Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.

Tea tree oil: contact allergy and chemical composition.

In this article, contact allergy to, and the chemical composition of, tea tree oil (TTO) are reviewed. This essential oil is a popular remedy for many skin diseases, and may be used as neat oil or be present in cosmetics, topical pharmaceuticals and household products. Of all essential oils, TTO has caused most (published) allergic reactions since the first cases were reported in 1991. In routine testing, prevalences of positive patch test reactions have ranged from 0.1% to 3.5%. Nearly 100 allergic patients have been described in case reports and case series. The major constituents of commercial TTO are terpinen-4-ol, γ-terpinene, 1,8-cineole, α-terpinene, α-terpineol, p-cymene, and α-pinene. Fresh TTO is a weak to moderate sensitizer, but oxidation increases its allergenic potency. The major sensitizers appear to be ascaridole, terpinolene, α-terpinene, 1,2,4-trihydroxymenthane, α-phellandrene, and limonene. The clinical picture of allergic contact dermatitis caused by TTO depends on the products used. Most reactions are caused by the application of pure oil; cosmetics are the culprits in a minority of cases. Patch testing may be performed with 5% oxidized TTO. Co-reactivity to turpentine oil is frequent, and there is an overrepresentation of reactions to fragrance mix I, Myroxylon pereirae, colophonium, and other essential oils.

Pooled Analysis of Six Pharmacologic and Nonpharmacologic Interventions for Vasomotor Symptoms.

OBJECTIVE: To describe the effects of six interventions for menopausal vasomotor symptoms relative to control in a pooled analysis, facilitating translation of the results for clinicians and symptomatic women. The Menopause Strategies: Finding Lasting Answers for Symptoms and Health network tested these interventions in three randomized clinical trials. METHODS: An analysis of pooled individual-level data from three randomized clinical trials is presented. Participants were 899 perimenopausal and postmenopausal women with at least 14 bothersome vasomotor symptoms per week. Interventions included 10-20 mg escitalopram per day, nonaerobic yoga, aerobic exercise, 1.8 g per day omega-3 fatty acid supplementation, 0.5 mg low-dose oral 17-beta-estradiol (E2) per day, and 75 mg low-dose venlafaxine XR per day. The main outcome measures were changes from baseline in mean daily vasomotor symptom frequency and bother during 8-12 weeks of treatment. Linear regression models estimated differences in outcomes between each intervention and corresponding control group adjusted for baseline characteristics. Models included trial-specific intercepts, effects of the baseline outcome measure, and time. RESULTS: The 8-week reduction in vasomotor symptom frequency from baseline relative to placebo was similar for escitalopram at -1.4 per day (95% confidence interval [CI] -2.7 to -0.2), low-dose E2 at -2.4 (95% CI -3.4 to -1.3), and venlafaxine at -1.8 (95% CI -2.8 to -0.8); vasomotor symptom bother reduction was minimal and did not vary across these three pharmacologic interventions (mean -0.2 to -0.3 relative to placebo). No effects on vasomotor symptom frequency or bother were seen with aerobic exercise, yoga, or omega-3 supplements. CONCLUSION: These analyses suggest that escitalopram, low-dose E2, and venlafaxine provide comparable, modest reductions in vasomotor symptom frequency and bother among women with moderate hot flushes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00894543 (MsFLASH 01), NCT01178892 (MsFLASH 02), and NCT01418209 (MsFLASH 03).

Simultaneous interstitial pneumonitis and cardiomyopathy induced by venlafaxine.

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used as an antidepressant. Interindividual variability and herb-drug interactions can lead to drug-induced toxicity. We report the case of a 35-year-old female patient diagnosed with synchronous pneumonitis and acute cardiomyopathy attributed to venlafaxine. The patient sought medical attention due to dyspnea and dry cough that started three months after initiating treatment with venlafaxine for depression. The patient was concomitantly taking Centella asiatica and Fucus vesiculosus as phytotherapeutic agents. Chest CT angiography and chest X-ray revealed parenchymal lung disease (diffuse micronodules and focal ground-glass opacities) and simultaneous dilated cardiomyopathy. Ecocardiography revealed a left ventricular ejection fraction (LVEF) of 21%. A thorough investigation was carried out, including BAL, imaging studies, autoimmune testing, right heart catheterization, and myocardial biopsy. After excluding other etiologies and applying the Naranjo Adverse Drug Reaction Probability Scale, a diagnosis of synchronous pneumonitis/cardiomyopathy associated with venlafaxine was assumed. The herbal supplements taken by the patient have a known potential to inhibit cytochrome P450 enzyme complex, which is responsible for the metabolization of venlafaxine. After venlafaxine discontinuation, there was rapid improvement, with regression of the radiological abnormalities and normalization of the LVEF. This was an important case of drug-induced cardiopulmonary toxicity. The circumstantial intake of inhibitors of the CYP2D6 isoenzyme and the presence of a CYP2D6 slow metabolism phenotype might have resulted in the toxic accumulation of venlafaxine and the subsequent clinical manifestations. Here, we also discuss why macrophage-dominant phospholipidosis was the most likely mechanism of toxicity in this case.

Simultaneous interstitial pneumonitis and cardiomyopathy induced by venlafaxine / Pneumonite intersticial e miocardiopatia simultâneas induzidas por venlafaxina

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used as an antidepressant. Interindividual variability and herb-drug interactions can lead to drug-induced toxicity. We report the case of a 35-year-old female patient diagnosed with synchronous pneumonitis and acute cardiomyopathy attributed to venlafaxine. The patient sought medical attention due to dyspnea and dry cough that started three months after initiating treatment with venlafaxine for depression. The patient was concomitantly taking Centella asiatica and Fucus vesiculosus as phytotherapeutic agents. Chest CT angiography and chest X-ray revealed parenchymal lung disease (diffuse micronodules and focal ground-glass opacities) and simultaneous dilated cardiomyopathy. Ecocardiography revealed a left ventricular ejection fraction (LVEF) of 21%. A thorough investigation was carried out, including BAL, imaging studies, autoimmune testing, right heart catheterization, and myocardial biopsy. After excluding other etiologies and applying the Naranjo Adverse Drug Reaction Probability Scale, a diagnosis of synchronous pneumonitis/cardiomyopathy associated with venlafaxine was assumed. The herbal supplements taken by the patient have a known potential to inhibit cytochrome P450 enzyme complex, which is responsible for the metabolization of venlafaxine. After venlafaxine discontinuation, there was rapid improvement, with regression of the radiological abnormalities and normalization of the LVEF. This was an important case of drug-induced cardiopulmonary toxicity. The circumstantial intake of inhibitors of the CYP2D6 isoenzyme and the presence of a CYP2D6 slow metabolism phenotype might have resulted in the toxic accumulation of venlafaxine and the subsequent clinical manifestations. Here, we also discuss why macrophage-dominant phospholipidosis was the most likely mechanism of toxicity in this case.

A venlafaxina é um inibidor de recaptação de serotonina e noradrenalina utilizado como antidepressivo. A variabilidade individual ou interações entre fitoterápicos e fármacos podem causar toxicidade induzida por drogas. Relatamos o caso de uma paciente de 35 anos diagnosticada com pneumonite intersticial e miocardiopatia dilatada atribuídas à venlafaxina. A paciente procurou atendimento médico devido a dispneia e tosse seca, que começaram três meses após iniciar tratamento com venlafaxina para depressão. Concomitantemente tomava suplementos fitoterápicos contendo Centella asiatica e Fucus vesiculosus. A radiografia e a CT de tórax revelaram doença pulmonar parenquimatosa (micronódulos difusos e opacidades em vidro fosco) e, simultaneamente, foi diagnosticada uma miocardiopatia por ecocardiograma, que revelou uma fração de ejeção ventricular esquerda (FEVE) de 21%. Uma investigação ampla foi realizada, incluindo LBA, estudos de imagem, detecção de doenças autoimunes, cateterismo cardíaco direito e biópsia miocárdica. Após a exclusão de outras etiologias e a aplicação da Escala de Probabilidade de Reações Adversas a Medicamentos de Naranjo, foi assumido o diagnóstico de pneumonite/miocardiopatia síncronas associadas à venlafaxina. Já foi demonstrado que os suplementos fitoterápicos utilizados pela paciente podem inibir a isoenzima do complexo enzimático citocromo P450, responsável pelo metabolismo da venlafaxina. Após a descontinuação da venlafaxina, verificou-se uma rápida melhora clínica com regressão das alterações radiológicas e normalização da FEVE. Este é um importante caso de toxicidade cardiopulmonar induzida por droga. A administração circunstancial de inibidores da isoenzima CYP2D6 e a presença de um fenótipo de metabolização lenta de CYP2D6 podem ter resultado na acumulação tóxica da venlafaxina e na manifestação clínica subsequente. Aqui, é discutida a hipótese de a fosfolipidose macrofágica ser o mecanismo de toxicidade.

The K2/Spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products.

In 2008, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) detected unregulated, psychoactive synthetic cannabinoids (SCBs) in purportedly all-natural herbal incense products (often known as K2 or Spice) that were being covertly abused as marijuana substitutes. These drugs, which include JWH-018, JWH-073 and CP-47,497, bind and activate the cannabinoid receptors CB1R and CB2R with remarkable potency and efficacy. Serious adverse effects that often require medical attention, including severe cardiovascular, gastrointestinal and psychiatric sequelae, are highly prevalent with SCB abuse. Consequently, progressively restrictive legislation in the US and Europe has banned the distribution, sale and use of prevalent SCBs, initiating cycles in which herbal incense manufacturers replace banned SCBs with newer unregulated SCBs. The contents of the numerous, diverse herbal incense products was unknown when SCB abuse first emerged. Furthermore, the pharmacology of the active components was largely uncharacterized, and confirmation of SCB use was hindered by a lack of known biomarkers. These knowledge gaps prompted scientists across multiple disciplines to rapidly (1) monitor, identify and quantify with chromatography/mass spectrometry the ever-changing contents of herbal incense products, (2) determine the metabolic pathways and major urinary metabolites of several commonly abused SCBs and (3) identify active metabolites that possibly contribute to the severe adverse effect profile of SCBs. This review comprehensively describes the emergence of SCB abuse and provides a historical account of the major case reports, legal decisions and scientific discoveries of the "K2/Spice Phenomenon". Hypotheses concerning potential mechanisms SCB adverse effects are proposed in this review.

The effects of venlafaxine and cognitive behavioral therapy alone and combined in the treatment of co-morbid alcohol use-anxiety disorders.

The effects of the antidepressant venlafaxine (VEN-225 mg daily) and transdiagnostic cognitive behavioral treatment (CBT) alone and in combination on alcohol intake in subjects with co-morbid alcohol use disorders (AUDs) and anxiety disorders were compared. Drinking outcomes and anxiety were assessed for 81 subjects treated for 11 weeks with one of 4 conditions: 1) VEN-CBT, 2) VEN-Progressive Muscle Relaxation therapy (PMR), 3) Placebo (PLC)-CBT and 4) a comparison group of PLC-PMR. For subjects who reported taking at least one dose of study medication, the Time×Group interaction was significant for percent days of heavy drinking and drinks consumed per day. For the measure of percent days heavy drinking, the paired comparison of PLC-CBT versus PLC-PMR group indicated that the PLC-CBT group had greater drinking reductions, whereas other groups were not superior to the comparison group. In Week 11, the proportion of subjects in the PLC-CBT group that had a 50% reduction from baseline in percent days heavy drinking was significantly greater than those in the comparison group. Of the 3 "active treatment" groups only the PLC-CBT group had significantly decreased heavy drinking when contrasted to the comparison group. This finding suggests that the transdiagnostic CBT approach of Barlow and colleagues may have value in the management of heavy drinking in individuals with co-morbid alcoholism and anxiety.

Effective and clinically meaningful non-hormonal hot flash therapies.

Although many non-hormonal compounds have shown statistically significant benefit over placebo in hot flash randomized controlled trials (RCTs), these studies have varied considerably in basic methodology making it challenging to deduce which compounds have the greatest potential to provide clinically meaningful benefit. This review used evidence-based methodology closely mirroring the FDA and EMEA guidelines as a template to identify "well-designed" RCTs from which effective and clinically meaningful non-hormonal hot flash therapies could be identified. In addition, pertinent safety information was reviewed. Out of 3548 MEDLINE citations and abstracts, 51 well-designed hot flash RCTs were identified. From these trials, gabapentin, oxybutynin ER, desvenlafaxine, soy-derived isoflavones and black cohosh each showed a clinically meaningful treatment effect in at least 1 RCT. Among these 5 compounds, only gabapentin demonstrated consistent and statistically significant benefit over placebo in all of its well-designed RCTs. Desvenlafaxine, soy-derived isoflavones, and black cohosh demonstrated statistically significant benefit over placebo in 75%, 21%, and 17% of the well-designed RCTs for each compound, respectively. There was only 1 well-designed RCT using oxybutynin ER, which showed it to have a robust and clinically meaningful benefit. In terms of safety, there have been cardiovascular risks associated with desvenlafaxine use in postmenopausal women with hot flashes. The use of anticonvulsants, in general, has been associated with an absolute 0.21% increase in suicidal thoughts and behavior. Further research is needed with several of these nonhormonal compounds to replicate these findings and to also directly compare their efficacy and tolerability with those of hormone replacement therapy.

Agomelatine: new drug. Adverse effects and no proven efficacy.

(1) When an antidepressant is considered a necessary addition to psychological support in treating patients with depression, the first-line drug is a tricyclic such as clomipramine or a selective serotonin reuptake inhibitor (SSRI) such as paroxetine; (2) Agomelatine, a melatonin receptor agonist, is approved in the European Union for the treatment of depression; (3) Available evaluation does not include any clinical trials designed to compare the efficacy of agomelatine with that of a tricyclic or a selective serotonin reuptake inhibitor. Most data come from 7 placebo-controlled trials; (4) Agomelatine (25 mg/day) was statistically more effective (on a rating scale) than placebo in only 3 of these 7 trials. The clinical relevance of the score improvements is questionable. No data are available on the cure rate or on suicide prevention; (5) In one trial, increasing the daily dose from 25 mg to 50 mg provided no supplementary benefit; (6) A trial in 367 patients failed to show that agomelatine was any more effective than placebo in preventing new depressive episodes (29% after one year). In another trial including 339 patients, the relapse rate was statistically lower after 6 months on agomelatine (20.6%) than on placebo (41.4%); (7) Very high doeses of agomelatine are oncogenic in animals. The risk in humans is not known. Dizziness, gastrointestinal and cutaneous disorders have been observed. Agomelatine is probably hepatotoxic; (8) In summary, agomelatine has unproven efficacy and poorly documented adverse effects. It is better to continue to use older antidepressants such as tricyclics or serotonin reuptake inhibitors.

Concomitant therapy with Cineole (Eucalyptole) reduces exacerbations in COPD: a placebo-controlled double-blind trial.

BACKGROUND: The clinical effects of mucolytics in patients with chronic obstructive pulmonary disease (COPD) are discussed controversially. Cineole is the main constituent of eucalyptus oil and mainly used in inflammatory airway diseases as a mucolytic agent. We hypothesised that its known mucolytic, bronchodilating and anti-inflammatory effects as concomitant therapy would reduce the exacerbation rate and show benefits on pulmonary function tests as well as quality of life in patients with COPD. METHODS: In this double-blind, placebo-controlled multi-center-study we randomly assigned 242 patients with stable COPD to receive 200 mg of cineole or placebo 3 times daily as concomitant therapy for 6 months during winter-time. The frequency, duration and severity of exacerbations were combined as primary outcome measures for testing as multiple criteria. Secondary outcome measures included changes of lung function, respiratory symptoms and quality of life as well as the single parameters of the exacerbations. RESULTS: Baseline demographics, lung function and standard medication of both groups were comparable. During the treatment period of 6 months the multiple criteria frequency, severity and duration of exacerbations were significantly lower in the group treated with cineole in comparison to placebo. Secondary outcome measures validated these findings. Improvement of lung function, dyspnea and quality of life as multiple criteria were statistically significant relative to placebo. Adverse events were comparable in both groups. CONCLUSION: Concomitant therapy with cineole reduces exacerbations as well as dyspnea and improves lung function and health status. This study further suggests cineole as an active controller of airway inflammation in COPD by intervening in the pathophysiology of airway inflammation of the mucus membrane. TRIAL REGISTRATION: ISRCTN07600011.

Activation of cannabinoid-1 receptors disrupts sensory gating and neuronal oscillation: relevance to schizophrenia.

BACKGROUND: Impaired auditory gating and abnormal neuronal synchrony are indicators of dysfunctional information processing in schizophrenia patients and possible underlying mechanisms of their impaired sensory and cognitive functions. Because cannabinoid receptors and endocannabinoids have been linked to psychiatric disorders, including schizophrenia, the aim of this study was to evaluate the effects of cannabinoid-1 (CB1) receptor activation on sensory gating and neuronal oscillations in rats. METHODS: Auditory sensory gating has been recorded from the hippocampus and entorhinal cortex (EC) in anesthetized rats. Neuronal network oscillations were recorded from the hippocampus, medial septum, EC, and medial prefrontal cortex in anesthetized and freely moving rats. Effects of systemic administration of CB1 receptor agonist CP-55940 were evaluated on these parameters. RESULTS: CP-55940 significantly disrupted auditory gating both in the hippocampus and EC in anesthetized rats. Theta field potential oscillations were disrupted in the hippocampus and EC, with simultaneous interruption of theta-band oscillations of septal neurons. Administration of the CB1 receptor antagonist AM-251 reversed both the agonist-induced gating deficit and the diminished oscillations. In freely moving rats, CP-55940 significantly reduced theta and gamma power in the hippocampus, whereas in the EC, only gamma power was attenuated. However, novelty-induced theta and gamma activities were significantly diminished by CP-55940 in both the hippocampus and EC. CONCLUSIONS: Our data indicate that activation of CB1 receptors interferes with neuronal network oscillations and impairs sensory gating function in the limbic circuitry, further supporting the connection between cannabis abuse and increased susceptibility of developing schizophrenia spectrum disorders.

Effects of selective serotonin reuptake inhibitors and venlafaxine during pregnancy in term and preterm neonates.

OBJECTIVES: Our goals were to (a) describe neonatal behavioral signs in a group of newborns exposed in utero to selective serotonin reuptake inhibitors or venlafaxine at the time of delivery, (b) compare the rate of neonatal behavioral signs, prematurity, and admission to specialized neonatal care between a group of exposed and unexposed newborns, and (c) compare the effects in exposed preterm and term newborns. PATIENTS AND METHODS: This was a retrospective cohort study including mothers taking selective serotonin reuptake inhibitors or venlafaxine during the third trimester and mothers who were not taking any antidepressants, psychotropic agents, or benzodiazepines at the time of delivery of their newborns. Neonatal behavioral signs included central nervous, respiratory, and digestive systems, as well as hypoglycemia and the need for phototherapy. RESULTS: Seventy-six mothers taking antidepressants and 90 untreated mothers and their newborns were analyzed. Smoking, alcohol intake, and substance abuse were more frequent among treated mothers. In infants in the exposed group, signs involving the central nervous and the respiratory systems were often observed (63.2% and 40.8%, respectively). These signs appeared during the first day of life, with a median duration of 3 days for exposed newborns. The signs resolved in 75% of cases within 3 to 5 days for term and premature newborns, respectively. All exposed premature newborns presented behavioral manifestations compared with 69.1% of term exposed newborns. Median length of stay was almost 4 times longer for exposed premature newborns than for those who were unexposed (14.5 vs 3.7 days). CONCLUSIONS: Neonatal behavioral signs were frequently found in exposed newborns, but symptoms were transient and self-limited. Premature infants could be more susceptible to the effects of selective serotonin reuptake inhibitors and venlafaxine.

[Selective serotonin reuptake inhibitors in major depressive disorder in children and adolescents (ratio of benefits/risks)]. / Indication des inhibiteurs de la recapture de la sérotonine au cours d'un épisode dépressif majeur chez l'enfant et l'adolescent (bénéfices/risques).

UNLABELLED: Major depressive disorder in children and adolescents is associated with high risk of suicide and persistent functional impairment. While psychological treatments are used as a first line treatment in mild and moderately severe depression in this age group, the number of prescriptions for antidepressant medication (SSRI) has grown in recent years. Recently, FDA and MHRA advised that most of SSRI should not be used to treat MDD under the age of 18 years. They may increase the risk of suicidal thoughts and self harm. We reviewed the recent literature on efficacy and suicide risks of SSRI in depressed young people. Conflicting findings of SSRI efficacy have been reported in clinical studies. The discrepancies could be related to the heterogeneous samples and the absence of a standard definition of treatment effectiveness. In randomised placebo-controlled antidepressant clinical trials (RCT), the assessment of treatment effectiveness is commonly made with the CDRS-R (improvement of 20% or 30% or 40%) and CGI. SSRI demonstrated significantly, but modest, improvement compared with placebo in CGI score of 1 or 2: 10% more for sertraline, 16.8% more for paroxetine and between 16 to 24% more for fluoxetine. In adults, RCT studies have shown placebo response rates of 30% to 50%, drug response rates of 45% to 50% and drug-placebo differences of 18% to 25%. The highest placebo response rates, in young people, may be related to the highly selected group not representative of the general population of depressed patients and/or to the high youths' sensibility of psychotherapy. Patients participating in antidepressant clinical trials have a low BDI and CDI in Emslie's study for example (2002). In adults, previous reports suggest that SSRI use is associated with increased suicidal risk. But the analyse of 48 277 depressed patients participating in RCT for nine FDA approved antidepressants fail to support an overall difference in suicide risk between antidepressants (SSRI) and placebo treated subjects. An inverse relationship between regional change in use of antidepressants (increased) and suicide (decreased) is found in young -people in United States from 1990 and 2000. We can not draw a conclusion from few studies with few -participants. None suicide have been reported in pharmacological studies. And the link between "suicidality" and MDD can not be excluded. The instruments of assessment in depressed young patients are based on extensions of adult procedures. Whereas clinical picture of MDD in children, adolescents and adults have some differences. Depressed youngsters have more pronounced mood lability. Depressed adolescents have more anhedonia than depressed children. Future investigations into the efficacy and safety of treatments for children and adolescents depression should use specific instruments directly built on phenomenological and clinical picture of depressed children and adolescents. Comparison studies of pharmacotherapy, specific psychotherapies (not only CBT) and combined therapies are necessary to identify the adolescents who will benefit the most from specific or combined therapies. Further studies into the factors that influence treatment outcome including clinical picture (clinical dimensions, severity, duration, co morbidity), genetic factor, age, and i-llness course may help identify appropriate treatments for children and adolescents with MDD. Studies should include patients more severely ill, with associated psychiatric troubles, treatment resistance, history of relapses... In clinical studies, the link between "suicidality" and some clinical dimensions (which take part in clinical picture or not) must be analysed by assessing anhedonia, hopelessness feel, impulsive trait, borderline personality, familial inter-action, biological indices. New treatment should be expand and their efficacy and safety must be study: St John's worth, Bright light therapy, Trans-cranial Magnetic Stimulation. IN PRACTICE: suicide and MDD have a strongest relation and it must be investigate syste-matically during the course of MDD. The suicide risk increases in the context of past history of suicide attempts, hopelessness, psychosis, impulsivity traits, substance abuse, familial dysfunction, life events, open access of arms. The use of SSRI in depressed children and adolescents is also the question of the quality and the support of the consultant and the mode of the prescription.

[Occurrence of ileus after voglibose treatment in an elderly diabetic patient with gait disturbance caused by cerebral hemorrhage].

Alpha-glucosidase inhibitor can suppress postprandial hyperglycemia by delaying the absorption of carbohydrates in the intestine, and may be useful in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) and preserved insulin secretion. We encountered an obese elderly patient with NIDDM in whom gait disturbance had developed after cerebral hemorrhage and who suffered from ileus after treatment with voglibose. The patient had received voglibose which is reported to cause fewer abdominal symptoms than acarbose, for 15 days. The patient, a 63-year-old woman, was given a diagnosis of NIDDM in February 1995, and was treated with a sulfonylurea agent. However, her glycemic control remained poor and she was admitted to our hospital in April 1995. Her body mass index was 30.5 kg/m2 and laboratory investigation revealed a fasting plasma glucose level of 211 mg/dl, a postprandial (2 h) plasma glucose level of 288 mg/dl, HbAlc of 9.9%, a fasting insulin level of 9 microU/ml, urinary C-peptide excretion of 95.7 micrograms/ day, and an coefficient of variation of R-R value of 2.1%. Fifteen days after glibenclamide was replaced by to voglibose, abdominal pain, nausea, constipation, and ausculatory sounds of gurgling developed, and niveau were noted on an abdominal roentgenogram which indicated that simple ileus had developed. Voglibose was discontinued and the patient was treated with an enema and hot air. She recovered from simple ileus on the next day. This patient had had two abdominal surgeries and a cerebral hemorrhage, and her daily physical activities were limited, which might have contributed to ileus. In elderly patients with NIDDM, a history of abdominal surgery and the amount of daily exercise must be considered when deciding whether or not to give alpha-glucosidase inhibitors.