Abstract: Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.
Abstract: AIMS: To evaluate putative associations between drugs and dilated cardiomyopathy. METHODS: We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were all the observations with dilated cardiomyopathy registered into the FPVD between 1 January 1990 and 30 June 2007. Noncases were all other reports other than those studied. Anthracyclines were used as positive controls. Data were expressed as reporting odds ratio (ROR) with their 95% confidence intervals. RESULTS: Out of the 258 729 adverse drug reaction (ADR) reports recorded in the FPVD between 1 January 1990 and 30 June 2007, 47 (22 men, mean age 49 years) were defined as dilated cardiomyopathy. In these 47 patients, 67 drugs were 'suspect'. A significant ROR was found with cytotoxic (epirubicin, mitoxantrone, cyclophosphamide, gemcitabine, fluorouracil) and antiretroviral (lamividune, zidovudine, abacavir) but also with isotretinoin, prednisone, appetite suppressant (clobenzorex) and psychotropic [antipsychotic (clozapine, olanzapine), lithium, antidepressant (clomipramine, amitriptyline, fluvoxamine)] drugs. CONCLUSIONS: The present study describes an association between some drugs and reports of dilated cardiomyopathies. This relationship involves not only some already suspected drugs (anthracyclines, antiretrovirals), but also other drugs (antipsychotics, lithium, antidepressants, retinoids) less known to induce such an ADR. Despite the mandatory limits of this kind of study (underreporting, confounding factors . . .), these data represent a pharmacovigilance signal and could contribute to establish further prospective studies in order to confirm such signals.
Abstract: Parkinson's disease (PD) is characterized by a triade of motor symptoms due to the degeneration of nigrostriatal pathway. In addition to these motor impairments, cognitive disturbances have been reported to occur in PD patients in the early stage of the disease. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of PD. In a previous work, we showed that MPTP altered the expression of proteins involved in mTOR antiapoptotic and PKR apoptotic pathways of translational control (TC) in neuroblastoma cells. In the present study, the results indicated that a subchronic MPTP intoxication in mice decreased the dopaminergic neuron number, produced an activation of PKR way and an inhibition of mTOR way of TC especially in striatum and frontal cortex associated with a great activation of PKR in hippocampus. Moreover, in parallel to biochemical analysis, the mnesic disturbances induced by MPTP were characterized in C57Bl/6 mice, by testing their performance in three versions of the Morris Water Maze task. Behavioral results showed that the MPTP lesion altered mice learning of a spatial working memory, of a cued version and of a spatial reference memory task in the water maze. Furthermore, we previously demonstrated that the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) could counteract the MPTP toxicity on TC factors in neuroblastoma cells. Thus, the second objective of our study was to assess the PACAP effect on MPTP-induced TC impairment and cognitive deficit in mice. The pretreatment with PACAP27 by intravenous injections partially protected TH-positive neuron loss induced by MPTP, prevented the MPTP-induced protein synthesis control dysregulation and mnesic impairment of mice. Therefore, our results could indicate that PACAP may be a promising therapeutic agent in Parkinson's disease.
Abstract: Neonatal acute adrenal insufficiency (AAI) is a rare but severe condition. We report a case of AAI following maternal exposure to moderate doses of corticosteroids during pregnancy. The neonate, born at term, presented with hypoglycaemia complicated by seizures. The AAI was confirmed by endocrine tests and after exclusion of differential diagnoses. Early diagnosis and treatment led to full recovery.
Abstract: Stimulation of cholinergic muscarinic receptors has been shown to provide substantial protection from DNA damage, oxidative stress and mitochondrial impairment, insults that may be encountered by neurons in development, aging, or neurodegenerative diseases. A study recently indicated that the activation of muscarinic receptors in astrocytoma cells modified the expression of the kinase p70S6K involved in the translational control. The translational control is in part regulated by a cascade of phosphorylation affecting proteins of the anti-apoptotic way controlled by mTOR (mammalian target of rapamycin) and the pro-apoptotic way controlled by PKR. The aim of our study was to investigate the effect of cholinergic muscarinic stimulation by an agonist oxotremorine on the anti-apoptotic way of translational control, in human neuroblastoma cells and in mice brain. Our results showed that muscarinic receptor activation significantly increased the expression of phosphorylated p70S6K, eIF4E and ERK without modification of mTOR activity in neuroblastoma cells and in cerebral cortex and hippocampus of mice, suggesting a stimulation of protein synthesis. Our findings support the notion that synaptic activity, through activation of neurotransmitter receptors, can provide substantial support of cellular survival mechanisms and suggest that loss of such synaptic input increases vulnerability to insult-induced programmed cell death.
Abstract: The increased incidence of dementia on the aging population makes this disease a major public health problem. Among known causes of dementia, drug etiology is under considered. We investigated the relationship between exposure to drug therapy and dementia with a case/non-case study using reports of the French Pharmacovigilance database. Among 263 962 adverse effects recorded between 1985 and 2005, 79 (0.03%) are dementia. Median age is 66 (range 3-91). There was 41 women and 37 men. The therapeutic drug class associated with dementia were anticonvulsants, antiparkinsonians, antidepressants, anxiolytics, hypnotics, antipsychotics and morphinics. An association between reporting of dementia and non neurotropic drugs were also found, i.e. interferon alfa-2B, vancomycin and allopurinol. The term "Dementia" is only mentioned in the summary of the characteristics of valproate, but it may concern other drugs. Drug etiology for dementia is a reality but is not necessarily attributed as a cause in aging population, in particular.
Abstract: BACKGROUND: Midazolam (MDZ) is used as an assessment of human cytochrome P450 3A (CYP3A) activity. A single blood measurement is used as a marker of its activity based on an observed correlation between MDZ clearance and the 1'-hydroxymidazolam (1'-OH-MDZ): MDZ plasma ratio is assessed at 0.5 h followig the intake of a single 7.5 mg oral dose of MDZ in healthy young volunteers. In addition, a 4-h plasma MDZ measurement has been found to be an excellent predictor of AUC and CYP3A activity. OBJECTIVES: The main aim of this study was to define a single-point blood sampling in healthy elderly volunteers. The secondary objective was to investigate the pharmacological effects of a low oral dose of MDZ (5 mg) and its potential psychometric changes. METHODS: Eight healthy elderly Caucasian volunteers participated in a single-dose, open-label, non-comparative study. Each subject received a single 5 mg oral dose of MDZ. Plasma concentrations of MDZ and its major metabolite, 1'-OH-MDZ, were assayed over 12 h. Secondary assessments of critical flicker fusion (CFF), body sway and mini-mental state examination were also carried out during the 12-h post-administration period. RESULTS: A moderate correlation was observed between MDZ clearance and the 1'-OH-MDZ: MDZ plasma concentration ratio at 9 h post-dosing (Rho=0.81; p=0.04), but an even better correlation (Rho=0.99; p<0.009) was found between MDZ AUC and MDZ plasma concentration at 6 h post-dosing, with the latter value corresponding approximately to the average mean residence time (MRT) determined in our trial. This study was well-tolerated despite a significant transitory decrease (relative to baseline) in cortical arousal at 1 h post-dosing, as assessed by CFF, and a non-significant decrease (relative to baseline) in balance and vigilance also measured at 1 h and assessed on body sway, compared to baseline values. CONCLUSION: Despite the small sample size, based on the results of healthy, elderly volunteers, a single MDZ plasma measurement taken at 6 h post-oral administration may represent an accurate marker of CYP3A phenotype. This single-time-point method could be used safely for predicting drug-drug or diet interactions and identifying individuals with genetic polymorphism that affect CYP3A activity.
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease of the central nervous system characterized by two major lesions: extracellular senile plaques and intraneuronal neurofibrillary tangles. beta-Amyloid (Abeta) is known to play a major role in the pathogenesis of AD. Protein synthesis and especially translation initiation are modulated by different factors, including the PKR/eIF2 and the mTOR/p70S6K pathways. mRNA translation is altered in the brain of AD patients. Very little is known about the translation control mediated by mTOR in AD, although mTOR is a central regulator of translation initiation and also ribosome biogenesis and cell growth and proliferation. In this study, by using Western blotting, we show that mTOR pathway is down-regulated by Abeta treatment in human neuroblastoma cells, and the underlying mechanism explaining a transient activation of p70S6K is linked to cross-talk between mTOR and ERK1/2 at this kinase level. This phenomenon is associated with caspase-3 activation, and inhibition of mTOR by the inhibitor rapamycin enhances Abeta-induced cell death. Moreover, in our cell model, insulin-like growth factor-1 is able to increase markedly the p70S6K phosphorylation controlled by mTOR and reduces the caspase-3 activity, but its protective effect on Abeta cell death is mediated via an mTOR-independent pathway. These results demonstrate that mTOR plays an important role as a cellular survival pathway in Abeta toxicity and could represent a possible target for modulating Abeta toxicity.
Abstract: Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP(SL)/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.
Abstract: We aimed to assess the plasma and urine concentrations of beta2-agonists and evaluate the difference between three routes of administration in trained adults in order to distinguish doping from prevention of exercise-induced asthma. Ten young healthy Caucasian male subjects received during a four treatment period study: 1) inhaled salbutamol (S(I)) 2 x 100 microg t.i.d. for 3 days, 2) inhaled formoterol (F(I)) 2 x 12 microg b.i.d. for 3 days, 3) a single subcutaneous injection of salbutamol (S(S)) 0.5 mg, and 4) salbutamol 2 x 2 mg t.i.d. orally for 3 days (S(O)). Blood samples were taken during the first and the third day of experimentation at baseline, 30 min, 1 h, 2 h, 4 h and 6 h after administration; additional blood samples were drawn at 15 min for S(I), S(S) and F(I) and at 12 h for F(I). Urinary samples were collected at baseline, 2 h, 4 h, 6 h and 12 h after administration. Urinary concentrations were 20 to almost 50 times higher after S(O) than after S(I). Mean urinary concentration after S(O) increased to above 800 ng.mL(-1) within the two hours and above 1000 ng.mL(-1) at 6 to 12 hours post-drug administration. Urinary concentrations after S(S) were maximal during the first 2 hours (mean: 340 +/- 172 ng.mL(-1)). Plasma concentrations were very low, whatever the routes of administration. Results showed that we could eliminate the use of S(I) (authorized) and S(S) administration when individual urinary concentrations are higher than 230 ng.mL(-1) and 615 ng.mL(-1), respectively. Therefore, at rest, the cut-off value used to discriminate therapeutic from doping salbutamol intake could be fixed at 250 ng.mL(-1) instead of the 1000 ng.mL(-1) still authorized by international committees.
Abstract: In Alzheimer's disease, neuropathological hallmarks include the accumulation of beta-amyloid peptides (Abeta) in senile plaques, phosphorylated tau in neurofibrillary tangles and neuronal death. Abeta is the major aetiological agent according to the amyloid cascade hypothesis. Translational control includes phosphorylation of the kinases mammalian target of rapamycin (mTOR) and p70S6k which modulate cell growth, proliferation and autophagy. It is mainly part of an anti-apoptotic cellular signalling. In this study, we analysed modifications of mTOR/p70S6k signalling in cellular and transgenic models of Alzheimer's disease, as well as in lymphocytes of patients and control individuals. Abeta 1-42 produced a rapid and persistent down-regulation of mTOR/p70S6k phosphorylation in murine neuroblastoma cells associated with caspase 3 activation. Using western blottings, we found that phosphorylated forms of mTOR and p70S6k are decreased in the cortex but not in the cerebellum (devoid of plaques) of double APP/PS1 transgenic mice compared with control mice. These results were confirmed by immunohistochemical methods. Finally, the expression of phosphorylated p70S6k was significantly reduced in lymphocytes of Alzheimer's patients, and levels of phosphorylated p70S6k were statistically correlated with Mini Mental Status Examination (MMSE) scores. Taken together, these findings demonstrate that the mainly anti-apoptotic mTOR/p70S6k signalling is altered in cellular and transgenic models of Alzheimer's disease and in peripheral cells of patients, and could contribute to the pathogenesis of the disease.
Abstract: The purpose of this survey in 50 healthy volunteers from a single-centre study was to assess from a questionnaire filled in by the participants, their comprehension and evaluation of the written and oral information and the legal framework, as well as their uncertainty regarding participation, in terms of age, gender and profession. Overall satisfaction with regard to comprehension and oral information was recorded, but 42% of volunteers considered the informed consent form too long and one-quarter of them did not read it completely. Knowledge of the legal framework (20%) did not influence either their understanding or hesitation to participate. The hesitant individuals (26%) more often judged this framework to be reassuring than the non-hesitant individuals (77% versus 38%; p = 0.015). These findings concerned females, medics or paramedics and younger individuals (< or =35 years). In individuals who do not give their consent, it would be interesting to study the reasons for refusal to participate and the influence of the ethical and legal framework in clinical trials in enhancing the patients' partnership in a context of evidence-based medicine.
Abstract: Our previous work on rat hippocampus showed that a loss of docosahexaenoic acid (DHA) occurs in the fatty acid composition of phosphatidylethanolamine (PE), plasmenylethanolamine (PmE) and phosphatidylserine (PS) with increasing age. The present study investigated whether a DHA-enriched phospholipid dietary supplement could restore DHA levels and cholinergic activity. Male rats were fed a balanced diet containing both linoleic and alpha-linolenic acids until the age of 2, 18 and 21 months. From 18 to 21 months, one subgroup received a diet supplemented with DHA-enriched phospholipids from egg yolk (E-PL), and another a diet with DHA-enriched phospholipids from pig brain (B-PL). Compared to the control diet, the E-PL diet restored the proportion of polyunsaturated fatty acids (PUFAs: 22:6n-3 and 20:4n-6) in PE and PmE, while enhancing spontaneous and evoked-acetylcholine (Ach) release. The B-PL diet had no effect on PUFAs, but increased basal extracellular levels of Ach in 21-month-old rats as compared to the age-matched control. Our results show that supplementation with DHA-enriched egg PL can enhance Ach release and correct PUFA composition.
Abstract: BACKGROUND: Beta-2 agonists such as salbutamol are used, not only by asthmatic athletes to prevent exercise induced asthma, but also by non-asthmatic athletes as a potentially ergogenic agent. We have investigated whether inhaled salbutamol enhances endurance performance in non-asthmatic athletes. METHODS: A prospective double blind, randomised, three way crossover design was used to study the effects of 200 microg and 800 microg inhaled salbutamol versus a placebo in 12 trained triathletes. The treatments were compared in three identical cycle ergometer sessions at 85% of the predetermined maximal oxygen uptake. Lung function, endurance time, metabolic parameters (glucose, potassium, lactate, free fatty acid, and glycerol), and psychomotor performance were evaluated. RESULTS: Neither endurance time nor post-exercise bronchodilation were significantly different between the treatments. Metabolic parameters were affected by exercise but not by treatment. CONCLUSIONS: Inhaled salbutamol, even in a high dose, did not have a significant effect on endurance performance in non-asthmatic athletes, although the bronchodilating effect of the drug at the beginning of exercise may have improved respiratory adaptation. Our results do not preclude an ergogenic effect of beta2 agonists given by other routes or for a longer period.
Abstract: The authors have constructed a problem-based learning (PBL) computer program that makes full use of Internet facilities, and is aimed at providing a stimulating supplement to standard teaching practices. The authors report on students' reactions to this new method of teaching.
Abstract: Since 1996, marketing of new drugs called protease inhibitors has revolutionized the treatment of patients suffering from AIDS. The side-effects of this new therapeutic family are quite well known but we wanted to evaluate the attitude of the clinician: can these adverse effects be corrected by symptomatic treatment, do they regress spontaneously or do they lead to an alternative PI therapy? We therefore carried out a retrospective survey in the Infectious Diseases Department of Poitiers Hospital consisting in research on files of patients (n = 70) treated in this department (hospitalization and consultation) for any clinical or biological abnormality attributable to the PI. For each drug we determined what sort of side-effects could be found and the position adopted by the clinician. For 30 patients the PI was stopped and for 21 of these cases because of drug toxicity (gastrointestinal, neurological, renal and metabolic effects). The biological anomalies are quite well tolerated and regress spontaneously in most cases.
Abstract: Hospital admissions resulting from an adverse drug reaction have been studied in the emergency unit of the university hospital in Poitiers during a 27-day period. This prospective study consisted in documenting all observations considered as an ADR by the medical practitioner in charge of the patient. There were 1235 hospital admissions to the emergency unit during the study period. Thirty-one (2.5 per cent) of admissions were considered to be drug-related. Women were more often affected than men. Patients with ADR were classified taking into account the type of pathology and the drug responsible for the effect. Dermatological and gastrointestinal reactions were predominant. Antibiotic and analgesic drugs were the most common drug groups implicated in causing an ADR.
Abstract: Despite the recognition of lead poisoning in children as a major public health problem in France since the 1980's, the setting-up of systematic detection of lead poisoning at a national level has not yet been done. The main source of intoxication in children is in paintings containing ceruse in housing built before 1948. Moderate chronic poisoning, although leading to irreversible lesions, particularly of the central nervous system, remains usually unnoticed. The biological diagnosis is mainly based upon blood lead level, completed by the protoporphyrine-zinc level. Large scale identification of dangerous housing and the control of rehabilitation are the only means available to decrease the incidence of lead posioning. Targeted screening is difficult because it concerns children excluded from classical health care systems. Prevention and long-term treatment requires elimination of the source of lead intoxication after an environmental inquiry. This raises the problems of rehousing and follow-up of intoxicated children.
Abstract: Voluntary drug intoxications are not systematically recorded. Main aspects of this important problem have been studied in the unit responsible for medico-psychological emergencies in the university hospital of Poitiers. Files of all patients admitted to the unit from January to December 1994 have been analysed and 598 patients were included in our study. Of these, 67 per cent were females. 31 per cent were 20 to 29 years old and for the most part unemployed (62.5 per cent). Drugs most commonly used are benzodiazepines (39 per cent), alone or often associated with alcohol (33 per cent). A fatal outcome was observed in one patient. In many cases (50 per cent) this was not the first episode of voluntary intoxication; 53 per cent of the patients were discharged from hospital after a psychiatric consultation. For many years, voluntary drug intoxication frequency has increased continually. All cases have a specific intention that we have to clarify in order to take effective preventive measures to prevent recidivism.
Abstract: BACKGROUND/AIM: The aim of this case-control study was to assess the risk of bleeding from esophageal varices associated with aspirin and non-steroidal anti-inflammatory drug consumption. METHODS: Between January 1992 and May 1994, patients admitted for bleeding from esophageal or gastric lesions related to portal hypertension were matched with a control patient of the same age and sex, who was free of gastrointestinal bleeding. A structured interview was conducted with the cases and controls to determine drug consumption during the 2 weeks preceding admission. Fifty-nine cases and 59 controls were recruited. RESULTS/CONCLUSIONS: Use of aspirin was more prevalent among the cases than the controls (odds ratio 3.81; 95% confidence interval 1.36-11.64; p = 0.004). This difference remained significant in the subgroups of patients with a first episode of variceal bleeding (odds ratio 3.9; 95% confidence interval 1.2-13.9, p = 0.01), but was not significant in the subgroups of patients with a recurrent episode of variceal bleeding. The use of aspirin was associated with a high risk of a first episode of variceal bleeding, suggesting that patients with portal hypertension should avoid taking these drugs.
Abstract: BACKGROUND: Caffeine is the most widely used psychostimulant. PURPOSE: This study evaluated the pharmacokinetics and effects of mood and alertness of a single oral administration of 600 mg of a slow release caffeine (SRC) on a large group of healthy subjects. METHOD: In this double-blind, parallel-group study, 120 young adult males were randomly assigned to either a caffeine group (CG, n = 100) or a placebo group (PC, n = 20). After a normal sleep, each subject took 600 mg of a SRC or a placebo. Circulating caffeine was determined by salivary caffeine assays after acetylation phenotype categorization. Mood, alertness and nocturnal sleep were evaluated by visual analog scales (VAS). RESULTS: This SRC was well tolerated probably due to its relative low plasmatic Cmax (10.37 micrograms.ml-1). Between CG and PG, there were no differences for alertness, contentedness and sleep quality of the night after treatment (N2) compared to the previous night (N1). VAS scores showed a decrease in calmness in the CG (p < 0.01). Sleep latency in N2 was significantly increased with caffeine (p < 0.01). Calmness, sleep onset latency, quality of sleep onset and overall rating of N2 compared to N1 were correlated with caffeine levels, which were only influenced by tobacco consumption. CONCLUSIONS: Although a single oral dose of 600 mg of a SRC is well tolerated, further evaluation must be done on alertness and pharmacokinetics with fatigued subjects and with females using oral contraceptives.
Abstract: 1. The possible interaction between a new H1 antihistamine, mizolastine, and lorazepam was assessed in a randomised, double-blind, cross-over, placebo-controlled study involving 16 healthy young male volunteers who received mizolastine 10 mg or placebo once daily for 8 days with a 1 week wash-out interval. The interaction of mizolastine, at steady-state, with a single oral dose of lorazepam or placebo was assessed on days 6 or 8 of each treatment period. 2. Psychomotor performance and cognitive function were evaluated using objective tests (critical flicker fusion threshold, choice reaction time, tapping, arithmetic calculation, body sway) and self-ratings (visual analogue scale, ARCI) before and at 2, 4, 6 and 8 h after dosing. Short-term memory (Sternberg memory scanning immediate free recall of a word list) and long-term memory (delayed free recall and recognition of words and pictures) were assessed before and at 3 h after dosing. Pharmacodynamic interactions were evaluated by repeated measures ANOVA in a 2 x 2 factorial interaction model. 3. Mizolastine, 10 mg once daily, at steady-state, was devoid of sedation and detrimental effect on skilled performance and memory. 4. In contrast, a single 2 mg dose of lorazepam produced marked impairment of psychomotor performance, cognitive functions (significant reduction in flicker fusion threshold, tapping and arithmetic calculation and increase in reaction times and body sway) and subjective sedation from 2 to 8 h after dosing. In addition, lorazepam induced an anterograde amnesia, characterised by a decrease in delayed free recall and recognition, and a deficit in short term memory.(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: The therapeutic drug monitoring of antidepressant drugs is of interest to adapt dosage regimens to reduce the number of non-responder patients, to reduce drug side effects and to detect non-compliant patients. A therapeutic range is defined for many of these drugs and their linear or non-linear kinetics are important parameters in clinical practice to define the posology. Some patients, because of when there is drug biotransformation polymorphism, are exposed to drug accumulation a deficit in isoenzymes of cytochrome P450. The existence of these isoenzymes explains the possibility of non-linear kinetics and drug interactions.
Abstract: Cytochrome P450 IID6 has got typical features (genetical polymorphism, competitive inhibition, saturability) which can be at the origin of pharmacokinetic modifications of molecules using it for their metabolism. In the field of pharmacology, many molecules are substrates or inhibitors of this cytochrome. They are presented. The results of a study of the dextromethorphan variation test performed before and after 28 days of clomipramine therapy with depressed patients are explained. They show a significant decreasing of the cytochrome P450 IID6 oxidation capacities between both of these times. A patient has passed from the phenotype "effective metabolizer" to the one of "poor metabolizer" with clomipramine.
Abstract: Suriclone is a novel cyclopyrrolone exhibiting anxiolytic activity. Twelve healthy Caucasian male volunteers participated in the study. A single dose of suriclone 0.4 mg, imipramine 75 mg, suriclone 0.4 mg + imipramine 75 mg, or placebo was given according to a 4 x 4 Latin-square design in order to assess the effect of drug association on pharmacokinetics and psychomotor performances. Visual analogue scale ratings, critical flicker frequency, choice visual reaction time, and Pauli, picture memory and Sternberg tests were performed before and 1.5, 6 and 9 h after drug administration. Suriclone, with the exception of the Pauli test, had no effect on psychomotor performances. The imipramine-suriclone association appeared to disturb some performances (no statistical significance), probably due to the effect of imipramine. Blood samples were collected for determination of imipramine and suriclone plasma levels respectively by high-performance liquid chromatography and radioimmunoassays. Suriclone AUC, Cmax and Tmax were not affected by imipramine, and reciprocally.
Abstract: Polytherapy is often used in clinical practice. The drug associations may lead to pharmacokinetic and/or pharmacodynamic interactions, with clinical implications. The authors reported a quantified illustration of 2 types of interactions in a depressed patient: between antidepressants, amitriptyline and fluoxetine, between these antidepressants and antituberculosis. Firstly, when fluoxetine was added to amitriptyline, it was observed, as expected, an increase of the tricyclic and its metabolite plasma levels, despite a decrease of its dosage. Secondly, when antituberculosis were added to the 2 antidepressants, it was observed a decrease of the tricyclic drug plasma levels. These levels remained below the therapeutic window even when the tricyclic antidepressant dosage was increased. It seems that the fluoxetine interaction disappeared. The competition between the inhibitory effect of fluoxetine and the induction of rifampicin, on the metabolism of amitriptyline is discussed.
Abstract: To collect informations about drugs prescribed during pregnancy in France we carried out a retrospective survey from august to december 1989. This study was based on a questionnaire at delivery for 225 women. Socio-economic status, obstetrical past history and patterns of prescribing medications were studied. 99.5% of the women were found to have used drugs during pregnancy with a mean of 6.84 medications per woman. There was no influence of age, geographic origins, number of previous pregnancies on drug consumption; socio-professional status was also found to have a poor correlation with drug intake. Patterns of prescribing were compared to those of a previous French study made in 1976: changing pattern of prescribing were found for progestatives, corticoids, neurotropes, aspirin and beta adrenergic agents. We also pointed out that self-administered drugs decreased from 25.9 to 17.9%. This evaluation supports the need of further epidemiological studies in our country.
Abstract: The possibility of a pharmacokinetic interaction between amitriptyline and toloxatone (a new MAOI-A) has been studied in 17 depressed in-patients. Amitriptyline and its demethylated and hydroxylated metabolites in blood and urine were measured at steady state after the administration of amitriptyline with and without toloxatone in steady state. The metabolic status of patients was determined using the dextromethorphan phenotyping test. There was only a minor pharmacokinetic interaction between amitriptyline (AMT) and toloxatone, with a small increase in the AMT/NT (nortriptyline) plasma ratio: 0.68 before and 0.78 after toloxatone. The urinary excretion and plasma levels of AMT and its metabolites were not affected by the co-therapy. Three of the patients were poor metabolisers, but this did not predict the magnitude of the drug interaction. The interaction does not justify plasma level monitoring of amitriptyline as the change in pharmacokinetics was so small.
Abstract: 5-fluoro-uracil (5-FU) cardiotoxicity has been often reported during chemotherapy. We collect four atypical cases of cardiac side effects in patients treated by 5-FU for head and neck tumors. We review the literature about the subject, and we propose criteria to detect patients with a high risk level, and to prevent this adverse effect incidence.
Abstract: Nicotine has a small molecular weight and is absorbed via the mucosa (Guccal or nasal), the pulmonary alveoli and the skin. The phenomenon of autotitration explains how a dependent smoker can unconsciously change his method of smoking to maintain a steady nicotine level. Nicotine leads to a liberation of catecholamines by acting on the nervous system through the intermediary of nicotine receptors. There is increased vigilance and powers of intellectual concentration, an awakening reaction and some anxiolytic and euphoriant effects. From the cardiac stand point there is an increased heart rate and blood pressure, as a result of the sympathomimetic effects. Elimination is via the kidneys as unchanged nicotine, cotinine and 1'-N-oxide of nicotine. Nicotine has an addictive action and is capable of inducing pharmacological dependency, tolerance and withdrawal syndrome in cases of abrupt cessation. A knowledge of the pharmacology of nicotine is important in the process of stopping smoking.
Abstract: The correlation between debrisoquine and dextromethorphan oxidation polymorphism was studied in 16 depressed in-patients. There was a close correlation between both phenotypes (r = 0.81 p less than 0.0017). During a treatment with amitriptyline during two weeks there was no significant modification of the dextromethorphan polymorphism. In the same way, the association of amitriptyline and toloxatone during two other weeks did not change this polymorphism in a significant way, even if there was a non significant shift towards higher values of the dextromethorphan metabolic ratio.
Abstract: The cyclosporine is widely used as an immuno-suppressive agent in association with others drugs. Its narrow therapeutic range requires frequent monitoring. We suggest a literature review of suspected or confirmed drug interactions. The classification is presented as: absorption interactions; pharmacokinetic interactions in antiinfectious, anticonvulsants, cardiovascular drugs, H2 antagonists agents, hormonotherapy; pharmacodynamic interactions associated to increased cyclosporine nephrotoxicity.
