Brucella central carbon metabolism: an update.

The brucellae are facultative intracellular pathogens causing brucellosis, an important zoonosis. Here, we review the nutritional, genetic, proteomic and transcriptomic studies on Brucella carbon uptake and central metabolism, information that is needed for a better understanding of Brucella virulence. There is no uniform picture across species but the studies suggest primary and/or secondary transporters for unknown carbohydrates, lactate, glycerol phosphate, erythritol, xylose, ribose, glucose and glucose/galactose, and routes for their incorporation to central metabolism, including an erythritol pathway feeding the pentose phosphate cycle. Significantly, all brucellae lack phosphoenolpyruvate synthase and phosphofructokinase genes, which confirms previous evidence on glycolysis absence, but carry all Entner-Doudoroff (ED) pathway and Krebs cycle (and glyoxylate pathway) genes. However, glucose catabolism proceeds through the pentose phosphate cycle in the classical species, and the ED pathway operates in some rodent-associated brucellae, suggesting an ancestral character for this pathway in this group. Gluconeogenesis is functional but does not rely exclusively on classical fructose bisphosphatases. Evidence obtained using infection models is fragmentary but suggests the combined or sequential use of hexoses/pentoses, amino acids and gluconeogenic substrates. We also discuss the role of the phosphotransferase system, stringent reponse, quorum sensing, BvrR/S and sRNAs in metabolism control, an essential aspect of the life style of facultative intracellular parasites.

[Varenicline: an aid to smoking cessation therapy]. / Le sevrage tabagique: une nouvelle molécule orale, la varenicline (Champix).

Varenicline orally administered nicotine acetylcholine receptor partial agonist is approved by the US FDA and the MEA for use as an aid to smoking cessation therapy. Varenicline is more effective than bupropion but does not reduce weight gain after cessation. The superiority of de varenicline on the nicotine is not demonstrated. Nausea is a frequent adverse effect. The long term safety of varenicline is unknown. The major weapons for smoking cessation are represented by the motivation of the patient and a long term psychotherapy. As to the subject of drugs, varenicline is situated in second position, after the failure of a nicotine substitute.

[Pregabalin (Lyrica) and neuropathic pain syndromes]. / La prégabaline (Lyrica) et les douleurs neuropathiques périphériques.

Pregabalin is a novel central nervous system (CNS) drug with no interaction at benzodiazepine or GABA receptor. Its mechanism of action is correlated with its high affinity for the alpha/delta submit of the voltage-dependant CNS calcium channel. Pregabalin is rapidly absorbed with at least 90% bioavailable irrespective of dose, does not bind to plasma proteins and is excreted virtually unchanged by the kidneys. Pharmacokinetics are linear and predictable across the therapeutic dose range (150-600 mg/ day). Pregabalin is indicated, like gabapentin, in the treatment of neuropathic pain syndromes like post-herpetic neuralgia (PHN) and diabetic polyneuropathy (DPN). Efficacy in other neuropathic pain syndromes need further investigations. This paper emphasizes advantages and disadvantages on a clinical point of view.

[Omalizumab, an anti-IgE monoclonal antibody to treat severe asthma]. / L'omalizumab (Xolair), un anticorps monoclonal anti-IgE pour traiter l'asthme sévère.

Omalizumab (Xolair) is the first representative of a new therapeutical class for severe allergic asthma. By neutralizing Ac IgE, omalizumab fulfils an anti-inflammatory action of which the effect has been shown beneficial in the treatment of severe allergic asthma and particularly in severe asthma for which the therapeutical arsenal is for the time being disappointing and associated to frequent side effects there where omalizumab is well tolerated.

[Omalizumab, an anti-IgE monoclonal antibody to treat severe asthma]. / L'omalizumab (Xolair), un anticorps monoclonal anti-IgE pour traiter l'asthme sévère.

Omalizumab (Xolair) is the first representative of a new therapeutical class, which will be soon available in severe allergic asthma. By neutralizing Ac IgE, omalizumab fulfils an anti-inflammatory action of which the effect has been shown beneficial in the treatment of severe allergic asthma and particularly in severe asthma for which the therapeutical arsenal is for the time being disappointing and associated to frequent side effects there where omalizumab is well tolerated.

[Insulin analogues: place of detemir (Levemir)]. / Les analogues de l'insuline: la place de la détémir (Levemir).

Insulin detemir (Levemir) is a soluble long-acting human insulin analogue acylated with a 14-carbon fatty acid. Insulin detemir is 98-99% albumin bound in plasma. It has a more predictable glucose-lowering effect than NPH insulin or insulin glargin. There is a dose-response relationship, but at the dose of 0.4 units/kg (an average normal dose), the duration of action reaches nearly 24 h. Therefore, detemir, most often injected once per day at bedtime, seems to be the ideal basal insulin in the basal-prandial therapy for type 1 diabetic patients. The boli of insulin, in order to cover shown to reduce the risk of (severe) hypoglycaemias, particularly nocturnal (up to 50 %). Fasting hyperglycaemia is often lower, but it is not necessarily true for glycated haemoglobin. In addition, detemir has been associated with less weight gain than NPH insulin. Detemir is well tolerated and no specific safety concerns have been raised.

[Insulin analogues: place of detemir (levemir)]. / Les analogues de l'insuline: la place de la détémir (levemir).

Insulin detemir (Levemir) is a soluble long-acting human insulin analogue acylated with a 14-carbon fatty acid. Insulin detemir is 98-99% albumin bound in plasma. It has a more predictable glucose-lowering effect than NPH insulin or insulin glargin. There is a dose-response relationship, but at the dose of 0.4 units/ kg (an average normal dose), the duration of action reaches nearly 24 h. Therefore, detemir, most often injected once per day at bedtime, seems to be the ideal basal insulin in the basal-prandial therapy for type 1 diabetic patients. The boli of insulin, in order to cover the meals, may be done with a rapid acting human insulin and/or a fast acting analogue. In comparison with NPH insulin, detemir has been shown to reduce the risk of (severe) hypoglycaemias, particularly nocturnal (up to 50%). Fasting hyperglycaemia is often lower, but it is not necessarily true for glycated haemoglobin. In addition, detemir has been associated with less weight gain than NPH insulin. Detemir is well tolerated and no specific safety concerns have been raised.

[Omega-3 fatty acids and cardiovascular diseases]. / Les acides gras oméga-3 et les pathologies cardio-vasculaires.

Most--but not all--epidemiological studies have demonstrated that omega-3 intake, either from nutrition or supplementation, reduces cardiovascular risk. A few intervention studies have shown a reduction of studden death in patients followed after a myocardial infarction. However EBM studies from the Cochrane Library do not confirm the real advantage of omega-3 in any group of subjects. Probably, the most interesting prescription of omega-3 supplementations would benefit to the patients after myocardial infarction, in addition to drugs that have proved their efficacy (aspirine, beta-blocker statin and ACE inhibitor).

[Inhaled human insulin (Exubera): a revolution?]. / L'insulinothérapie par voie inhalée (Exubera), une révolution?

Type 2 diabetes is a step by step process which, at the end, leads to insulin injections. This last step is accomplished in many cases with great delay which increases the risk of micro- and macro-vascular complications. Patients are often reluctant to accept insulin injections and clinicians frequently postpone insulin prescription for many reasons. Any method which could favour more insulin initiation is welcome and this is the case with inhaled insulin. Efficacy has been demonstrated in type 2 and type 1 patients as well as safety if indications are strictly followed by patients and physicians. Long-term results (about 4 years) have been published, indicating efficacy and safety. At the present time, no cost/benefit study has been published and the extra cost of such a treatment will probably retard its clinical application.

[Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system]. / Le rimonabant (Acomplia), inhibiteur spécifique du système endocannabinoïde.

The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.

[Rimonabant (Acomplia), specific inhibitor of the endocannabinoid system]. / Le rimonabant (Acomplia), inhibiteur spécifique du système endocannabinoïde.

The endocannabinoid system plays a major role in the regulation of body energy by stimulation of the appetite in the hypothalamus and increase of fat accumulation in adipocytes. The blockade of the cannabinoid system (CB1) by the specific inhibitor (rimonabant) decreases food intake and adiposity in animals and in humans. Moreover rimonabant lowers tobacco addiction. Clinical studies (RIO-LIPIDS and RIO-EUROPE) have recently confirmed that rimonabant combined with a hypocaloric diet over 1 year, promoted significant decrease of body weight, waist circumference and improvement of dyslipidemia. Rimonabant was well tolerated with mild and transient side effects. The future place of rimonabant in the strategy of obesity is still to be clarified.

[Dutasteride (Avodart): a novel 5-alpha reductase inhibitor for treatment of benign prostate hypertrophy]. / Dutasteride (Avodart): un nouvel inhibiteur de la 5-alpha réductase pour traiter l'hypertrophie bénigne de la prostate.

Dutasteride (Avodart), a novel dual 5-alpha reductase inhibitor is effective for the treatment of benign prostate hypertrophy, of more than 30 cc because the reduction of the level of dihydrotestosterone. By reducing prostatic volume, dutasteride improves moderate to severe symptoms and flow rate. It allows a reduction of disease progression by reducing the rate of acute urinary retention and need for surgery.

[Obesity in adult patients: check up and treatment]. / L'obésité chez l'adulte: mise au point et prise en charge.

Obesity is now one of the major health problems in industrial countries as well as in developing world. Excess caloric intake and reduction of the physical activity are the main causes of obesity. This epidemic precedes a tremendous increase of type 2 diabetes, which is generally linked to weight excess. Obesity and type 2 diabetes are associated with morbidity and mortality and are very expensive for the social security. The important point is to define the risks linked to obesity taking into account the Body Mass Index and the importance of visceral obesity evaluated by waist measurement. After medical check up, a strategy will be discussed with the patient, including moderate caloric restriction and increased physical activity. Our patients and also some doctors suggest "popular diets" whose efficacy has not been demonstrated as superior. On a short time basis, low carbohydrate and high protein diets have some advantages, which can help our obese subjects but on long term, only hypocaloric and equilibrated diets are advisable. Drugs that proved their efficacy and tolerance may be prescribed in case of failure. Three drugs are presented, orlistat, sibutramine and metformine: their efficacy, secondary effects, interactions and finally their positioning. Bariatric surgery will be proposed to highly selected patients presenting morbid obesity.

[Treatment of Paget's disease of bone with zoledronic acid]. / Le traitement de la maladie osseuse de Paget par l'acide zolédronique.

Bone pain and bone deformities are the most common manifestations of Paget's disease of bone, even if the diagnosis is nowadays most often made by chance following a routine measurement of serum alkaline phosphatase. Woven bone is formed following a marked increase in bone resorption due to a stimulation of osteoclast activity. Biphosphonates constitute the modern treatment of Paget's disease of bone. Tiludronate (Skelid), or better risedronate (Actonel), are administered orally every day during at least 2 months. Zoledronic acid (Aclasta), as a single 15-min 5 mg infusion, has been recently compared to risedronate, 30 mg/d orally for 2 months, in two randomized studies including 357 patients. Zoledronic acid had a superior therapeutic efficacy, as judged by its rapidity of action, the duration of the biochemical response and the percentage of responders. Thus, at 6 months, alkaline phosphatase levels were normalized in 89% of the patients in the zoledronic acid group as compared to 58% in the risedronate group. The most frequent side effect was a flu-like syndrome, observed in 10% of the patients. An adequate intake of calcium and vitamin D is recommended to avoid posttreatment hypocalcemia. The introduction of Aclasta should simplify and improve the therapeutic management of Paget's disease of bone.

[Ezetimibe (Ezetrol): the statins' partner]. / L'ezétimibe (Ezetrol): le partenaire des statines.

Ezetimibe is a new cholesterol absorption inhibitor that selectively inhibits dietary and biliary cholesterol absorption from the intestine. This drug inhibits cholesterol absorption without affecting the absorption of triglycerides, biliary salts and fat-soluble vitamins. Inhibition of cholesterol absorption using ezetimibe 10 mg/day alone resulted in substantial reductions of plasma LDL-C concentrations (approximately 18%). Coadministration of ezetimibe 10 mg/day with statins 10 mg/day showed LDL lowering comparable to or greater than that of the highest dose of the respective statin alone. Combination therapy of ezetimibe with statins helped more patients in achieving their target LDL-C goal. Ezetimibe in coadministration with statins or alone had also favourable effects on triglycerides and HDL. In clinical studies, ezetimibe alone or coadministered with a statin was shown to have a safety profile (asymptomatic mild increases in aminotransferase levels, without evidence of rhabdomyolysis) similar to placebo or to the statin alone. Large clinical studies on clinical endpoints are in progress.

[Memantine (Ebixa), glutaminergic modulator]. / La mémantine (Ebixa), modulateur glutamatergique.

Alzheimer's disease (AD) is the most common etiology of dementia. Its incidence increases with age following an exponential trend of line between 60 and 90 years old. Anti-cholinesterasic drugs reduce modestly AD symptoms. However, they have no basic impact on the pathological evolution of the disease. Memantine offers another therapeutic approach in AD with a dissimilar mechanism of action, confronting neurotoxic effects of glutamate overload. It prevents the elevation of glutamate which destroys cholinergic neurons by inhibiting the N-methyl-D-aspartate (NMDA) receptors. Its clinical efficiency has been demonstrated during 28 weeks with 20 mg/day, in patients presenting moderate or severe AD and mild or moderately vascular dementia. Its use in association with anti-cholinesterasic (donepezil) revealed more interesting results with a significant improvement of cognitive functions and activities of daily live, compared to association placebo-donepezil. We are waiting for results of further lenghter studies, including more, well-defined, patients.

[Linezolid (Zyvoxid)]. / Le linézolide (Zyvoxid).

Linezolid is a novel antibiotic administrable by the intravenous as well as the oral route. It is aimed by its re-imbursement conditions at treating proven beta-lactam- or glycopeptide-resistant staphylococcal and enterococcal infections in the hospital and post-discharge outpatient. It has various indications: pulmonary infections, complicated skin and soft tissue infections, infections in the febrile neutropenic patient, urinary tract infections, intra-abdominal infections, chronic osteitis. Bacteriologic documentation of the infection is required to avoid overconsumption and development of resistance. The oral forms exhibit complete bio-availability. Caution is recommended with regard to linezolid's MAO inhibitory effect and the risk of thrombocytopenia requiring weekly hematologic monitoring.

[Antiplatelet therapy in 2005]. / Les antiagrégants plaquettaires en 2005.

Atherothrombosis is a common physiopathologic process resulting in morbid or fatal ischemic events affecting the cerebral, coronary, or peripheral arterial circulation. Antiplatelet agents are effective in preventing recurrence of vascular events among patients with established vascular disease or with multiple risk factors. Aspirin was the most widely studied antiplatelet drug but the optimal dose remains difficult to define. This article summarizes new data on antiplatelet agents including aspirin, clopidogrel, dipyridamole and glycoprotein IIb/IIIa antagonists with the aim of giving practical recommendations in this very moving field of therapy.