Adverse events of recreational cannabis use reported to the French addictovigilance network (2012-2017).

AIMS: To describe the adverse events (AEs) of recreational cannabis use in France between 2012 and 2017. METHODS: AEs related to recreational cannabis use, alone or in combination with alcohol and/or tobacco reported to the French Addictovigilance Network were analysed (excluding cannabidiol and synthetic cannabinoids). RESULTS: Reporting of AEs tripled between 2012 (n = 179, 6.3%, 95% confidence interval [CI] = 5.4-7.2) and 2017 (n = 562, 10.1%, 95% CI = 9.3-10.9), reaching 2217 cases. They concerned mainly men (76.4%) and users aged between 18 and 34 years (18-25: 30.9%; 26-34: 26.3%, range: 12-84 years). Cannabis was mainly inhaled (71.6%) and exposure was most often chronic (64.2%). Many types of AEs were reported: psychiatric (51.2%), neurological (15.6%), cardiac (7.8%) and gastrointestinal (7.7%), including unexpected AEs (n = 34, 1.1%). The most common effect was dependence, ranging from 10.1% (95% CI = 7.9-12.3) to 20.3% (95% CI = 17.3-23.2) over the study period. Cannabinoid hyperemesis syndrome (n = 87, 2.8%) emerged from 2015. Deaths accounted for 0.2% of all AEs (4 men and 3 women aged on average 35 years). A chronic pattern of cannabis use was reported in 4 of them (intracranial hypertension in the context of lung cancer, suicide, cerebral haematoma, neonatal death with concomitant chronic alcohol use), while in the other cases the toxicological analysis identified cannabis use (ruptured aneurysm and unknown aetiology). CONCLUSION: This study showed a multitude of AEs related to recreational cannabis use, including unexpected AEs and deaths. It highlights the problem of dependence and the emergence of cannabinoid hyperemesis syndrome.

Cerebellar lesions at a young age predict poorer long-term functional recovery.

Early studies on long-term functional recovery after motor and premotor lesions showed better outcomes in younger monkeys than in older monkeys. This finding led to the widespread belief that brain injuries cause less impairment in children than adults. However, this view has limitations and a large body of evidence now indicates that cerebral damages can be more harmful when inflicted at young age, during critical periods of neural development. To date, this issue has been mainly investigated in the context of focal and diffuse cortical lesions. Much less is known about the potential influence of early cerebellar damages. Several studies exist in survivor of posterior fossa tumours. However, in these studies, critical confounders were not always considered and contradictory conclusions were provided. We studied the impact or early cerebellar damage on long-term functional recovery in three groups of 15 posterior fossa survivors, comparable with respect to their tumour characteristics (type, size and location) but operated at different ages: young (≤7 years), middle (>7 and ≤13 years) and older (>13 years). Daily (health-related quality of life scale, performance status scale), motor (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive (full-scale intelligence quotient) functioning were assessed. A general linear model controlling for age at surgery, radiotherapy, preservation of deep cerebellar nuclei, tumour volume and delay between surgery and assessment was used to investigate significant variations in outcome measures. Early age at surgery, lesion of deep cerebellar nuclei and postoperative radiotherapy had a significant, independent negative influence on long-term recovery. Tumour volume and delay between surgery and assessment had no statistically detectable impact. The negative influence of early age at surgery was significant in all domains: daily functioning (health-related quality of life scale, performance status scale), motor functioning (International Cooperative Ataxia Rating Scale, Pegboard Purdue Test) and cognitive functioning (full-scale intelligence quotient). These results support the existence of an early critical period of development during which the cerebellar 'learning machine' is of critical importance. Although the extent to which the early deficits here observed can be reversed needs now to be established, our data plead for the implementation of prompt and intense rehabilitation interventions in children operated before 7 years of age.

Selective Inhibition of Volitional Hand Movements after Stimulation of the Dorsoposterior Parietal Cortex in Humans.

Inhibition is a central component of motor control. Although current models emphasize the involvement of frontal networks [1, 2], indirect evidence suggests a potential contribution of the posterior parietal cortex (PPC). This region is active during inhibition of upper-limb movements to undesired targets [3], and its stimulation with single magnetic pulses can depress motor-evoked potentials [4, 5]. Also, it has been speculated that alien hand movements caused by focal parietal lesions reflect a release of inhibition from PPC to M1 [6]. Considering these observations, we instructed 16 patients undergoing awake brain surgery to perform continuous hand movements while electrical stimulation was applied over PPC. Within a restricted dorsoposterior area, we identified focal sites where stimulation prevented movement initiation and instantly inhibited ongoing responses (which restarted promptly at stimulation offset). Inhibition was selective of the instructed response. It did not affect speech, hand movements passively generated through muscle electrical stimulation, or the ability to initiate spontaneous actions with other body segments (e.g., the feet). When a patient inadvertently performed a bilateral movement, a bilateral inhibition was found. When asked to produce unilateral movements, this patient presented a contralesional but not ipsilateral inhibition. This selectivity contrasted sharply with the unspecific inhibitions reported by previous studies within frontal regions, where speech and all limbs are typically affected (as we here confirm in a subset of patients) [7-10]. These results provide direct evidence that a specific area in the dorsoposterior parietal cortex can inhibit volitional upper-limb responses with high selectivity.

Resveratrol distinctively modulates the inflammatory profiles of immune and endothelial cells.

BACKGROUND: The phenolic substance resveratrol (RES) is a plant metabolite known to modulate numerous physiological functions and to exert beneficial effects as a cancer-chemopreventing agent and on neurological, hepatic, and cardiovascular systems. Since the compound affects the lifespan of yeast and flies it might be an anti-aging substance. Mechanistically, RES is involved in down regulating the inflammatory response. The pleiotropic effects of RES in cells of the immune and endothelial system were examined in this study. RESULTS: Murine macrophages (RAW264.7 cells), human monocytic/leukemia cells (THP-1), PBLs and HUVECs were incubated with RES and activated with inflammatory stimuli such as LPS or TNF-α. Inflammatory mediators and adhesion molecules were measured by multiplex analysis and gene expression was quantified by RT-PCR. In PBLs, which were activated with LPS, RES blunted the production of TNF-α, CCL2/MCP-1, CCL5/RANTES, CXCL8/IL-8, whereas it increased the production of IL-1ß, IL-6, CCL4/MIP-1ß and CXCL10/IP-10. Thus, in the blood compartment chemokines attracting mainly monocytes were up-regulated by RES, while those attracting T lymphocytes or neutrophils were diminished. At conditions of endothelial dysfunction (ED), RES reduced the expression of cytokines, chemokines, ICAM and GM-CSF in TNF-α activated HUVECs, whereas eNOS expression was corrected to pre-ED homeostasis. In macrophages nitric oxide, PGE2, cytokines (TNF-α, IL-1ß, IL-6) and chemokines (CCL2/MCP-1, CCL4/MIP-1ß, CCL5/RANTES, CXCL10/IP-10) were reduced by the phenolic substance. CONCLUSIONS: RES had cell-specific and context-dependent effects, in particular on the expression of IL-1ß, IL-6, CCL4/MIP-1ß and CXCL10/IP-10. It enhanced cellular features that mirror increased alertness to disturbed immune homeostasis in the vascular-endothelial compartment (e.g. increased production of IL-1ß or IL-6), whereas it blunted inflammatory mediators in macrophages and consequently chronic inflammation. We infer from the present in vitro study, that RES has unique properties in the regulation of inflammatory and immune responses, which are controlled in a complex hierarchical and temporal order.

Carnosol and Related Substances Modulate Chemokine and Cytokine Production in Macrophages and Chondrocytes.

Phenolic diterpenes present in Rosmarinus officinalis and Salvia officinalis have anti-inflammatory and chemoprotective effects. We investigated the in vitro effects of carnosol (CL), carnosic acid (CA), carnosic acid-12-methylether (CAME), 20-deoxocarnosol and abieta-8,11,13-triene-11,12,20-triol (ABTT) in murine macrophages (RAW264.7 cells) and human chondrocytes. The substances concentration-dependently reduced nitric oxide (NO) and prostaglandin E2 (PGE2) production in LPS-stimulated macrophages (i.e., acute inflammation). They significantly blunted gene expression levels of iNOS, cytokines/interleukins (IL-1α, IL-6) and chemokines including CCL5/RANTES, CXCL10/IP-10. The substances modulated the expression of catabolic and anabolic genes in chondrosarcoma cell line SW1353 and in primary human chondrocytes that were stimulated by IL-1ß (i.e., chronic inflammation In SW1353, catabolic genes like MMP-13 and ADAMTS-4 that contribute to cartilage erosion were down-regulated, while expression of anabolic genes including Col2A1 and aggrecan were shifted towards pre-pathophysiological homeostasis. CL had the strongest overall effect on inflammatory mediators, as well as on macrophage and chondrocyte gene expression. Conversely, CAME mainly affected catabolic gene expression, whereas ABTT had a more selectively altered interleukin and chemokine gene exprssion. CL inhibited the IL-1ß induced nuclear translocation of NF-κBp65, suggesting that it primarily regulated via the NF-κB signalling pathway. Collectively, CL had the strongest effects on inflammatory mediators and chondrocyte gene expression. The data show that the phenolic diterpenes altered activity pattern of genes that regulate acute and chronic inflammatory processes. Since the substances affected catabolic and anabolic gene expression in cartilage cells in vitro, they may beneficially act on the aetiology of osteoarthritis.

Tomato Aqueous Extract Modulates the Inflammatory Profile of Immune Cells and Endothelial Cells.

Nutrients transiently or chronically modulate functional and biochemical characteristics of cells and tissues both in vivo and in vitro. The influence of tomato aqueous extract (TAE) on the in vitro inflammatory response of activated human peripheral blood leukocytes (PBLs) and macrophages was investigated. Its effect on endothelial dysfunction (ED) was analyzed in human umbilical vein endothelial cells (HUVECs). Murine macrophages (RAW264.7 cells), PBLs and HUVECs were incubated with TAE. They were activated with LPS or TNF-α in order to induce inflammatory processes and ED, respectively. Inflammatory mediators and adhesion molecules were measured by immune assay-based multiplex analysis. Gene expression was quantified by RT-PCR. TAE altered the production of interleukins (IL-1ß, IL-6, IL-10, IL-12) and chemokines (CCL2/MCP-1, CCL3/MIP-1α, CCL5/RANTES, CXCL8/IL-8, CXCL10/IP-10) in PBLs. TAE reduced ED-associated expression of adhesion molecules (ICAM-1, VCAM-1) in endothelial cell. In macrophages, the production of nitric oxide, PGE2, cytokines and ILs (TNF-α, IL-1ß, IL-6, IL-12), which reflects chronic inflammatory processes, was reduced. Adenosine was identified as the main bioactive of TAE. Thus, TAE had cell-specific and context-dependent effects. We infer from these in vitro data, that during acute inflammation TAE enhances cellular alertness and therefore the sensing of disturbed immune homeostasis in the vascular-endothelial compartment. Conversely, it blunts inflammatory mediators in macrophages during chronic inflammation. A novel concept of immune regulation by this extract is proposed.

ω-3 PUFAs and Resveratrol Differently Modulate Acute and Chronic Inflammatory Processes.

ω-3 PUFAs and polyphenols have multiple effects on inflammation in vivo and in vitro. The effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and resveratrol (RV) were investigated in LPS-stimulated peripheral blood leukocytes (PBLs) (i.e., acute inflammation) and IL-1ß activated human chondrocytes (i.e., chronic inflammation). Inflammatory mediators including chemokines, cytokines, interleukins, and PGE2 were measured by multiplex analysis and gene expression was quantified by RT-PCR. In PBLs, RV decreased the secretion of PGE2, CCL5/RANTES, and CXCL8/IL-8 but increased IL-1ß, IL-6, and IL-10. In contrast to RV, ω-3 PUFAs augmented the production of PGE2 and CXCL8/IL-8. EPA and DHA similarly affected the pattern of inflammatory mediators. Combination of RV and ω-3 PUFAs exerted synergistic effects on CCL5/RANTES and had additive effects on IL-6 or CXCL8/IL-8. Both ω-3 PUFAs and RV reduced catabolic gene expression (e.g., MMPs, ADAMTS-4, IL-1ß, and IL-6) in activated chondrocytes. The data suggest that ω-3 PUFAs and RV differ in the regulation of acute inflammation of peripheral blood leukocytes but have common properties in modulating features related to chronic inflammation of chondrocytes.

Neural representations of ethologically relevant hand/mouth synergies in the human precentral gyrus.

Complex motor responses are often thought to result from the combination of elemental movements represented at different neural sites. However, in monkeys, evidence indicates that some behaviors with critical ethological value, such as self-feeding, are represented as motor primitives in the precentral gyrus (PrG). In humans, such primitives have not yet been described. This could reflect well-known interspecies differences in the organization of sensorimotor regions (including PrG) or the difficulty of identifying complex neural representations in peroperative settings. To settle this alternative, we focused on the neural bases of hand/mouth synergies, a prominent example of human behavior with high ethological value. By recording motor- and somatosensory-evoked potentials in the PrG of patients undergoing brain surgery (2-60 y), we show that two complex nested neural representations can mediate hand/mouth actions within this structure: (i) a motor representation, resembling self-feeding, where electrical stimulation causes the closing hand to approach the opening mouth, and (ii) a motor-sensory representation, likely associated with perioral exploration, where cross-signal integration is accomplished at a cortical site that generates hand/arm actions while receiving mouth sensory inputs. The first finding extends to humans' previous observations in monkeys. The second provides evidence that complex neural representations also exist for perioral exploration, a finely tuned skill requiring the combination of motor and sensory signals within a common control loop. These representations likely underlie the ability of human children and newborns to accurately produce coordinated hand/mouth movements, in an otherwise general context of motor immaturity.

Umeclidinium in patients with COPD: a randomised, placebo-controlled study.

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients. This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 µg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 85. Secondary end-points were 0-6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George's Respiratory Questionnaire), pharmacokinetics and safety. 246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 µg significantly improved least squares mean change from baseline in trough FEV1 (127 and 152 mL, respectively; p<0.001) compared with placebo. On day 84, umeclidinium 62.5 and 125 µg significantly improved least squares mean change from baseline in 0-6-h weighted mean (166 and 191 mL, respectively; p<0.001) and serial FEV1 at each time point (p≤0.003). Significant improvements in least squares mean transitional dyspnoea index focal score for UMEC 125 mg(1.3 units; p,0.05) and change from baseline St George's Respiratory Questionnaire total score for both UMEC doses (-7.9 and -10.87 units, for UMEC 62.5 mg and 125 mg, respectively; both p,0.001) were noted compared with placebo at week 12 [DOSAGE ERROR CORRECTED].The incidence of adverse events was low and similar across treatments. Umeclidinium 62.5 and 125 µg significantly improved lung function, dyspnoea and health status compared with placebo, and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks.

Mapping motor representations in the human cerebellum.

The cerebellum is a major motor structure. However, in humans, its efferent topographical organization remains controversial and indirectly inferred from neuroimaging and animal studies. Even central questions such as 'Can we evoke limb movements by stimulating the cerebellar cortex?' have no clear answer. To address this issue, we electrically stimulated the posterior cerebellum of 20 human patients undergoing surgery for tumours located outside this structure (e.g. pineal gland, quadrigeminal plate). Stimulation, delivered at a 60-Hz frequency for 2 s, evoked focal (single-joint) ipsilateral movements. Different regions were associated with the production of head (vermal lobule VI), face/mouth (hemispheric lobule VI) and lower-limb (hemispheric lobules VIIb-IX) responses. Upper-limb representations were more widely distributed. They intermingled with face/mouth representations in the superior posterior cerebellum (hemispheric lobule VI) and lower-limb representations in the inferior posterior cerebellum (hemispheric lobules VIIb-IX). No intra- or inter-limb somatotopy was found in these areas. Functionally, upper-limb (face/mouth movements) and upper limb-lower limb postural coordinations are major elements of our motor repertoire. Representation of these pairs of segments in common regions might favour the production of integrated motor behaviours. The intermediate region of the posterior cerebellum (hemispheric lobule VII and vermal lobules VII-VIII) was mostly silent. Latency results in conjunction with previous electrophysiological evidence in animals suggest that electrically evoked motor responses were not mediated by a cortical route but rather by brainstem structures. The potential role of this descending efferent pathway for fine motor control is discussed.

Potential implication of new torque teno mini viruses in parapneumonic empyema in children.

An unexplained increase in the incidence of parapneumonic empyema (PPE) in pneumonia cases has been reported in recent years. The present study investigated the genetic and biological specifications of new isolates of torque teno mini virus (TTMV) detected in pleural effusion samples from children hospitalised for severe pneumonia with PPE. A pathogen discovery protocol was applied in undiagnosed pleural effusion samples and led to the identification of three new isolates of TTMV (TTMV-LY). Isolated TTMV-LY genomes were transfected into A549 and human embryonic kidney 293T cells and viral replication was assessed by quantitative real-time PCR and full-length genome amplification. A549 cells were further infected with released TTMV-LY virions and the induced-innate immune response was measured by multiplex immunoassays. Genetic analyses of the three TTMV-LY genomes revealed a classic genomic organisation but a weak identity (<64%) with known sequences. We demonstrated the in vitro replication of TTMV-LY in alveolar epithelial cells and the effective release of infectious viral particles. We also showed a selective production of inflammatory mediators in response to TTMV infection. This study reports the description of replicative TTMV-LY isolated from parapneumonic effusions of children hospitalised with PPE, suggesting a potential role of the virus in the pathogenesis of pneumonia.

Rose hip and its constituent galactolipids confer cartilage protection by modulating cytokine, and chemokine expression.

BACKGROUND: Clinical studies have shown that rose hip powder (RHP) alleviates osteoarthritis (OA). This might be due to anti-inflammatory and cartilage-protective properties of the complete RHP or specific constituents of RHP. Cellular systems (macrophages, peripheral blood leukocytes and chondrocytes), which respond to inflammatory and OA-inducing stimuli, are used as in vitro surrogates to evaluate the possible pain-relief and disease-modifying effects of RHP. METHODS: (1) Inflammatory processes were induced in RAW264.7 cells or human peripheral blood leukocytes (PBL) with LPS. Inflammatory mediators (nitric oxide (NO), prostaglandin E(2) (PGE(2)) and cytokines/chemokines) were determined by the Griess reaction, EIA and multiplex ELISA, respectively. Gene expression was quantified by RT-PCR. RHP or its constituent galactolipid, GLGPG (galactolipid (2S)-1, 2-di-O-[(9Z, 12Z, 15Z)-octadeca-9, 12, 15-trienoyl]-3-O-ß-D-galactopyranosyl glycerol), were added at various concentrations and the effects on biochemical and molecular parameters were evaluated. (2) SW1353 chondrosarcoma cells and primary human knee articular chondrocytes (NHAC-kn) were treated with interleukin (IL)-1ß to induce in vitro processes similar to those occurring during in vivo degradation of cartilage. Biomarkers related to OA (NO, PGE(2), cytokines, chemokines, metalloproteinases) were measured by multiplex ELISA and gene expression analysis in chondrocytes. We investigated the modulation of these events by RHP and GLGPG. RESULTS: In macrophages and PBL, RHP and GLGPG inhibited NO and PGE(2) production and reduced the secretion of cytokines (TNF-α, IFN-γ, IL-1ß, IL-6, IL-12) and chemokines (CCL5/RANTES, CXCL10/IP-10). In SW1353 cells and primary chondrocytes, RHP and GLGPG diminished catabolic gene expression and inflammatory protein secretion as shown by lower mRNA levels of matrix metalloproteinases (MMP-1, MMP-3, MMP-13), aggrecanase (ADAMTS-4), macrophage inflammatory protein (MIP-2, MIP-3α), CCL5/RANTES, CXCL10/IP-10, IL-8, IL-1α and IL-6. The effects of GLGPG were weaker than those of RHP, which presumably contains other chondro-protective substances besides GLGPG. CONCLUSIONS: RHP and GLGPG attenuate inflammatory responses in different cellular systems (macrophages, PBLs and chondrocytes). The effects on cytokine production and MMP expression indicate that RHP and its constituent GLGPG down-regulate catabolic processes associated with osteoarthritis (OA) or rheumatoid arthritis (RA). These data provide a molecular and biochemical basis for cartilage protection provided by RHP.

Hydroxytyrosol is the major anti-inflammatory compound in aqueous olive extracts and impairs cytokine and chemokine production in macrophages.

Substances in olive products contribute to improved health as suggested by epidemiological data. In this study we assessed the effects of hydroxytyrosol (HT) on inflammatory mediators, cytokines and chemokines, and identified anti-inflammatory constituents of aqueous olive extracts, I.E., olive vegetation water (OVW). Murine macrophages (RAW264.7 cells) were stimulated with lipopolysaccharide (LPS) in the absence or presence of substances; inflammatory mediators [nitric oxide (NO), prostaglandin E2 (PGE2), cytokines, interleukins, chemokines] were determined by the Griess reaction, EIA, or multiplex ELISA (Luminex technology). Expression of inflammatory genes was determined by RT-PCR. Aqueous olive extracts were fractionated by preparative HPLC and the fractions investigated for their effects on NO and PGE2 production. Results were further analyzed by principal component analysis. HT inhibited production of NO and PGE2 with an IC50 of 11.4 and 19.5 µM, respectively, reflecting strong anti-inflammatory activity. HT and OVW diminished secretion of cytokines (IL-1 α, IL-1 ß, IL-6, IL-12, TNF- α), and chemokines (CXCL10/IP-10, CCL2/MCP-1). HT and OVW concentration-dependently reduced the expression of genes of inducible nitric oxide synthase (iNOS), IL-1 α, CXCL10/IP-10, MIP-1 ß, matrix metalloproteinase-9, and prostaglandin E2 synthase (PGES). The effects of HT were partly mediated VIA the NF- κB pathway, as shown by RT-PCR analysis. HT was identified as the main bioactive compound of OVW. The data provide a molecular basis for elucidating the effects of HT on inflammatory processes. The effects of HT on NO and chemokine production point to their impact on chronic inflammatory processes in endothelium or arthritis.

Movement intention after parietal cortex stimulation in humans.

Parietal and premotor cortex regions are serious contenders for bringing motor intentions and motor responses into awareness. We used electrical stimulation in seven patients undergoing awake brain surgery. Stimulating the right inferior parietal regions triggered a strong intention and desire to move the contralateral hand, arm, or foot, whereas stimulating the left inferior parietal region provoked the intention to move the lips and to talk. When stimulation intensity was increased in parietal areas, participants believed they had really performed these movements, although no electromyographic activity was detected. Stimulation of the premotor region triggered overt mouth and contralateral limb movements. Yet, patients firmly denied that they had moved. Conscious intention and motor awareness thus arise from increased parietal activity before movement execution.

Bupropion extended release compared with escitalopram: effects on sexual functioning and antidepressant efficacy in 2 randomized, double-blind, placebo-controlled studies.

OBJECTIVE: To compare the effects on sexual functioning and the antidepressant efficacy of once-daily bupropion extended release (XL) and escitalopram in adults with major depressive disorder (MDD). METHOD: Adult outpatients with moderate to severe DSM-IV-defined MDD and normal sexual functioning were randomly assigned to receive bupropion XL (300-450 mg/day; N = 276), escitalopram (10-20 mg/day; N = 281), or placebo (N = 273) for up to 8 weeks in 2 identically designed, randomized, double-blind, parallel-group studies (study 1 conducted from February 6, 2003, to June 10, 2004; study 2 conducted from January 21, 2003, to June 15, 2004). Data were analyzed prospectively for each study individually, and pooled data were analyzed retrospectively. RESULTS: In both the individual studies and the pooled dataset, the incidence of orgasm dysfunction at week 8 (primary endpoint) and the incidence of worsened sexual functioning at the end of the treatment period were statistically significantly lower with bupropion XL than with escitalopram (p < .05), not statistically different between bupropion XL and placebo (p > or = .067), and statistically significantly higher with escitalopram than with placebo (p < or = .001). The percentages of patients with orgasm dysfunction at week 8 in study 1, study 2, and the pooled dataset, respectively, were 13%, 16%, and 15% with bupropion XL; 32%, 29%, and 30% with escitalopram; and 11%, 8%, and 9% with placebo. The respective percentages of patients with worsened sexual functioning at the end of the treatment period were 18%, 22%, and 20% with bupropion XL; 37%, 34%, and 36% with escitalopram; and 14%, 16%, and 15% with placebo. Mean changes in Changes in Sexual Functioning Questionnaire scores for all domains at week 8 were statistically significantly worse for escitalopram compared with bupropion XL (p < or = .05). Separation from placebo could not be established at a statistical .05 level for bupropion on 17-item Hamilton Rating Scale for Depression (HAM-D-17) total score. However, escitalopram showed statistical superiority to placebo on HAM-D-17 total score in one of the 2 studies and in the pooled data. Bupropion XL did not statistically differ from escitalopram with respect to mean change in HAM-D-17 total score, HAM-D-17 response or remission rates, percentage of patients much or very much improved on Clinical Global Impressions-Improvement scale scores, or mean changes in the Hospital Anxiety and Depression (HAD) scale total score or Clinical Global Impressions-Severity of Illness scale score at week 8. CONCLUSIONS: Bupropion XL had a sexual tolerability profile significantly better than that of escitalopram with similar HAM-D-17 remission rates and HAD total scores in patients with MDD.

Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials.

BACKGROUND: Although it is widely believed that the various classes of antidepressants are equally effective, clinically meaningful differences may be obscured in individual studies because of a lack of statistical power. The present report describes a meta-analysis of original data from a complete set of studies comparing the norepinephrine/dopamine reuptake inhibitor (NDRI) bupropion with selective serotonin reuptake inhibitors (SSRIs; sertraline, fluoxetine, or paroxetine). METHOD: Individual patient data were pooled from a complete set of 7 randomized, double-blind studies comparing bupropion (N = 732) with SSRIs (fluoxetine, N = 339; sertraline, N = 343; paroxetine, N = 49) in outpatients with major depressive disorder (DSM-III-R or DSM-IV); 4 studies included placebo (N = 512). Response and remission rates were compared at week 8 or endpoint in both the intent-to-treat sample, using the last-observation-carried-forward (LOCF) method to account for attrition, and the observed cases. Tolerability data, including incidence of sexual side effects, were also compared. RESULTS: The LOCF response and remission rates for the bupropion (62% and 47%) and SSRI (63% and 47%) groups were similar; both active therapies were superior to placebo (51% and 36%; all comparisons, p < .001). The same pattern of results was demonstrated on the observed cases analyses. Although bupropion and SSRIs were generally well tolerated, SSRI therapy resulted in significantly higher rates of sexual side effects as compared to both bupropion and placebo. SSRIs were also associated with more somnolence and diarrhea, and bupropion was associated with more dry mouth. CONCLUSION: Bupropion and the SSRIs were equivalently effective and, overall, both treatments were well tolerated. The principal difference between these treatments was that sexual dysfunction commonly complicated SSRI therapy, whereas treatment with bupropion caused no more sexual dysfunction than placebo.

Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study.

BACKGROUND: Data remain limited on treatment strategies for adults with attention-deficit/hyperactivity disorder (ADHD). This study evaluated the efficacy and safety of an extended-release, once-daily formulation of bupropion (XL) in the treatment of adults with ADHD. METHODS: This multisite, placebo-controlled, 8-week prospective trial evaluated 162 adult patients diagnosed with ADHD (combined and inattentive types). Subjects were treated with up to 450 mg/day of bupropion XL. The primary efficacy endpoint was the proportion of ADHD responders (defined as at least a 30% reduction in the investigator-rated ADHD Rating Scale score) at week 8 (last observation carried forward [LOCF]). RESULTS: Bupropion XL responders (53%) exceeded placebo responders (31%) (p =.004 at week 8) with a significantly greater proportion of bupropion XL responders as early as week 2 (p = .01). Treatment effect size calculated for the ADHD Rating Scale total score was .6. Bupropion XL appeared to provide sustained benefit throughout the day compared with placebo (morning p =.033, afternoon p =.004, evening p = .024). Bupropion XL was safe and well tolerated, with no serious or unexpected adverse events and a low rate of drug-related study discontinuation (5%). CONCLUSIONS: The results from this multisite study indicate that bupropion XL is an effective and well-tolerated nonstimulant treatment for adult ADHD.

Effects of resveratrol, piceatannol, tri-acetoxystilbene, and genistein on the inflammatory response of human peripheral blood leukocytes.

Inflammatory processes are involved in the etiology of diseases. We analyzed the effect of resveratrol, piceatannol, synthetic tri-acetoxystilbene (TAS), and genistein (Bonistein(TM)) on the production of inflammatory mediators including prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha), interleukins, and chemokines, which participate in the progression of inflammation. In order to induce inflammatory responses, human peripheral blood mononuclear and/or polymorphonuclear leukocytes were stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN(gamma)) and the production of PGE2, interleukin-8 (IL-8), and TNF-alpha was determined. In response to the stimuli, genes were substantially activated within < 2 h (e. g., TNF-alpha, IL-1alpha), or at a later stage, (e. g., COX-2, IL-6, IL-8). Unlike genistein, resveratrol and related compounds dose-dependently reduced PGE2 production. Genistein, piceatannol, and TAS diminished secretion of TNF-alpha, and IL-8. TAS reduced mRNA levels of COX-2, TNF-alpha, IL-8, IL-6, and IL-1alpha, while resveratrol impaired early expression of IL-8 and TNF-alpha. Piceatannol out-performed resveratrol, yet without matching TAS. Genistein downregulated TNF-alpha and IL-8 expression. These substances altered the LPS/IFNgamma-induced gene expression in mononuclear cells rather than in polymorphonuclear leukocytes. Immunoblot analyses corroborated the distinct activity pattern of resveratrol and genistein. In conclusion, resveratrol and their derivatives attenuated the inflammatory response of PBLs at several levels, whereas genistein acts on cytokines and pro-inflammatory interleukins.

Bupropion SR vs. placebo for weight loss in obese patients with depressive symptoms.

OBJECTIVE: This randomized, double-blind, placebo-controlled study evaluated the efficacy and tolerability of bupropion sustained-release (bupropion SR) in reducing weight and depressive symptoms in obese adults. RESEARCH METHODS AND PROCEDURES: Obese adults (body mass index, 30 to 44 kg/m(2)) not currently meeting criteria for major depression but with depressive symptoms (Beck Depression Inventory score 10-30) received bupropion SR 300 mg/d or placebo for 26 weeks with a 500 kcal/d-deficit diet. Patients who lost <5% of baseline weight at week 12 had bupropion SR dosage or placebo increased to 400 mg/d in a blinded fashion. RESULTS: The bupropion SR group (n = 193) lost an average of 4.4 kg (4.6% of baseline weight) vs. 1.7 kg (1.8% of baseline weight) on placebo (n = 191, p < 0.001, last-observation-carried-forward analysis). More patients in the bupropion SR group than in the placebo group (40% vs. 16% of intent-to-treat sample, 50% vs. 28% of completers, respectively) lost at least 5% of baseline weight (p < 0.05 at week 4, p < 0.001 at weeks 6 to 26). The percentage of patients reporting > or =50% decrease in depressive symptoms did not differ between groups, but depressive symptoms improved more with bupropion SR than with placebo among patients with a history of major depression (p < 0.05, weeks 4 to 26). In the sample as a whole, improvement in depressive symptoms was related to weight loss of > or =5% regardless of treatment (p < 0.0001). Bupropion SR was well-tolerated. DISCUSSION: Bupropion SR in combination with a 500 kcal/d-deficit diet facilitated weight loss. Weight loss of > or =5% may improve mood in obese patients with depressive symptoms.