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Proton pump inhibitors are widely prescribed but their long-term use can expose patients to adverse effects. Some of these are not very well known, including hypomagnesemia. Hypomagnesemia can be manifested by cardiac complications such as supraventricular arrhythmia or QT prolongation, increasing the risk of torsade de pointe. We present a case of atrial fibrillation triggered by severe hypomagnesemia secondary to proton pump inhibitor use and exacerbated by thiazide diuretic treatment. Conversion to sinus rhythm showed a prolonged corrected QT interval. We approach the pathophysiology and the electrophysiologic effects of hypomagnesemia.

AldaraCase 1. Five sachets weekly of imiquimod were prescribed for Bowen's disease on the forearm in a patient known to have essential thrombocytosis under Hydrea. The literature review identified reports of dose-dependent lymphopenia under oral imiquimod but not under Aldara

In the last decade, a growing body of evidence has highlighted the major role of cancer immunosurveillance. The immune system can recognize tumor cells and keep them under check for long period of time, but is impeded by escape mechanisms induced by the tumor itself. Interestingly, the efficacy of chemotherapy has been shown to depend on the immune response, which in turn is potentiated by chemical agents, creating a positive feedback loop leading to long term tumor resistance. In this review, we summarize some mechanisms underlying the synergy between chemo- and immuno-therapy.

Lithium is among the most classically recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with lithium requires achieving plasma levels above 0.5 mEq/L. Mood-stabilizing antiepileptic drugs such as carbamazepine, valproate derivatives or lamotrigine have not demonstrated conclusive therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Thyroid hormones are considered among the currently recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with thyroid hormones requires achieving plasma concentration of TSH close to the lower limits at the normal range (0.4 μUI/L) or even below it. Second-generation antipsychotics such as aripiprazole or quetiapine have consistently demonstrated significant therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Second-generation antipsychotics however require the careful monitoring of both cardiovascular and metabolic adverse effects.

Triplixam is a fixed dose combination of three well known antihypertensive agents, with complementary activities, to control blood pressure in patients with arterial hypertension: perindopril, an angiotensin converting enzyme inhibitor, indapamide, a diuretic whith thiazide-like effects but also specific properties, and amlodipine, a long-acting calcium antagonist of the dihydropyridine family. The potential synergic action allows better control of blood pressure with once daily administration, while limiting the incidence of adverse events. Various presentations with different dosages are available to facilitate individualized therapy. Warnings and precautions for use of every molecule should of course be respected. Such a fixed dose combination should contribute to limit clinical inertia and to improve therapeutic compliance.

Antithrombotic (anticoagulants and antiplatelets) are responsible for iatrogenic accidents, with a specific impact in neurosurgery. Bleeding complications are the most common and best-known. But the link to antiplatelet or to dual association of antithrombotic treatment with intracranial haemorrhage is not complete yet. We studied the proportion of patients under antithrombotic treatment, when an intracranial hemorrhage occurred, as well as the morbi-mortality of each group of patients (with or without antithrombotic treatment). Finally, we studied the proportion of off-label prescriptions.We conducted a monocentric and comprehensive prospective study on a group of patients. All patients that had been admitted for intracranial hemorrhage to our hospital, in a 5-month period were included in the study.One hundred and sixty patients admitted for an intracranial hemorrhage were included during 70days of call. Seventy-four of these patients (46.25%) were under antithrombotic treatment: 40 under antiplatelet treatment (54%), 29 under anticoagulant treatment (39.2%), four under dual antithrombotic treatment (5.4%), and one under Arixtra(®). Half of the patients under antithrombotic treatment had poor prognosis as compared to 40% of patients without antithrombotic treatment. Off-label antithrombotic therapy was estimated at 27.3% of all prescriptions.The prevalence of antithrombotic therapy in patients is high when intracranial hemorrhage occurs. Some complications could be avoided by decreasing the number of off-label prescriptions and by better controlling their use (using standardized INR). Antiplatelet treatments and new antithrombotic therapies require better drug monitoring which could be part of the establishment of a specific register.

Poly(ADP-ribose) polymerase (PARP) family has become a promising therapeutic target in various malignancies including breast cancer. When homologous recombination repair is deficient, as it is observed in BRCA1/2-mutated tumor models, inhibition of PARP was shown to induce massive and selective tumor cell death (the so-called "synthetic lethality"). In breast cancer, PARP inhibitors have been developed as single-agent in BRCA1/2-mutated tumors or in combination with chemotherapy. Recently, a randomized phase III clinical trial failed to demonstrate any survival improvement by combining the iPARP iniparib to chemotherapy in triple-negative metastatic breast cancer patients. This emphasizes the need for future development of this class of compounds to resolve critical issues such as optimal schedule of administration and association to other anticancer treatments, as well as identification of pertinent biomarkers predictive for efficacy.

International audience; With the approval of mechlorethamine by the FDA in 1949 for the treatment of hematologic malignancies, alkylating agents are the oldest class of anticancer agents. Even though their clinical use is far beyond the use of new targeted therapies, they still occupy a major place in specific indications and sometimes represent the unique option for the treatment of refractory diseases. Here, we are reviewing the major classes of alkylating agents and their mechanism of action, with a particular emphasis for the new generations of alkylating agents. As for most of the chemotherapeutic agents used in the clinic, these compounds are derived from natural sources. With a complex but original mechanism of action, they represent new interesting alternatives for the clinicians, especially for tumors that are resistant to conventional DNA damaging agents. We also briefly describe the different strategies that have been or are currently developed to potentiate the use of classical alkylating agents, especially the inhibition of pathways that are involved in the repair of DNA lesions induced by these agents. In this line, the development of PARP inhibitors is a striking example of the recent regain of interest towards the "old" alkylating agents.

The importance of targeted therapies has been emphasized by clinical trials using antiangiogenic or HER2 inhibitors in breast cancer. First with trastuzumab, it was demonstrated that targeted therapies may improve outcome in patients with HER overexpressing breast cancer in metastatic or adjuvant settings. The emerging role for angiogenesis inhibitors has also been demonstrated with bevacizumab. Unfortunately, there is growing clinical and biological evidence that tumour cells may develop unexpected and complex mechanisms of resistance to those targeted therapies. This review outlines the mechanisms by which tumour cells may resist to new targeted agents. Most recent developments are also highlighted.

Treatment of hypertension increasingly requires association of drugs. Among them, the association of calcium antagonists with angiotensin converting enzyme inhibitors is a new tempting approach since the two pharmaceutical classes have synergistic effects on blood pressure lowering and target organ protection whereas their effect is antagonistic for adverse events. Numerous large randomized clinical trials have validated this treatment strategy, and new fixed association are being developed. They apply to hypertensive patients, but also to coronary artery disease patients and more generally speaking to high cardiovascular risk subjects.

Isolation of a bacterial strain at the infectious site and determination of the susceptibility profile may help to guide appropriate antibiotic treatment. However technical difficulties justify interpretative reading to recognize interfering resistance mechanisms from resistance phenotypes. The aim of this article is to give some examples showing interpretative reading of routine sensitivity test data.

In spite of its seriousness, dependence on alcohol and benzodiazepines during substitution treatment are poorly documented. Its frequency is nonetheless significant. According to studies, between one and two thirds of patients are affected. This consumption is under verbalized by patients and underestimated by carers. In one study, where the average diazepam doses were from 40 to 45 mg per day, 30% of the patients were taking 70 to 300 mg per day, two thirds having experimented with a fixed dose of 100mg. Benzodiazepines, especially diazepam and flunitrazepam, were studied versus placebo. Thus, 10 to 20mg of diazepam gave rise to euphoria, a sensation of being drugged, sedation and lessening of cognitive performance. The aim of this consumption is to potentiate the euphoria induced by opioids, a "boost" effect during the hour after taking it, or the calming of the outward signs of withdrawal. The most sought after molecules are the most sedative, those with pronounced plasmatic peaks, and the most accessible.In multidependant subjects, opioid dependence had been earlier in adolescence, with a number of therapeutic failures. They had been faced with repetitive rejection and separation during childhood, medicolegal and social problems. Somatization, depression, anxiety and psychotic disorders are frequent in this subgroup. Heavy drinkers under methadone treatment are highly vulnerable to cocaine. Their behaviour is at risk, with exchange of syringes; their survival rate is 10 years less than that of moderate consumers of alcohol. Most are single, with a previous prison, psychiatric or addictive cursus and they present significant psychological vulnerability. For some authors, benzodiazepines indicate a psychiatric comorbidity. Methadone significantly reduces the consumption of alcohol by nonalcoholic heroin addicts. Although alcohol is an enzymatic inductor of methadone catabolism, with bell-shaped methadone plasma curves over 24 hours, a substitution treatment is recommended. It has a minimum impact on care, in spite of efficiency and retention in therapeutical programs, allowing the subject's inclusion in the framework of a more regular and sustained medical follow-up. Treatment of benzodiazepine dependence by a progressive regression of doses has little efficacy in subjects which cannot control how much medication they are taking. Certain authors have suggested maintenance treatments of clonezepam. The most appropriate therapeutic propositions are: (1) maintenance of therapeutic links though a framework of deliverance from flexible substitution treatment; (2) prevention by cautious prescribing and control of dispensing medication; (3) parallel treatment of psychiatric comorbidities and related personality disorders; (4) individual psychiatric treatment, either institutional or in consistent networks.

The delay for loss of consciousness can be shortened by using high concentration sevoflurane6% and by adding N2O during inhalation induction with sevoflurane in paediatrics. Mean time for tracheal tube insertion is lower than 5 min in the majority of studies. This shorter delay is not associated with any significant increase in clinical side effects. However, recent studies have demonstrated the epileptogenic effect of high effect site sevoflurane concentration (occurrence of spike wave on the EEG). Inhalation induction with high alveolar sevoflurane concentration is questionable mainly when it is associated with hyperventilation. Positive pressure ventilation or pressure support ventilation make it possible to maintain normocapnia and to monitor FeSevo. Adding a narcotic decreases the target cerebral concentration required to perform tracheal intubation and consequently the risk of spike wave occurrence.

When boosted by ritonavir, protease inhibitors trough concentration and inhibitory quotient are increased, thus enhancing their therapeutic margin. Although the inhibitory quotient is less high when patients are pre-treated and have developed resistance mutations, it nonetheless offers a precious alternative for patients experiencing therapeutic failure. Despite great inter-individual variability in virologic responses, boosted protease inhibitors can be compared to boosted lopinavir. The latter seems superior to saquinavir boosted and indinavir boosted in terms of virologic efficacy and resistance mutations selection. A conclusion regarding boosted atazanavir and boosted fos-amprenavir versus lopinavir cannot be absolutely drawn on the basis of present results.

Anthracyclines are topoisomerase II inhibitors that are used for various malignancies, but their usefulness is limited by cardiotoxicity. Three types of cardiotoxicity are distinguished: acute, sub-acute, and chronic. The chronic toxicity is related to the peak plasma concentration and the cumulative dose. Generation of free radicals appears to be the main cause of myocardial damage in late-onset cardiotoxicity. Anthracycline toxicity is exacerbated in pediatric and elderly population. An increased toxicity is also observed after heart irradiation and with some chemotherapy combinations. Myocardial damages are asymptomatic for a long time, but echocardiography detects a reduction of left ventricular ejection fraction. Endomyocardial biopsy is the only specific test for early diagnosis of anthracycline-induced toxicity. This cardiotoxicity can be reduced by anthracycline administration modifications, pharmacological cardioprotection, and doxorubicin analogues with a better tolerance profile, as epirubicin or liposomal anthracyclines.

International audience; Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms.

Persistent asthma is a chronic airway inflammatory disease that requires treatment with anti-inflammatory drugs. Inhaled corticosteroids are the cornerstone of the treatment of airway inflammation. Clinical studies have shown that asthmatic patients treated with long-acting beta(2)-agonists and inhaled corticosteroids have more reduced exacerbations than those given higher doses of corticosteroids suggesting synergistic effects on the inflammatory process. The understanding of the molecular modes of action of these two classes of drugs explained part of the enhanced anti-inflammatory activity of the combination therapy. However, the production of cysteinyl-leukotrienes is not well controlled by corticosteroids. Anti-leukotrienes, by the blockade of the effects of cysteinyl-leukotrienes, exert therefore a complementary anti-inflammatory action.

In response to the increase of resistant depressive disorders and in spite of improved treatments, numerous studies were conducted in the last thirty Years aiming at assessing the pre-morbid thyroid state of depressed patients resistant to well conducted tricyclic treatments. "Minimal" thyroid abnormalities were evidenced as well as central thyroid disorders which may not be detected by peripheral-i.e plasmatic- dosages. Regarding the premorbid thyroid status, the hypothesis of subclinical hypothyroidism was considered by many Authors. It is marked by four grades including T3 and T4 decreased levels, basal TSH concentration abnormalities as well as increased TSH response to TRH stimulation, and the presence of antimicrosomal and antithyroglobulin antibodies. Although, there are different views on the existence or not of these abnormalities, we'll focus our attention on a metaanalysis including six studies. It shows in a population with a resistant depression, 52% of patients with subclinical hypothyroidism, against 8 to 17% in patients with simple depression and 5% in the overall population.Similarly, antithyroid antibody levels (group IV hypothyroidism) were significantly higher in depressed patients (9% to 20% against 7,5% in the overall population). For many Years, a central hypothyroidism was hypothesized on the basis of an exhausted T3-T4 transference mechanism and a lowered TRH hypothalamic biodisponibility.In the last Years, new data emerged on the role of transthyretin, a cerebral carrier T4 protein, whose concentration in the CSF was found significantly lower in depressed patients than in a control group, the lowest levels being observed in the most severely depressed. This decreased level of transthyretin would result in a lower central T4 biodisponibility-hence, in view of a T4-T3 desiodation insufficiency, a T3 deficit is observed. A low transthyretin level associated or not to subclinical hypothyroidism could be a factor of depressive vulnerability on one hand, of resistance to tricyclic treatment on the other one. Conversely, subclinical hypothyroidism could be a predictive factor of a good response to a potentializing strategy. The pharmacological mechanisms involved in this potentializing phenomenon are now well known: they consist in an interaction between depression, adrenergic receptors and thyroid hormones biodisponibility. The decreased norepinephrine level observed in depressive patients is associated, in case of increased thyroid hormones biodisponibility, with a higher sensitivity of adre-nergic receptors, mostly betaadrenergic. This seems to underly the recovery process. According to some Authors, the serotoninergic system might be involved in the potentialization of tricyclics by thyroid hormones. We know that in animals with hypothyroidism, the serotonin synthesis is decreased and that the administration of T3 increases the brain levels of serotonin and its 5HIA catabolite. In addition, T3 could correct the down-regulation induced by serotoninergics on beta-adrenergic receptors. On the basis of numerous studies carried out on the potentializing of tricyclics, we suggest practical modalities of treatment - which until today did not materialize in every day practice in the absence of a clear consensus based on statistically reliable data: after four to six weeks of inefficient tricyclic or serotoninergic treatment on a correct dosage testified by plasmatic dosages, it is recommended to initiate a T3 treatment on a effective posology (25 to 50 micrograms per day), which must be reached in 2 or 3 days, except in case of rare and transitory side effects (sweating, shaking, tachycardia, nervousness, anxiety). If the treatment is not rapidly efficient, it must be discontinued in case there is no improvement after 3 weeks. Until today, there is no consensus about the duration of a T3 treatment. It is important to take into account the predictive criteria of good or bad response to a T3 potentialization, since they have direct consequences on the management of depressed patients. For example, a high degree of chronic evolution with resistance to numerous treatments, associated disorders according to the DSM IV axis I and a comorbidity of addiction, point to a bad prognosis of a potentialization treatment. In addition, we'll examine the few recent studies on the potentializing of serotoninergic antidepressant drugs by thyroid hormones.

The risk of haemorrhagic complications associated with heparin therapy can be reduced by good clinical practice. The aim of this study was to describe outpatient heparin therapy by using the database of the National Health Fund. The study population consisted of affiliates of the salaried employees insured by the health fund branch of the Midi-Pyrénées region, and corresponded to 62% of the residents of that region. Analysis of treatments and biological monitoring was carried out on a 1-year period. During this period, 16,462 patients started a treatment with heparin, 92% for a single treatment. The mean age of the patients was 55 years (SD = 19.8) and the majority were women (53%). Nine percent of these patients were switched to oral anticoagulant therapy. Of the other patients, 52% received heparin for less than 10 days, 36% for between 10 days and 5 weeks, and 12% for more than 5 weeks; 33% of the last group where heparin was prescribed for more than 5 weeks corresponds to a prescription of more than 3 months. Seventy-three percent of the heparin treatment durations complied with the authorities' (l'Agence française de sécurité sanitaire des produits de santé [AFSSAPS]) recommendations. Biological monitoring comprised a platelet count, an APTT (activated partial thromboplastin time) or an anti-Xa check in 41.9%, 27.8% and 3.1% of treated patients, respectively. Creatininaemia was measured in 27% of patients aged75 years (a group at increased risk of adverse drug reactions). Even considering some of the differences noted between the medical prescriptions and the reimbursement data of the health fund, results from this study allowed an evaluation of medical practices and suggests that monitoring of patients receiving heparin treatments remains insufficient, thus decreasing the benefit/risk ratio of such therapies.

Antivitamin K treatments (AVK) are related to increased morbidity and mortality, notably in elderly patients. The International Normalized Ratio (INR) should be well controlled and its stabilisation within the therapeutic range help to prevent the haemorrhagic complications.A one-year prospective survey on all the cases of excess AVK was conducted in hospitalised patients aged over 70.During the study period, 225 hospitalised patients treated with AVK (mean age 84 years) were identified: 62% received warfarin, 19% fluindione, 8% acenocoumarol and 11% received several successive AVK. During this period, 1.904 INR measurements were recorded: 97 (5.1%) wereor =5.0 and 12 (0.63%) wereor =9.0. In all, 59 patients (23.1%) exhibited one or several episodes of excess AVK (INRor =5.0) and 57 exhibited a target INR of 2.5. Three patients died of accidental haemorrhage--two of them due to intra-cerebral bleeding--among the 59 patients with excess AVK. In three cases, the INR was greater than 7.0 at the time of the accident.In half of the cases of excess, the episode occurred during the month following initiation of treatment with AVK. In nearly two thirds of cases, a change had been made in drug therapy in the 10 days preceding the excess, with the prescription of a drug enhancing the effect of the AVK: anti-infection agents (antibiotics and anti-fungals) and amiodarone were the drugs most frequently involved. Oral or intravenous vitamin K1 was administered in only 19% of cases.In very old patients treated with oral anticoagulants, certain risk factors must be identified: the initiation period of treatment, the occurrence of an intercurrent disease and the subsequent change in the drug therapy. INR monitoring should be intensified in order to detect any excess and, if detected, ensure the optimal management of the patient.

Polycystic ovary syndrome is a frequent endocrine disorder often associated with insulin resistance and hyperinsulinaemia which may play a role in hyperandrogenism and anovulation. The use of "insulin sensitizing" agents has been suggested to reduce insulin resistance and hyperandrogenism. In that respect, the use of metformin in polycystic ovary syndrome is reviewed. Although its mechanism of action is still unclear, metformin proved to be effective to restore cyclicity and spontaneous ovulation. The synergistic effect of clomiphene citrate and metformin was demonstrated in some studies, suggesting that metformin could be helpful for women with clomiphene citrate resistance. However, the potential effect of metformin administration for reducing hyperstimulation in women treated with exogenous FSH, or for preventing early miscarriages has to be confirmed. Here, we propose a guideline for the use of metformin, as an adjuvant therapy, to restore cyclicity and ovulation in women with polycystic ovary syndrome.

The purpose of this article is to clarify interactions between oral contraception (using low- and high-dose oral contraceptives) and the main neurological diseases occurring in genitally active women. Vascular disorders predominate, since contraception is in itself a well-recognized a risk factor, especially in case of other intercurrent risk factors (high blood pressure, smoking, diabetes, history of vascular event) contradicting contraception. Low-dose oral contraception can be proposed for women free of these risk factors. There is however a formal contraindication for oral contraception, even with mini-dose contraceptives, for women with a history of cerebral venous thrombosis. In case of migraine headache, which is also a risk factor of vascular disease (especially in case of aura), oral contraceptives should be discussed on an individual basis, depending on the presence of other risk factors. Contraception has no effect on epilepsy but oral contraceptives may be inhibited by inducing anti-seizure drugs. Non-inducing drugs are preferable. The course of certain brain tumors known to express estrogen or progesterone receptors (particularly meningiomas and hemangioblastomas) may worsen with oral contraception, which is formally contradicted except when search for hormone receptors is negative. Oral contraception has no influence in other disease such as multiple sclerosis

In case of resistance to quinupristin, the bacteriostatic synergism is preserved but the in vivo bactericidal effect of Synercid declines. On the other hand, no selection of resistant mutants has been observed. In case of isolated resistance to dafopristin, there is no reduction in the bactericidal effect of Synercid; there is however a possible risk of selecting resistant mutants. To become resistant to Synercid, S. aureus strains have to become resistant to both quinupristin and dafopristin, a highly unlikely situation. POTENTIAL COMBINATIONS: Among the combinations of Synercid with other antibiotics, the combination with vancomycin would have particular interest for clinical applications, increasing bactericidal activity. This would be the case for severe S. aureus infections with a large inoculum and even more so for meti-R resistant strains with a C-MLSB phenotype. Combination with rifampicin would be another possibility, but only for strains not resistant to quinupristin.

SYNERCID ALONE IN A RAT MODEL OF EXPERIMENTAL ENDOCARDITIS: Trials conducted using 2 injections daily showed that animals infected with meti-R resistant Staphylococcus aureus strains sensitive to erythromycin were cured in 3 days. The same is not true for infections caused by C-MLSB-R staphylococci. The daily dose cannot be increased due to the venous toxicity of Synercid, leading to the idea of testing Synercid in combination with other antibiotics.Several antibiotics have been tested in combination with Synercid. Several beta-lactams have been shown to exhibit an additive or synergetic effect on a collection of meti-R and meti-S S. aureus strains.In animals infected with C-MLSB-R meti-R S. aureus, the combination Synercid + cefepime increases the activity of cefipime and prevents selection of beta-lactam highly resistant strains. The results obtained with the Synercid + cefpirome combination are even more eloquent. Finally, Synercid, alone or in combination with these 2 cephalosporins, does not select resistant strains.

We used knockout mice and receptor antagonist strategies to investigate the contribution of the serotonin (5-hydroxytryptamine, 5-HT) 5-HT1B receptor subtype in mediating the effects of selective serotonin reuptake inhibitors (SSRIs). Using in vivo intracerebral microdialysis in awake mice, we show that a single systemic administration of paroxetine (1 or 5 mg/kg, i.p.) increased extracellular serotonin levels [5-HT]ext in the ventral hippocampus and frontal cortex of wild-type and mutant mice. However, in the ventral hippocampus, paroxetine at the two doses studied induced a larger increase in [5-HT]ext in knockout than in wild-type mice. In the frontal cortex, the effect of paroxetine was larger in mutants than in wild-type mice at the 1 mg/kg dose but not at 5 mg/kg. In addition, either the absence of the 5-HT1B receptor or its blockade with the mixed 5-HT1B/1D receptor antagonist, GR 127935, potentiates the effect of a single administration of paroxetine on [5-HT]ext more in the ventral hippocampus than in the frontal cortex. Furthermore, we demonstrate that SSRIs decrease immobility in the forced swimming test; this effect is absent in 5-HT1B knockout mice and blocked by GR 127935 in wild-type suggesting therefore that activation of 5-HT1B receptors mediate the antidepressant-like effects of SSRIs. Taken together these data demonstrate that 5-HT1B autoreceptors appear to limit the effects of SSRI on dialysate 5-HT levels particularly in the hippocampus while presynaptic 5-HT1B heteroreceptors are likely to be required for the antidepressant activity of SSRIs.

The causal effect of cannabis, associated or not with smoking, in juvenile thromboangiitis disorders such as Leo Buerger disease, has been suggested. We describe here a case of a 30-year-old woman who smoked cannabis and developed intermittent claudication of the lower limbs. Female sex and proximal localization of the lesions (external iliac artery) are not usually described in "cannabis arteritis". Cannabis would be involved not only in the pathogenesis of juvenile obstructive arteriopathy, but also in the development of atheromatous lesions in the young subject.

Hydroxyurea is an anticancerous product, used recently in the treatment of HIV-1 infection thanks to its inhibitory action in viral replication, potentialization of the nucleosides activity (particularly ddI or didanosine) and its cytostatic properties on CD4 and CD8 lymphocytes. Many studies showed its efficiency, as further drug, in initial regimen of a tritherapy (containing ddI) and salvage therapy. The dosage of 500 mg bid seems tolerated well by adults, and 20 mg/kg by children. Long-term tolerance remains unknown. With ddI, it could be proposed in developing countries.