Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors

Cannabidiol (CBD) is a major nonpsychotomimetic component of Cannabis sativa that has been shown to have an anxiolytic effect in human and animal models. Earlier studies suggest that these effects involve facilitation of serotonin, a neurotransmitter that has also been related to obsessive-compulsive disorder. On the basis of this evidence, this study investigated the effects of CBD in C57BL/6J mice submitted to the marble-burying test (MBT), an animal model proposed to reflect compulsive behaviour. CBD (15, 30 and 60 mg/kg) induced a significant decrease in the number of buried marbles compared with controls (34, 41 and 48%, respectively). A similar, although larger, decrease was also found after the serotonin selective reuptake inhibitor paroxetine (10 mg/kg, 77% decrease) and the benzodiazepine diazepam (2.5 mg/kg, 84% decrease). The effect of CBD (30 mg/kg) was still significant after 7 days of daily repeated administration, whereas the effect of diazepam disappeared. Pretreatment with WAY100635 (3 mg/kg), a 5HT1A receptor antagonist, prevented the effects of paroxetine but failed to alter those of CBD. These latter effects, however, were prevented by pretreatment with the CB1 receptor antagonist AM251 (1 mg/kg). These results indicated that CBD and paroxetine decrease the number of buried marbles in the MBT through distinct pharmacological mechanisms. They also suggest a potential role of drugs acting on the cannabinoid system in modulating compulsive behaviour. Behavioural Pharmacology 21: 353-358 (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Increased soluble Fas plasma levels in subjects at high cardiovascular risk - Atorvastatin on inflammatory markers (AIM) study, a substudy of ACTFAST

OBJECTIVE Increasing evidence indicates that the Fas/Fas ligand interaction is involved in atherogenesis. We sought to analyze soluble Fas (sFas) and soluble Fas ligand (sFasL) concentrations in subjects at high cardiovascular risk and their modulation by atorvastatin treatment. METHODS AND RESULTS ACTFAST was a 12-week, prospective, multicenter, open-label trial which enrolled subjects (statin-free or statin-treated at baseline) with coronary heart disease (CHD), CHD-equivalent, or 10-year CHD risk > 20%. Subjects with LDL-C between 100 to 220 mg/dL (2.6 to 5.7 mmol/L) and triglycerides < or = 600 mg/dL (6.8 mmol/L) were assigned to a starting dose of atorvastatin (10 to 80 mg/d) based on LDL-C at screening. Of the 2117 subjects enrolled in ACTFAST, AIM sub-study included the 1078 statin-free patients. At study end, 85% of these subjects reached LDL-C target. Mean sFas levels were increased and sFasL were reduced in subjects at high cardiovascular risk compared with healthy subjects. Atorvastatin reduced sFas in the whole population as well as in patients with metabolic syndrome or diabetes. Minimal changes were observed in sFasL. CONCLUSIONS sFas concentrations are increased and sFasL are decreased in subjects at high cardiovascular risk, suggesting that these proteins may be novel markers of vascular injury. Atorvastatin reduces sFas, indicating that short-term treatment with atorvastatin exhibits antiinflammatory effects in these subjects.

Randomized controlled study demonstrating failure of LPV/r monotherapy in HIV: the role of compartment and CD4-nadir.

BACKGROUND: Long-term side-effects and cost of HIV treatment motivate the development of simplified maintenance. Monotherapy with ritonavir-boosted lopinavir (LPV/r-MT) is the most widely studied strategy. However, efficacy of LPV/r-MT in compartments remains to be shown. METHODS: Randomized controlled open-label trial comparing LPV/r-MT with continued treatment for 48 weeks in treated patients with fully suppressed viral load. The primary endpoint was treatment failure in the central nervous system [cerebrospinal fluid (CSF)] and/or genital tract. Treatment failure in blood was defined as two consecutive HIV RNA levels more than 400 copies/ml. RESULTS: The trial was prematurely stopped when six patients on monotherapy (none in continued treatment-arm) demonstrated a viral failure in blood. At study termination, 60 patients were included, 29 randomized to monotherapy and 13 additional patients switched from continued treatment to monotherapy after 48 weeks. All failures occurred in patients with a nadir CD4 cell count below 200/microl and within the first 24 weeks of monotherapy. Among failing patients, all five patients with a lumbar puncture had an elevated HIV RNA load in CSF and four of six had neurological symptoms. Viral load was fully resuppressed in all failing patients after resumption of the original combination therapy. No drug resistant virus was found. The only predictor of failure was low nadir CD4 cell count (P < 0.02). CONCLUSION: Maintenance of HIV therapy with LPV/r alone should not be recommended as a standard strategy; particularly not in patients with a CD4 cell count nadir less than 200/microl. Further studies are warranted to elucidate the role of the central nervous system compartment in monotherapy-failure.

La quétiapine dans le traitement des troubles liés à l’utilisation de substances psychoactives.

Contexte Les troubles liés à l’utilisation de substances psychoactives (TUS) sont associés à une variété de troubles psychiatriques entre autre une instabilité comportementale et affective. Plusieurs études suggèrent que les antipsychotiques atypiques peuvent être utiles dans le traitement de la toxicomanie. L’objectif principal de la présente étude à devis ouvert est d’évaluer l’efficacité de la quétiapine sur les variables reliés à la toxicomanie chez des poly-toxicomanes sans psychose comorbide entrant en désintoxication. Méthodes Dans le cadre d’une étude pharmacologique à devis ouvert d’une durée de 12 semaines, trente-trois polytoxicomanes entrant en désintoxication et répondant à un ou plusieurs critères d’abus/dépendance à une substance du DSM-IV ont été recrutés. Les patients présentant un autre trouble comorbide à l’Axe I ont été exclus. Les envies de consommer, les quantités consommées, les jours de consommation ainsi que la sévérité de la toxicomanie ont été évalués au point de départ (semaine 0) et à la fin de l’étude (semaine 12). Les symptômes psychiatriques et dépressifs furent aussi évalués. Résultats 26 des 33 patients complétèrent plus de 9 semaines de traitement. Les résultats relatifs à la dernière observation reportée (LOCF) ont montré une amélioration significative des envies de consommer, des quantités consommées, des jours de consommation, de la sévérité de la toxicomanie et des symptômes psychiatriques et dépressifs. Conclusions Nos résultats ne peuvent être attribués en soi aux effets pharmacologiques de la quétiapine, et ce compte tenu d’abord du type d’étude à devis ouvert à laquelle nous avons procédée, ainsi que le petit nombre de sujets impliqués et enfin le fait que les participants étaient impliqués dans une thérapie intensive. Ceci dit, nos résultats suggèrent quand même que la quétiapine peut être bénéfique dans le traitement des toxicomanes entrant en désintoxication. Des études randomisées sont de mises pour déterminer la pertinence de ces résultats.

Le blocage de la reconsolidation des souvenirs, une avenue possible pour le traitement du trouble de stress post-traumatique?

La présente thèse porte sur l’évaluation de l’efficacité d’un nouveau traitement pour le trouble de stress post-traumatique (TSPT). Le traitement a été développé selon les prémisses de la théorie de la reconsolidation des souvenirs. Il consiste en six courtes séances de remémoration de l’événement traumatique réalisées sous l’effet du propranolol, un bêtabloquant. La population de l’étude est constituée de patients souffrant d’un TSPT chronique. La thèse comporte cinq chapitres. Le premier chapitre est l’introduction, on y retrouve une description du TSPT, des traitements validés empiriquement, de diverses théories de la mémoire, d’un modèle étiologique du TSPT, d’études sur la consolidation et la reconsolidation, de la pharmacocinétique et du mécanisme d’action du propranolol,ainsi que des objectifs de la thèse. Le second chapitre est une revue critique de littérature sur la théorie de la reconsolidation. Comme l’étude du phénomène de la reconsolidation est récente, nous tentons de faire le point sur l’état des connaissances dans le domaine, dans un effort de réflexion sur la validité de la théorie. Nous proposons une série de critères permettant de différencier la reconsolidation d’autres processus connexes. Nous concluons que la théorie paraît valide, bien que d’autres études soient nécessaires afin de rendre compte de résultats négatifs publiés par le passé. Le troisième chapitre est un essai ouvert, et vise à évaluer l’efficacité d’un traitement basé sur la reconsolidation à diminuer la sévérité et l’incidence du TSPT, auprès de 42 patients souffrant d’un TSPT chronique. Le traitement consiste en six séances de remémoration de l’événement traumatique sous propranolol. Lors d’un suivi à trois mois, nous rapportons une diminution des symptômes de TSPT de 41%-56%, ainsi qu’une diminution de l’incidence du TSPT de 74%. En comparaison, seulement 2/25 patients du groupe contrôle (ayant participé uniquement aux évaluations) ne souffrent plus d’un TSPT. Dans le groupe traitement, les tailles d’effet (d de Cohen)varient entre 1.32-2.19. Le quatrième chapitre a comme objectif d’identifier des caractéristiques des patients prédisant l’efficacité du traitement, et d’explorer s’ils s’améliorent dans des domaines de santé autres que le TSPT. Nous rapportons que les femmes s’améliorent davantage que les hommes, mais que d’autres facteurs, tels que la sévérité des traits de personnalité borderline ou le type de trauma (enfance versus adulte), n’influent pas sur l’efficacité. Également, les patients s’améliorent dans les domaines de santé suivants : la qualité de vie, la symptomatologie dépressive, l’intensité des émotions négatives au rappel de l’événement traumatique et dans la vie courante. Le cinquième chapitre contient la discussion générale de la thèse. Nous effectuons une synthèse et interprétation des résultats, nous examinons les hypothèses alternatives à l’amélioration clinique et abordons des pistes de recherches futures. Nous concluons que le traitement à l’étude a été efficace dans notre échantillon de patients souffrant d’un TSPT chronique. Étant donné la méthodologie employée (essai ouvert), nous ne pouvons statuer sur le mécanisme d’action du traitement, à savoir si l’amélioration clinique a été réellement causée par un blocage de la reconsolidation des souvenirs.

Helicobacter pylori and Iron-deficiency Anemia in Adolescents in Brazil

Aim: The aim of the study was to evaluate the association between Helicobacter pylori infection and iron deficiency (ID) in adolescents attending a public school. Patients and Methods: From March to June 2001, a cross-sectional study was conducted among adolescents (10-16 years) enrolled in a single public school in Sao Paulo, Brazil. Of 400 eligible students, 195 agreed to participate, but 1 was excluded due to sickle cell disease. A blood sample was collected from each subject to measure hemoglobin and ferritin. H pylori status was investigated with the 13 C-urea breath test. All of the subjects with either anemia or ID were given iron therapy. Results: H pylori prevalence was 40.7% (79/194), being higher in male subjects (45/90 vs 34/104, P = 0.014). There was no relation between infection and nutritional status. Abnormally low serum ferritin was observed in 12 subjects, half of whom were positive for H pylori (odds ratio [OR] 1.49, 95% confidence interval [CI] 0.38-5.81). The median serum ferritin was 33.6 ng/mL (interquartile range 23.9-50.9) in infected subjects and 35.1 ng/mL (interquartile range 23.7-53.9) in uninfected subjects. Anemia was detected in 2% (4/194) of the students, half of whom were infected (OR 1.47, 95% CI 0.1-20.6). The mean hemoglobin value in infected subjects was 13.83 g/dL +/- 1.02 versus 14 g/dL +/- 1.06 in uninfected subjects. Conclusions: The study was not able to find a relation between H pylori infection and ID or anemia.

LIRAGLUTIDE: NEW RESULTS IN THE TREATMENT OF TYPE 2 DIABETES MELLITUS

New drugs for type 2 diabetes that act on incretin metabolism have been shown to improve glycemic control, reduce body weight and have a low risk for hypoglycemia. Among these, liraglutide is the first glucagon-like peptide 1 (GLP-1) analogue approved for subcutaneous, once-daily administration. According to results from clinical trials, liraglutide is on attractive alternative for the early treatment of type 2 diabetes. The results of the LEAD (Liraglutide Effect and Action in Diabetes) study program demonstrated the efficacy and safety of liraglutide in terms of reduction of glycated hemoglobin (HbA(tc)) levels, significant loss of body weight that was maintained over the long term, better control of the lipid profile and systolic arterial pressure, reduction of the risk for hypoglycemia and reduction of cardiovascular risk. Moreover, the drug was demonstrated to be safe and can be co-administered with oral antidiabetic agents. The product's tolerability has been demonstrated, with nausea as the most common adverse event, which waned from the fourth week of treatment.

Effects on cycle control and bodyweight of the combined contraceptive ring, NuvaRing, versus an oral contraceptive containing 30 microg ethinyl estradiol and 3 mg drospirenone

BACKGROUND: The objective of this study was to compare cycle control, cycle-related characteristics and bodyweight effects of NuvaRing with those of a combined oral contraceptive (COC) containing 30 microg of ethinyl estradiol and 3 mg of drospirenone. METHODS: A randomized, multicentre, open-label trial in which 983 women were treated (intent-to-treat population) with NuvaRing or the COC for 13 cycles. RESULTS: Breakthrough bleeding or spotting during cycles 2-13 was in general less frequent with NuvaRing than that with the COC (4.7-10.4%) and showed a statistically significant odds ratio of 0.61 (95% confidence interval: 0.46, 0.80) with longitudinal analysis. Intended bleeding was significantly better for all cycles with NuvaRing (55.2-68.5%) than that with the COC (35.6-56.6%) (P < 0.01). Changes from baseline in mean bodyweight and body composition parameters were relatively small for both groups with no notable between-group differences. CONCLUSION: NuvaRing was associated with better cycle control than the COC, and there was no clinically relevant difference between the two groups in bodyweight.

Simvastatin and ezetimibe in addition to nonpharmacological risk factor modification for achieving new low-density lipoprotein cholesterol targets

BACKGROUND: Though guidelines emphasize low-density lipoprotein cholesterol (LDL-C) lowering as an essential strategy for cardiovascular risk reduction, achieving target levels may be difficult. PATIENTS AND METHODS: The authors conducted a prospective, controlled, open-label trial examining the effectiveness and safety of high-dose fluvastatin or a standard dosage of simvastatin plus ezetimibe, both with an intensive guideline-oriented cardiac rehabilitation program, in achieving the new ATP III LDL-C targets in patients with proven coronary artery disease. 305 consecutive patients were enrolled in the study. Patients were divided into two groups: the simvastatin (40 mg/d) plus ezetimibe (10 mg/d) and the fluvastatin-only group (80 mg/d). Patients in both study groups received the treatment for 21 days in addition to nonpharmacological measures, including advanced physical, dietary, psychosocial, and educational activities. RESULTS: After 21 days of treatment, a significant reduction in LDL-C was found in both study groups as compared to the initial values, however, the reduction in LDL-C was significantly stronger in the simvastatin plus ezetimibe group: simvastatin plus ezetimibe treatment decreased LDL-C to a mean level of 57.7 +/- 1.7 mg/ml, while fluvastatin achieved a reduction to 84.1 +/- 2.4 mg/ml (p < 0.001). In the simvastatin plus ezetimibe group, 95% of the patients reached the target level of LDL-C < 100 mg/dl. This percentage was significantly higher than in patients treated with fluvastatin alone (75%; p < 0.001). The greater effectiveness of simvastatin plus ezetimibe was more impressive when considering the optional goal of LDL-C < 70 mg/dl (75% vs. 32%, respectively; p < 0.001). There was no difference in occurrence of adverse events between both groups. CONCLUSION: Simvastatin 40 mg/d plus ezetimibe 10 mg/d, on the background of a guideline-oriented standardized intensive cardiac rehabilitation program, can reach 95% effectiveness in achieving challenging goals (LDL < 100 mg/dl) using lipid-lowering medication in patients at high cardiovascular risk.

Cholinesterase inhibitors in advanced dementia with Lewy bodies: increase or stop?

INTRODUCTION There is little data on stopping cholinesterase inhibitors in Dementia with Lewy bodies (DLB). Equally, it is not known if increasing the dose of cholinesterase inhibitors may help neuropsychiatric symptoms in advanced DLB. METHOD We conducted an open label trial with donepezil involving 16 patients with LBD when the dose was reduced and treatment stopped over 4 weeks. Another 7 patients were given a trial of an increased dose of donepezil (15 mg) to resolve rehyphen;emergent neuropsychiatric symptoms. RESULTS The slow discontinuation protocol was well tolerated in advanced DLB. Five of the seven patients given a trial of a higher dose of donepezil were rated as clinically improved after 12 weeks treatment. CONCLUSION Cholinesterase inhibitors can be discontinued slowly in advanced DLB. Increasing the dose of donepezil may be of benefit to some patients with DLB who experience a recurrence in their neuropsychiatric symptoms.

Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments

After initial infection, human cytomegalovirus remains in a persistent state with the host. Immunity against the virus controls replication, although intermitent viral shedding can still take place in the seropositive immunocompetent person. Replication of cytomegalovirus in the absence of an effective immune response is central to the pathogenesis of disease. Therefore, complications are primarily seen in individuals whose immune system is immature, or is suppressed by drug treatment or coinfection with other pathogens. Although our increasing knowledge of the host-virus relationship has lead to the development of new pharmacological strategies for cytomegalovirus-associated infections, these strategies all have limitations-eg, drug toxicities, development of resistance, poor oral bioavailability, and low potency. Immune-based therapies to complement pharmacological strategies for the successful treatment of virus-associated complications should be prospectively investigated.

Objective clinical performance of ‘comfort-enhanced' daily disposable soft contact lenses

Purpose: To examine the objective clinical performance of ‘comfort-enhanced’ daily disposable contact lenses over a 16-h day. Methods: Four contact lenses (Hilafilcon B, Etafilcon A Plus, Nelfilcon A and Nelfilcon A Plus) were evaluated in an investigator masked, open label trial at the end of a week’s bilateral wear. Pre-lens noninvasive tear break-up time (PL-NITBUT), tear prism height, bulbar hyperaemia and ocular surface temperature (OST) were measured with the lens in situ at 8, 12 and 16 h of wear. Results: There was no difference between how many hours the lenses types were worn each day (F = 0.90, p = 0.44). The PL-NITBUT decreased with the duration of daily lens wear (F = 32.0, p < 0.001) and was more stable with Nelfilcon A Plus (F = 6.00, p = 0.002) than with the other lenses evaluated. Bulbar blood vessels increased in coverage (F = 11.5, p < 0.001) but not overall redness (F = 0.0, p = 0.99) with the duration of daily lens wear, but there was no difference between the lenses (p > 0.05). The tear prism height decreased with the duration of daily wear (F = 27.0, p < 0.001) and differed between lenses (F = 2.9, p = 0.04). The OST decreased with the duration of lens wear (F = 119.7, p < 0.001) and was reduced by daily disposable lens wear (F = 7.88, p < 0.001), but did not differ between lenses (F = 0.88, p = 0.45). Conclusions: Objective measures of tear film indicated a difference between the lenses evaluated for PLNITBUT and tear prism height, but not for wearing time or bulbar conjunctival hyperaemia. Therefore clinical benefits of daily disposable ‘comfort enhancing’ contact lenses can be measured, but challenges remain in producing contact lenses that do not compromise anterior eye physiology over the whole day. 2010 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

Sobreuso de analgésicos en pacientes con cefaleas primarias de un centro de referencia de Medellín

Introducción: Los pacientes con cefaleas primarias están predispuestos a desarrollar una cefalea secundaria al consumo excesivo de analgésicos. En nuestro medio, la adquisición fácil de medicamentos sin fórmula médica incrementa su frecuencia de presentación. Objetivo: Describir el perfil epidemiológico, clínico y de tratamiento de los pacientes con cefaleas primarias y cefalea secundaria por sobreuso de analgésicos atendidos en el programa especial de cefaleas del Instituto Neurológico de Colombia en el periodo 2014-2015. Pacientes y métodos: estudio descriptivo, retrospectivo. Se evaluaron características de la cefalea, comorbilidades, discapacidad y patrón de consumo de medicamentos. Resultados: Se incluyeron 834 pacientes con diagnóstico de cefalea por sobreuso de analgésicos, 85.1% con migraña crónica. El 87.6% de los pacientes eran mujeres y tenían 44 años en promedio. La mitad de los pacientes tomaba analgésicos todos los días de la semana (P25-P75: 4 – 7 días); consumiendo, en promedio, tres analgésicos/día (DE: 1.9). La mayoría de pacientes presentaba un consumo elevado de analgésicos simples (95.2%), AINES (92.2%) y analgésicos combinados (89.2%); 51% consumían opiodes y sólo 14.6% consumían triptanes. Conclusión: La identificación de esta cefalea secundaria es de vital importancia para un tratamiento adecuado. El uso medicamentos de libre venta afecta el manejo óptimo de esta entidad asociada a las cefaleas primarias, principalmente la migraña.

Efficacy and safety of non-hormonal remedies for vaginal dryness: open, prospective, randomized trial

OBJECTIVES To prove non-inferiority of the first non-hormonal vaginal cream in Germany, Vagisan(®) Moisturising Cream (CREAM), compared to a non-hormonal vaginal gel (GEL) for vulvovaginal atrophy (VVA) symptom relief. METHOD This was a 12-week multicenter, open-label, prospective, randomized, two-period, cross-over phase-III trial. The primary endpoint was the cumulative VVA subjective symptom score of the respective treatment period. Secondary endpoints were assessment of single VVA subjective and objective symptoms, VVA objective symptom score, vaginal pH, safety parameters, overall assessment of efficacy, tolerability and evaluation of product properties. In total, 117 women were randomly allocated to either one of the two treatments, each administered for 4 weeks; 92 women were included in the per-protocol analysis (primary analysis). The main outcome measure was cumulative VVA subjective symptom score. RESULTS Regarding VVA symptom relief, results confirmed non-inferiority of CREAM compared to GEL and even indicated superiority of CREAM. Frequency and intensity of subjective symptoms and objective findings were clearly reduced, with CREAM showing better results compared to GEL. Mean VVA objective symptom score significantly decreased; improvement was significantly greater with CREAM. Vaginal pH decreased only following CREAM treatment. Tolerability was superior for CREAM: burning and itching, mostly rated as mild, occurred markedly less often with CREAM than with GEL. Overall satisfaction with treatment efficacy, tolerability and most product properties were rated significantly superior for CREAM. CONCLUSIONS Subjective and objective VVA symptoms were reliably and safely reduced by both non-hormonal topical products. However, efficacy and tolerability of CREAM were shown to be superior to GEL.