[Resistance to vitamin K antagonist revealing interaction with soy lecithin]. / Résistance aux antivitamines K révélant une interaction avec la lécithine de soja.

Vitamin K antagonists (VKA) are difficult to use because of a narrow therapeutic index and of a marked inter- and intra-individual variability among patients in the required dosage. This drug may interact with many other drugs and same with certain food compounds. We report the case of potential interaction between soy lecithin and Vitamin K antagonists in a 46 years-old woman. Subtherapeutic INR values were detected despite the increase gradually in dose and replacing acenocoumarol by fluindione. An enquiry of pharmacovigilance was conducted found the consumption of soy lecithin capsules. Fifteen days after its stopping, the INR values have really increased. Clinicians should think to the possibility of interaction between oral anticoagulants and food supplement that is increasingly used.

Methyl thiophanate-induced toxicity in liver and kidney of adult rats: a biochemical, molecular and histopathological approach.

The aim of this study was to elucidate the redox effects of Thiophanate methyl (MT) in the rat liver and kidney. Our results showed, after 3 days of MT injection (700 mg/kg), an increase in malondialdehyde (MDA), hydrogen peroxide and advanced oxidation protein products levels. Glutathione peroxidase and superoxide dismutase activities were also remarkably increased in the liver but decrease in the kidney. Glutathione and vitamin C values were significantly reduced. The changes in biochemical parameters were substantiated by histological and molecular data. A smear without ladder formation on agarose gel was shown, indicating random DNA degradation in the liver and the kidney of MT treated rats. The increase in cyclooxygenase-2 gene expression, marker of inflammation, and an increase in genes expression of glutathione peroxidase and superoxide dismutase in liver and their decrease in the kidney were also occurred after MT exposure. These data confirmed the pro-oxidant and genotoxic effects of this fungicide.

Influence of age and co-medication on the steady-state pharmacokinetics of valproic acid in Tunisian patients with epilepsy.

AIM: Valproic acid (VPA) is a widely prescribed broad-spectrum antiepileptic drug. However, the use of VPA is complicated in clinical practice by its remarkably wide variability of pharmacokinetics. The objective of this study was to investigate the effects of demographic factors and associated therapies on steady-state plasma VPA concentrations in patients with epilepsy. METHODS: This retrospective cohort study was carried out using the routine therapeutic drug monitoring (TDM) database. Stepwise logistic regression analysis was used to compare serum VPA levels in 78 epilepsy patients treated with VPA in association with at least one other drug that could have interacted with CYP2C9, CYP2C19 or UGT enzymes. RESULTS: The frequency of subtherapeutic serum VPA levels was significantly increased with younger age (P<0.02), the number of co-medications (P<0.007) and use of enzyme-inducing co-medications (P<0.02). No significant correlations between VPA dose and trough plasma concentrations were found, as the latter did not increase in proportion to the dose. CONCLUSION: Routine monitoring of VPA serum levels would be extremely useful in epilepsy patients in the pediatric age group and in those who require associated enzyme-inducing medications.

Ameliorative effects of vanillin on potassium bromate induces bone and blood disorders in vivo.

The objective of this study was to investigate the propensity of potassium bromate (KBrO3) to induce oxidative stress in blood and bone of adult mice and its possible attenuation by vanillin. Our results demonstrated, after KBrO3 treatment, a decrease of red blood cells and hemoglobin and a significant increase of white blood cell. A decrease in plasma levels of folic acid, vitamin B12 and iron was also noted. Interestingly, an increase of lipid peroxidation, hydroperoxides, hydrogen peroxide, advanced oxidation protein products and protein carbonyl levels in erythrocytes and bone was observed, while superoxide dismutase, catalase and glutathione peroxidase activities and glutathione, non-protein thiol and vitamin C levels were decreased. KBrO3 treatment resulted in blood and bone DNA fragmentation, a hallmark of genotoxicity-KBrO3-induced, with reduction of DNA levels. Calcium and phosphorus levels showed a decrease in the bone and an increase in the plasma after KBrO3 treatment. These biochemical alterations were accompanied by histological changes in the blood smear and bone tissue. Treatment with vanillin improved the histopathological, hematotoxic and genotoxic effects induced by KBrO3. The results showed, for the first time, that the vanillin possesses a potent protective effect against the oxidative stress and genotoxicity in bone and blood of KBrO3-treated mice.

Mucosal lichenoid drug reaction associated with glimepiride: a case report.

We report the case of a 52-year-old man with type 2 diabetes, who developed severe mucosal erosions of the tongue, glans penis and perianal area, induced by glimepiride. A tissue biopsy was performed and revealed the characteristics of lichen planus (LP). The improvement of the patient's condition after withdrawal of glimepiride added to recurrence of the lesions when medication was reintroduced confirmed that the second generation anti-diabetic was the causative agent. To the best of our knowledge, this has not been reported previously.

Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis.

SETTING: Antituberculosis drug-induced hepatitis attributed to isoniazide (INH) is one of the most prevalent drug-induced liver injuries. INH is metabolized by hepatic N-acetyltransferase 2 (NAT2) to form hepatotoxins. AIM: To evaluate whether polymorphism of the NAT2 gene was associated with antituberculosis drug-induced hepatotoxicity in Tunisian patients. METHODS: A total of 66 patients with tuberculosis (TB) who received anti-TB treatment were followed prospectively. Their NAT2 genotype was determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). We identified three single nucleotide polymorphisms (SNPs); 481C to T (NAT2*5B), 590G to A (NAT2*6A) and 857G to A (NAT2*7B). Univariate analysis and logistic regression analysis were used to evaluate the risk factors of isoniazid-induced hepatitis. RESULTS: Fourteen patients (21.2%) were diagnosed with anti-TB drug-induced hepatitis. None of the rapid acetylators-type patients have expressed serum aminotransferase elevation. Among patients with hepatotoxicity, slow acetylators-type patients had a higher risk of hepatotoxicity than intermediate acetylators (21.4% vs. 78.6%, P=0.01). Statistical analysis revealed that the frequency of a variant diplotypes, NAT2*5B/5B and NAT2*6A/6A, were significantly increased in TB patients with hepatotoxicity, compared with those without hepatotoxicity (P=0.01, odds ratio [OR]=7.6 and P=0.029, OR=15, respectively). By contrast, the frequency of the rapid acetylation NAT2*4 allele was significantly lower in TB patients with hepatotoxicity than those without hepatotoxicity (P=0.02, OR=0.18). Moreover, 590G/G genotype was associated with decreased hepatotoxicity (P=0.01); by contrast, homozygous point mutation at position 481 and 590 were associated with a higher risk of hepatotoxicity (P=0.01). CONCLUSION: Our results suggest that the slow-acetylator status of NAT2 is risk factor for INH-induced hepatotoxicity. Moreover, diplotypes, NAT2*5B/5B, NAT2*6A/6A, 481T/T and 590A/A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

[Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses]. / Relation entre les concentrations plasmatiques d'acide valproïque et la survenue d'une hépatotoxicité.

INTRODUCTION: Valproic acid (VPA) is an anticonvulsivant drug widely prescribed in the treatment of many forms of generalized epilepsy. In literature, the incidence of liver damage induced by AVP is 0.01%. It is potentialized by the combination therapy (phenobarbital, carbamazepine). Severe hepatotoxicity is rare and appears to be independent of dose and to cause a high mortality. METHODS: The aim of our study was to evaluate the relationship between plasma concentrations of AVP and the occurrence of side effects especially hepatotoxicity in patients receiving high doses of AVP. RESULTS: In this period, 425 plasmatic AVP monitoring were carried out in our laboratory. From 128 patients treated by high doses of AVP, only 73 were included in this study. Our work showed that adverse effects in epileptics under high doses of AVP was related to the association of the AVP with other antiepileptic in particular carbamazépine, phenobarbital and benzodiazepines rather than supra-therapeutic plasmatic concentrations of AVP. The association of AVP to major antiepileptics (carbamazépine and or phenobarbital) does not seem to generate an increase in the plasmatic concentration of AVP, which was not associated with a greater risque of adverse effects. CONCLUSION: Consequently, clinical signs of liver toxicity may be present in AVP concentrations generally considered in the therapeutic range especially when used in high doses and or combined with antiepileptic drugs like phenobarbital or carbamazepine.

Les effets indesirables dus aux antibiotiques : etude retrospective sur trois ans au centre regional de pharmacovigilance de Sfax

Les effets indesirables aux antibiotiques constituent un reel probleme de sante publique. Dans ce travail; ont ete analyses la frequence; les types; les facteurs predisposant et la gravite des effets indesirables aux antibiotiques. Notre etude; de type retrospectif; porte sur les cas d'effets indesirables aux antibiotiques obtenus par notification spontanee au centre regional de pharmacovigilance de Sfax durant une periode de trois ans. Parmi 249 cas d'effets indesirables medicamenteux; 82 cas (32;93) ont ete lies aux antibiotiques. L'age variait de 5 a 86 ans. Il s'agissait de 55 femmes et de 27 hommes. Soixante dix effets indesirables lies aux antibiotiques (85.36) parmi 82 etaient de nature immunoallergique. Dans 60 cas (73.17); les patients avaient des antecedents medicaux: atopie; allergie medicamenteuse; maladies auto-immunes ou pathologies chroniques necessitant une polymedication. 54 patients (65.85) prenaient 3 medicaments ou plus. Les formes graves ont ete observees chez 12 patients parmi 82 (14.63). La polytherapie; les maladies chroniques et l'age avance sont des facteurs favorisant la survenue des effets indesirables aux antibiotiques. Nos resultats soulignent le risque augmente chez les sujets ayant un antecedent d'allergie a un antibiotique de developper une allergie a un autre antibiotique

[Medication adherence of a sample of hypertensive patients in the region of Sfax (Tunisia)]. / Observance médicamenteuse chez un échantillon d'hypertendus dans la région de Sfax (Tunisie).

THE AIM OF THE STUDY: Medication noncompliance is one of the daily problems of the physician. Improving the medication adherence allows better management of hypertension. The aim of this work was to determine the level of compliance for patients with hypertension and to identify factors that determine compliance. METHODS: A cross-sectional study was carried out among a sample of hypertensive patients attending general and specialist practitioners in public or private clinics of Sfax. Two hundred and seventy-three participants had accepted to be interviewed. Patients were identified as noncompliants using a questionnaire developed by the Comité de lutte contre l'hypertension artérielle (CFLHTA). RESULTS: Non-compliance rate was 63.4%. The low level of education was associated with a lower adherence. The monotherapy, the once-daily regimen with fewer number of tablets were associated with a better adherence (p<10(-6)). The welcome and the availability of drugs in the public clinic affect positively the adherence of patients (p<0.0002). A patient very satisfied with his consultation and the explanation given by the doctor about his illness and its treatment had a better adherence (p<0.00003). CONCLUSION: Our study had demonstrated a low compliance with antihypertensive drug therapy. Tunisian health care system should elaborate a management plan which takes into account our particular predictors of compliance to improve adherence to antihypertensive medication.

Investigation of the microcirculation and the state of oxidative stress in the rat after scorpion envenomation.

1. Severe cases of scorpion envenomation (SE) generally show both respiratory and cardiocirculatory dysfunction. However, the pathophysiology of SE remains controversial. In the present study, we tried to explain the pathophysiology of the haemodynamic perturbations and cardiac failure in rats poisoned by the venom of Buthus occitanus tunetanus through a histomorphometric study of myocardial and muscular skeletal microcirculation and analysis of the oxidative stress state in order to evaluate the implication of the inflammatory process in the pathogenesis of SE. 2. Experiments were performed on 96 rats divided into 16 groups (n = 6 in each group). Two groups were used to determine the optimum conditions of venom administration and times when to measure haemodynamic parameters. The B. occitanus tunetanus venom was administered at a dose of 800 microg/kg and tissues were removed 5 and 20 min after envenomation. Six groups were used for histomorphometric study: two control groups, two poisoned groups an two melatonin-pretreated and poisoned groups. The histomorphometric study was performed on isolated hearts and skeletal muscles. The final eight groups of rats (two control groups, two envenomated groups, two control groups pretreated with melatonin and two groups pretreated and envenomated) were used to investigate the state of tissue oxidative stress during SE and to evaluate the anti-oxidant effect of melatonin on rats poisoned with B. occitanus tunetanus venom. This study was based on the determination of tissue malondialdehyde in isolated organs as an indicator of thiobarbituric acid-reactive substances (TBARS). Melatonin was injected at a dose of 5 mg/kg, i.v., 15 min before the administration of serum or venom. Data were compared using analysis of variance and Tukey's test for multiple pair-wise comparisons. 3. Five minutes after venom injection, a significant reduction in the mean relative volume of venules and arterioles in the heart and skeletal muscles of poisoned rats was noted. Twenty minutes after venom injection, these volumes were significantly increased in the heart and skeletal muscles of poisoned rats. Pretreatment of envenomated rats with melatonin resulted in a significant decrease in the mean relative volume of the venules and arterioles in the heart and skeletal muscles 5 and 20 min after venom injection compared with untreated envenomated rats. Investigation of the oxidative stress state showed a highly significant increase in TBARS in poisoned rats compared with control groups 5 and 20 min after venom injection. Melatonin pretreatment of rats poisoned with B. occitanus tunetanus venom resulted in an important and highly significant reduction of TBARS compared with untreated envenomated rats. 4. It appears from the results of the present study that administration of B. occitanus tunetanus venom engendered an excessive myocardial and skeletal muscular vasoconstriction attributed to massive catecholamine release followed by arteriolar and venular vasodilatation. This venous stasis at the muscular microcirculation could be due to myocardiac failure. However, the concomitant presence of arteriolar vasodilatation suggests an inflammatory process in the pathophysiology of SE. This process was suggested by the genesis of a state of oxidative stress in relation to the important lipoperoxidation, which was inhibited by administration of the anti-oxidant melatonin. Thus, melatonin pretreatment seemed to accentuate the first phase of vascular reactivity in envenomed rats and inhibit the second vasodilator phase observed 20 min after administration of the venom.

Scorpion envenomation symptoms in pregnant women

Scorpion envenomation is common in many countries; however, its effects on pregnancy are still unclear. In the present paper, we described the effects of scorpion envenomation on pregnant patients. A retrospective study was carried out considering the clinical and laboratory exams of patients admitted to the emergency room of Habib Bourguiba Hospital, Sfax, Tunisia, from 1990 to 2004. Variability of these clinical and laboratory profiles according to maternal age, gestational age and number of previous parities was also discussed. Among 167 scorpion-envenomed women, age ranged from 17 to 42 years, 7.18 percent were pregnant. These presented symptoms similar to those of non-pregnant women envenomed by scorpions. Two pregnant patients developed intense pelvic pain and one manifested vaginal bleeding. Although the studied parameters showed non-significant differences, we could conclude that scorpion envenomation may lead to abnormal uterine contraction probably causing preterm delivery. Maternal disturbances induced by scorpion envenomation may influence the fetus development. The effects were more severe in the second trimester of pregnancy.(AU)

[Hemodynamics and microcirculation in a rat poisoned by scorpion venom]]. / Etude de l'hémodynamique et de la microcirculation chez le rat envenimé par le venin du scorpion.

The clinic table of serious scorpionic envenimation is dominated by cardiovascular and pulmonary perturbations. The physiopathology of cardiac failure in man as well as at animal is again badly elucidated. The aim of our study has consisted in evaluating the hemodynamic variations of the Rat poisoned by the venom of the Buthus occitanus scorpion and to contribute through the analyse of plasmatic concentrations of catecholamines and by an histomorphometric study of muscular microcirculation to explain the mechanism of the hemodynamic perturbations and cardiac failure. 51 rats corresponding to 9 groups (witness and poisoned) have been used. The venom of the scorpion Buthus occitanus has been administrated at 850 micrograms/kg. Two groups have been served for hemodynamic study, three groups for the dosage of catecholamines and four groups for histomorphometric study. It has been observed a biphasic variation of arterial pressure and cardiac frequency after venom injection. Four minutes after envenimation, the plasmatic level of catecholamines was strongly higher in the poisoned according to the witness one. Histomorphometric study of muscular skeletal microcirculation has shown a decrease of relative vascular volume contemporary with the increase of plasmatic catecholamines concentration and the peak of arteriel pressure appeared just after envenimation. 10 and 20 minutes after envenimation, the relative vascular volume has significantly increased as well as that interstitium according to witness lot. These hemodynamic perturbations can be attributed to the important dump in catecholamines. This hyperadrenergy was contemporary with decrease of relative muscular vascular volume. This decrease would be explained by a constriction of vessels. On the other hand, the second increase of the vascular relative volume suggests the possibility of development of venous stasis at the muscular microcirculation. It would be induced by a cardiac failure and/or the effect of vasoplegic mediators being able to entail an interstitial oedema in the muscular skeletal that would led to increase the relative interstitial volume observed in this study.

Characterization and mechanisms of the cardiovascular and haemodynamic alterations induced by scorpion venom in rats.

The scope of this work was to investigate the nature, chronology and mechanisms of the cardiovascular disorders induced by scorpion envenomation. Anaesthetized rats were instrumented for measurement of cardiac output (CO), renal (RBF) and muscular (HBF) blood flows (pulsed Doppler flowmetry), blood pressure, heart rate and dP/dt. Buthus occitanus venom (BO) was administered intravenously in the absence/presence of different pre-treatments. BO dose-dependently (150-300 microg/kg) increased blood pressure, dP/dt, total peripheral (TPR), renal (RVR) and muscular (HVR) vascular resistances, and decreased CO, RBF and HBF. Recovery occurred after 150 but not after 300 microg/kg. BO, 600 microg/kg, produced qualitatively similar effects but arrhythmias developed and mortality increased. Pre-treatment with phentolamine prevented the rises in TPR, RVR, HVR and blood pressure and the decreases in CO, RBF and HBF induced by BO, 300 microg/kg. Pre-treatment with propranolol prevented the rise in dP/dt and the occurrence of arrhythmias and limited the rise in RVR and the drop in RBF induced by BO, 300 microg/kg. Phentolamine, propranolol and their combination also prevented BO, 600 microg/kg-induced mortality. Other pre-treatments (bosentan, losartan, diltiazem, mepyramine) were almost ineffective vs. BO effects. Finally, BO, 300 microg/kg, induced a 30-40-fold increase in plasma epinephrine and norepinephrine levels, but no change in plasma endothelin-1 levels. Thus in anaesthetized rats, the pattern of the cardiac and systemic and regional haemodynamic effects of BO is typically that of and results from catecholamine outpouring-induced alpha- and beta-adrenoceptor stimulation.

[Free radicals and antioxidants: physiology, human pathology and therapeutic aspects (part II)]. / Radicaux libres et anti-oxydants: physiologie, pathologie humaine et aspects thérapeutiques (ilème partie).

Although they are considered as destructive agents, free radicals can sometimes become useful. Their presence is intimately coupled with the activity of certain hemal oxydases which insert an atom of oxygen into their substrate by a stereospecific radical mecanism. The cytochromes P450 and the enzymes of the eicosanoide metabolism are some examples. The free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract or to infer a myorelaxation. They can even play the role of neurotransmitters such as azote monoxyde. The activation of phagocytes, which is an essential event in the inflammatory reaction, integrates these notions at several levels: in the mechanisms of bacterial death, in the spread of the inflammatory reaction and in the alteration of the extra-cellular matrix. The inflammatory reaction is initiated by interactions between vascular endothelium, platelets and leukocytes including signal exchanges, adhesion molecule expression and secretion of chimiotactic mediators. Activation of vascular endothelium is a key event in the initiation of the phenomenon. The cells intervening in the precocious inflammatory phase were tissular mastocytes and platelet-liberating mediators (histamine) and neutrophile cells responsible for vascular injuries induced by oxygen free radicals and nitric oxide. Reactive oxygen intermediates play a critical role, primarily to limit tissue damage and prevent or inhibit infection, secondary to enhancing and prolonging reaction. The monocytes and platelets liberate cytokines early, which appears to be important in activation and production of an inflammatory response. In fact, cytokines, especially TNF alpha and IL-1, induce synthesis and secretion endothelial adhesion molecules such as ICAM-1, VCAM-1 and E-selectin, which have been demonstrated to mediate leukocyte recruitment to sites of inflammation. The cytokines also activate the fibroblasts and endothelial cells that produce, among others, free radicals and other chimiotactic cytokines of which some (IL-8 and related) can induce neutrophil degranulation and stimulate oxidative stress and formation of free radicals. Furthermore, endothelial cells have been shown to make use of a broad repertoire of cytokines including IL-1, IL-6, IL-8, MCP-1 and gro/MGSA, which may be secreted during an inflammatory response and exercise pro-inflammatory functions. Under the influence of the inflammatory mediators, other enzymes are also activated. The inducible isoforms of cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) play an important role in inflammatory reactions via the production respectively of prostaglandins and nitric oxide. The induction of cell adhesion molecules (ICAM-1, VCAM-1 and E-selectin), cytokines, acute phase proteins, growth factors, COX-2 and iNOS expression is mediated by the activation of transcriptional factors, especially the nuclear factor kappa B (NF-kappa B). The NF-kappa B system is essentially involved in immediate early expression of various immunoregulatory genes and has been demonstrated to represent an important regulatory system of endothelial activation. The target genes for NF-kappa B comprise a growing list of genes intrinsically linked to a coordinated inflammatory response. The NF-kappa B is a heterodimer composed of two subunits (p65 and p50). In non-stimulated cells, NF-kappa B resides in the cytoplasm as an inactive complex bound to its inhibitor, I kappa B. Upon stimulation with various agents including cytokines, mitogenes, viruses and reactive oxygen intermediates, I kappa B dissociates from the NF-kappa B-I kappa B complex and translocates to the nucleus, binding with high affinity to specific sites in the promoter regions of target genes and stimulating their transcription. In the case of any weakness of this anti-oxidizing defence or any over-production of radical species, a state of oxidative stress occurs. (ABSTRACT TRUNC

[Free radicals and antioxidants: human physiology, pathology and therapeutic aspects]. / Radicaux libres et anti-oxydants: physiologie, pathologie humaine et aspects thérapeutiques.

Oxygen has invaded progressively, and through the ages, an initially anaerobic world. Living organisms had to invent, in the course of evolution, diverse and ingenious defence systems, to survive the toxicity of this element, which was new for them. Strengthened by this experience over billions of years, the present superior organisms, and particularly human species, are thoroughly adapted to 21 per cent of atmospheric oxygen. Nevertheless, the equilibrium is fragile and the menace of oxygen hovers continually. This deleterious potential of oxygen is attributed to the formation, in vivo, of free radicals, a free radical being, by definition, any chemical species possessing one or several mismatched electrons. These free radicals are, in general, very active. They trigger chain reactions able to damage the different constituents of the living organism. Basic oxygen, must be pre-activated to manifest its toxicity. Such an activation can be achieved in two ways: it can be photodynamic, ending mainly in singlet oxygen, it can be reducing, followed by the formation of the anion hydrogen peroxide and of radical hydroxyl; the latter is the most reactive chemical species in the biological world. The reductive process is accelerated in the presence of transition metals, such as iron and copper, and/or specific enzymes (monoxygenase and certain oxydases). This activation takes place in different cellular compartments: mitochondria, microsomes, peroxysomes, cytoplasmic membrane. To this potential toxicity of oxygen the organism opposes different anti-oxidant defence systems. A first group works up the radical chain, inhibiting activation mechanisms. Such a group, as a consequence, warns of the initiation of radical reactions. The second group neutralizes the free radicals already formed and thus stops the chain of propagation. In this group can be found detoxifying enzymes, notably superoxide dismutase and catalase, producing jointly peroxidases, particularly peroxidase glutathions. Such enzymes for the most part have trace elements as cofactors. In this second group can also be found various molecules which act like 'substrate suicide', or as an anti-oxidant shield. Among these molecules, some can act in the lipidic phase, such as tocopherols, carotenoïds and ubiquinones. Other molecules which are lipophobic, mainly ascorbic acid and uric acid, are active in a hydrated environment. In the case of a weakening of such an antioxidant defence or excess production of radicals, a state of oxidative stress occurs. Uncontrolled, these radicals will damage different biological targets: lipids, DNA, proteins. Disturbances of cellular metabolism will occur, unless corrective defences intervene. The identification of these radical phenomena is an obligatory stage. But because of the very short life span of free radicals, identification poses a real analytical problem. However, three approaches are possible: identification of free radicals, either directly by means of paramagnetic electron resonance, or indirectly by identifying some more stable intermediates. evaluation of the traces of radical attack on biological molecules, for example by high performance liquid chromatography, gas-liquid chromatography, colorimetric tests, estimation of the antioxidant status, for example by colorimetric tests, immunoenzymatic methods, high performance liquid chromatography.

[Treatment of aplastic anemia with cyclosporine, prednisolone and androgens (primary results apropos of 10 cases]. / Traitement de l'aplasie médullaire par ciclosporine, prednisolone et androgènes (résultats préliminaires à propos de 10 cas).

Aplastic anaemia is a potentially fatal haematopoietic disorder whose aetiology is not yet clarified. In our preliminary study we have introduced cyclosporin in the aplastic anaemia treatment to evaluate its effect on the disease evolution. Ten aplastic anaemia patients, mean age 33.33 +/- 20.01 years, were treated with cyclosporine (9 +/- 2.35 mg/kg/d), prednisolone (0.5 mg/kg/d) and androgens (1 mg/kg/d). The prednisolone was always combined with cyclosporine. The androgens were administered concomitantly with the cyclosporine or alternately. Seven patients responded to the treatment after a median remission delay of 6 weeks (2-12 weeks). They became independent of blood requirements at a median of 36 weeks (8-108 weeks); the three other patients died during the first trimester without showing any improvement. Among the seven responders, two relapsed early and transiently. The rate of actuarial survival was 70 per cent. The median duration of survival was 10.5 months. The side effects observed included one case of malignant lymphoma, six cases of liver toxicity and five cases of kidney toxicity. This toxicity was reversible after dose adjustment of the cyclosporine. In our study, the introduction of cyclosporin in the aplastic anaemia treatment resulted in improved therapeutic response. Androgens should be used to maintain the haematologic response. This therapeutic protocol associated with drug monitoring seems promising and the side effects should not limit its use because of the severity of the underlying disease.

[Laser-Doppler velocimetry: a new technic for evaluating of microcirculation. A reproducibility study]. / La vélocimétrie laser-doppler: nouvelle technique d'évaluation de la microcirculation. Etude de la reproductibilité.

The recent introduction of the laser-Doppler technique to measure capillary flow velocity offers new prospects in clinical pharmacology. We used this technique in 45 healthy volunteers (23 women and 22 men) to study the capillary network at the distal end of the third finger of the non-dominant hand. Each subject was tested twice at one-week interval. The results showed that the data concerning flow velocity and amplitude were perfectly reproducible, under standard conditions, after one week in each subject. No correlation was found between the microcirculation parameters and the subjects age, weight and, paradoxically, blood pressure and heart rate. We would suggest that this innocuous, sensitive and reproducible technique be used more systematically to evaluate the haemodynamic effects of drugs on capillary blood flow.