 h. No degradation of ascorbic acid was detected., Conclusion: Ascorbic acid penetrates rapidly after its topical application. The persistent reservoir of ascorbic acid provides an important and attractive photoprotection strategy., (2004 S. Karger AG, Basel.)

The genetic polymorphism of human N-acetyltransferase 2 (NAT2) divides the human population into groups with rapid, intermediate and slow acetylator status. Slow acetylator status has been considered a predisposing factor for allergic diseases, lupus erythematosus, toxic epidermal necrolysis or Stevens-Johnson syndrome. The aim of this study was to investigate whether Caucasian patients suffering from atopic dermatitis differed from healthy individuals with regard to the genotype and phenotype of NAT2. Twenty unrelated healthy Caucasian volunteers (9 females and 11 males, aged from 22 to 59 years) and twenty unrelated Caucasian patients suffering from atopic dermatitis (9 females and 11 males, aged between 20 and 54 years) participated in this study. For each one, the NAT2 genotype was determined by polymerase chain reaction with DNA extracted from peripheral blood, using specific primers for the wild-type allele (wt) and the 3 most frequent mutated alleles of NAT2 (C481-->T, G590-->A and G857-->A). The NAT2 phenotype was evaluated with dapsone as a test substrate using high-pressure liquid chromatography. Statistical analysis was performed using the chi(2) test. Phenotype and genotype were distributed as follows: (1) of the healthy subjects, 60% were rapid acetylators (RA) and 40% were slow acetylators (SA); 10% of the RA and 15% of the SA were homozygous, 50% of the RA and 25% of the SA were heterozygous; (2) of the patients, 55% were RA, 40% were SA and 5% were intermediate acetylators (IA); 10% of the RA and 10% of the SA were homozygous, 45% of the RA and 35% of the SA were heterozygous. No significant statistical difference was found between the two groups for genotypes (p = 0.75) or phenotypes (p = 0.60). The phenotyping and genotyping results of healthy subjects were comparable to those found in previous studies. The absence of a significant statistical difference between healthy subjects and atopic dermatitis patients is in contrast to the results of previous studies. Some authors considered that allergic patients are mostly SAs. This could be explained by the fact that we only considered patients suffering from atopic dermatitis whereas, in other studies, patients suffered from different (one or several associated) allergic diseases. NAT2 polymorphism does not differ between patients suffering from atopic dermatitis and healthy subjects. The importance attributed to the SA status, which was previously considered a predisposing factor for allergic diseases such as atopic dermatitis, should be reviewed., (Copyright 2003 S. Karger AG, Basel)

The evolutions in treatments and clinical practices in organ transplantations led to modifications in the therapeutic drug monitoring (TDM) of immunosuppressive drugs. A focus is made regarding the C2 sampling of cyclosporin, as well as the TDM of mycophenolate mofetil and sirolimus. A review of literature about the evolution of drug monitoring, technical methods and sampling strategies is described. Arguments in favour of TDM are thus a decrease in the frequency of both graft rejection and adverse drug reactions, however, new strategies or new targets are needed in new associations or indications.

Background: Our purpose was to determine the effects of amifostine, a cytoprotective agent, on doxorubicin tolerance and cardiotoxicity in rats., Materials and Methods: Male Wistar rats were treated every other day with an intraperitoneal injection of amifostine or saline 30 minutes before intraperitoneal injection of doxorubicin or saline. Weight change was recorded, and contractile function was evaluated after 11 injections by means of the isolated heart., Results: Weight evolution and cardiac function were significantly improved by 7 and 20 mg/kg amifostine (p < 0.001) but not by 50 mg/kg. The final weight were: controls 349 +/- 16 g; doxorubicin alone 258 +/- 54 g; with amifostine: 7 mg/kg 314 + 28 g; 20 mg/kg 312 +/- 32 g; 50 mg/kg 250 +/- 34 g. Left ventricular developed pressure were: controls 137 +/- 15 mmHg; doxorubicin alone 119 +/- 20 mmHg; with amifostine: 7 mg/kg 140 +/- 20 mmHg; 20 mg/kg 137 +/- 25 mmHg; 50 mg/kg 124 +/- 20 mmHg., Conclusion: Seven and 20 mg/kg amifostine protected rats from the toxicity of doxorubicin at the cumulative dose of 18 mg/kg during a 12-day treatment, with regard to weight loss and heart contraction.

The therapeutic drug monitoring aims at optimising the prescribed dosages to improve efficacy and prevent toxicity. The aim of this study were to review the main pharmacodynamic and pharmacokinetic properties of aminoglycosides, glycopeptides and ceftazidime. Then, the therapeutic drug monitoring of these antibiotics and their methods of analysis is reviewed.

This study aimed at evaluating the role of nitric oxide (NO) when generated 24 h prior to ischemia-reperfusion. Three groups were studied in an isolated buffer-perfused heart model: Control (saline = 3.3 mL/kg, n = 10), the precursor of NO, L-arginine, (500 mg/kg, n = 10) and an inhibitor of NO synthase, L-NAME, (10 mg/kg, n = 9). All groups were injected intraperitoneally 24 h before heart extraction. Nitrites, nitrates (an index of nitric oxide release) and cardiac troponine I were assayed. During the reperfusion period, there was a low release of nitric oxide and cardiac troponine I associated with improved recovery of post-ischemic myocardial function. These results indicate that in this model, the pre-treatment improved myocardial function and thus, NO could play a role as a trigger and not as a mediator of cardioprotection.