Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc.

BACKGROUND: Temsavir (TMR), the active agent of the gp120-directed attachment inhibitor fostemsavir (FTR), the CD4-directed attachment inhibitor ibalizumab (IBA), and the CCR5 antagonist maraviroc (MVC) are antiretroviral agents that target steps in HIV-1 viral entry. Although mechanisms of inhibition of the three agents are different, it is important to understand whether there is potential for cross-resistance between these agents, as all involve interactions with gp120. METHODS: Envelopes derived from plasma samples from participants in the BRIGHTE study who experienced protocol-derived virologic failure (PDVF) and were co-dosed with FTR and either IBA or MVC were analyzed for susceptibility to the agents. Also, CCR5-tropic MVC-resistant envelopes from the MOTIVATE trials were regenerated and studies were performed to understand whether susceptibility to multiple agents were linked. RESULTS: The cloned envelopes exhibited reduced susceptibility to TMR and resistance to the co-dosed agent. At PDVF, emergent or preexisting amino acid substitutions were present at TMR positions of interest. When amino acid substitutions at these positions were reverted to the consensus sequence, full susceptibility to TMR was restored without effecting resistance to the co-dosed agent. In addition, five envelopes from MOTIVATE were regenerated and exhibited R5-tropic-MVC-resistance. Only one exhibited reduced susceptibility to TMR and it contained an M426L polymorphism. When reverted to 426M, full sensitivity for TMR was restored, but it remained MVC resistant. CONCLUSION: The data confirm that decreased susceptibility to TMR and resistance to IBA or MVC are not linked and that there is no cross-resistance between either of these two agents and FTR.

mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects.

The consensus that ketamine can produce rapid-onset antidepressant effects in patients combined with the recent approval of S(+)-ketamine (esketamine, Spravato) as an antidepressant, has fueled the search for other compounds that might recapitulate the remarkable therapeutic benefits of ketamine. At the same time, discovery efforts have been additionally directed toward minimization of the tolerability, side-effect, and safety issues associated with ketamine. The history of thought on the viability of metabotropic 2/3 (mGlu2/3) receptor antagonism as a potential mechanism for inducing rapid-acting antidepressant effects is reviewed here. The biological basis for predicting antidepressant efficacy of mGlu2/3 receptor antagonists in depressed patients is also presented. This prediction is based upon convergent biochemical, neurochemical, electrophysiological, and behavioral data that indicate a striking homology in the substrates that underlie the effects of mGlu2/3 receptor antagonists and the known antidepressant ketamine. The data reviewed to date also demonstrate that the preclinical side-effect/tolerability and toxicology profile of mGlu2/3 receptor antagonists are not concerning. Finally, preclinical data on a relatively new mGlu2/3 receptor antagonist, LY3020371, and its orally-bioavailable prodrug, LY3027788, are reviewed. The data on this mechanism provides optimism for successful translation of the mGlu2/3 receptor antagonist hypothesis into therapeutics for those suffering from depression.

In vitro anti-inflammatory effects of AZD8999, a novel bifunctional muscarinic acetylcholine receptor antagonist /ß2-adrenoceptor agonist (MABA) compound in neutrophils from COPD patients.

Recent evidence indicates that AZD8999 (LAS190792), a novel muscarinic acetylcholine receptor antagonist and ß2-adrenoceptor agonist (MABA) in development for chronic respiratory diseases, induces potent and sustained relaxant effects in human bronchi by adressing both muscarinic acetylcholine receptors and ß2-adrenoceptor. However, the anti-inflammatory effects of the AZD8999 monotherapy or in combination with corticosteroids are unknown. This study investigates the anti-inflammatory effects of AZD8999 in monotherapy and combined with fluticasone propionate in neutrophils from healthy and chronic obstructive pulmonary disease (COPD) patients. Peripheral blood neutrophils from healthy and COPD patients were incubated with AZD8999 and fluticasone propionate, individually or in combination, for 1h followed by lipopolysaccharide (LPS) stimulation for 6h. The IL-8, MMP9, IL-1ß, and GM-CSF release was measured in cell culture supernatants. AZD8999 shows ~ 50% maximum inhibitory effect and similar potency inhibiting the released cytokines in neutrophils from healthy and COPD patients. However, while fluticasone propionate suppresses mediator release in neutrophils from healthy patients, COPD neutrophils are less sensitive. The combination of non-effective concentrations of AZD8999 (0.01nM) with non-effective concentrations of fluticasone propionate (0.1nM) shows synergistic anti-inflammatory effects. The studied mechanisms that may be involved in the synergistic anti-inflammatory effects of this combination include the increase of glucocorticoid receptor (GR)α and MKP1 expression, the induction of glucocorticoid response element (GRE) activation and the decrease of ERK1/2, P38 and GR-Ser226 phosphorylations compared with monotherapies. In summary, AZD8999 shows anti-inflammatory effects in neutrophils from COPD patients and induces synergistic anti-inflammatory effects when combined with fluticasone propionate, supporting the use of MABA/ICS combination therapy in COPD.

Efficacy and safety of methionine aminopeptidase 2 inhibition in type 2 diabetes: a randomised, placebo-controlled clinical trial.

AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.

Calreticulin and integrin alpha dissociation induces anti-inflammatory programming in animal models of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is a chronic intestinal inflammatory condition initiated by integrins-mediated leukocyte adhesion to the activated colonic microvascular endothelium. Calreticulin (CRT), a calcium-binding chaperone, is known as a partner in the activation of integrin α subunits (ITGAs). The relationship between their interaction and the pathogenesis of IBD is largely unknown. Here we show that a small molecule, orally active ER-464195-01, inhibits the CRT binding to ITGAs, which suppresses the adhesiveness of both T cells and neutrophils. Transcriptome analysis on colon samples from dextran sodium sulfate-induced colitis mice reveals that the increased expression of pro-inflammatory genes is downregulated by ER-464195-01. Its prophylactic and therapeutic administration to IBD mouse models ameliorates the severity of their diseases. We propose that leukocytes infiltration via the binding of CRT to ITGAs is necessary for the onset and development of the colitis and the inhibition of this interaction may be a novel therapeutic strategy for the treatment of IBD.

Deep-Sequencing Analysis of the Dynamics of HIV-1 Quasiespecies in Naive Patients during a Short Exposure to Maraviroc.

In this study, we have characterized quasispecies dynamics and the evolution of viral tropism in naive HIV-1-infected patients treated with a short course of maraviroc monotherapy (ClinicalTrials.gov registration no. NCT01060618) independently of the tropism of the infecting virus. We randomly selected 20 patients infected with viruses displaying different basal tropisms-10 carrying R5 and 10 carrying dual/mixed X4 (DM/X4) viruses-at recruitment as determined by phenotypic assay (Trofile). Evolution of viral quasiespecies at the end of treatment was determined by ultradeep sequencing of the V3 region using a 454 Life Sciences Platform and geno2pheno (g2p) algorithm for viral tropism prediction. The false-positive rate (FPR) that defines the probability of classifying an R5 virus falsely as X4 was set at 10%. X4-specific HIV-1 viral load (VL) was calculated from sequences with an FPR of <3.75%. Virological response as defined as >1-log10 copies/ml reduction in VL was detected in 70% of patients independently of the basal tropism of the infecting virus. Viral tropism remained stable, and nonsignificant differences in FPR values before and after treatment were found for the majority of patients in both tropism groups. Only three patients (one with R5 and two with DM/X4 viruses) showed an increased (>1 log) X4 VL, and one patient harboring a DM/X4-tropic virus displayed a significant reduction in FPR values at the end of treatment. Fast changes in the composition of viral populations were observed in all patients after 10 days of maraviroc (MVC) monotherapy treatment, and a complete replacement of viral quasiespecies was found in 3/10 patients carrying R5-using viruses and 4/10 patients carrying DM/X4-using viruses.IMPORTANCE Initiation of treatment with maraviroc requires previous determination of viral tropism by genotypic or phenotypic methods because of the risk of treatment failure and selection of DM/X4-tropic variants. In this study, we confirm previous work showing that the virologic response to maraviroc is independent of basal tropism. By deep-sequencing analysis, we determined that fast changes in viral populations were due to the emergence of minority variants in some patients whereas in others generation of new strains was detected. The risk of DM/X4 selection was very low as FPR values remained stable, and only one patient showed a detrimental switch to DM/X4 variants. Our data show that some DM/X4 viruses are sensitive to maraviroc treatment probably because only a low proportion of DM/X4 viruses use preferentially the X4 receptor and contain authentically maraviroc-resistant viruses that are not accurately detected by current assays.

Seasonal Effects and the Impact of In-Hive Pesticide Treatments on Parasite, Pathogens, and Health of Honey Bees.

Honey bee, Apis mellifera (L.; Hymenoptera: Apidae), populations are in decline and their losses pose a serious threat for crop pollination and food production. The specific causes of these losses are believed to be multifactorial. Pesticides, parasites and pathogens, and nutritional deficiencies have been implicated in the losses due to their ability to exert energetic stress on bees. While our understanding of the role of these factors in honey bee colony losses has improved, there is still a lack of knowledge of how they impact the immune system of the honey bee. In this study, honey bee colonies were exposed to Fumagilin-B, Apistan (tau-fluvalinate), and chlorothalonil at field realistic levels. No significant effects of the antibiotic and two pesticides were observed on the levels of varroa mite, Nosema ceranae (Fries; Microsporidia: Nosematidae), black queen cell virus, deformed wing virus, or immunity as measured by phenoloxidase and glucose oxidase activity. Any effects on the parasites, pathogens, and immunity we observed appear to be due mainly to seasonal changes within the honey bee colonies. The results suggest that Fumagilin-B, Apistan, and chlorothalonil do not significantly impact the health of honey bee colonies, based on the factors analyzed and the concentration of chemicals tested.

Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. Its severity ranges from simple steatosis to cirrhosis. C-C chemokine ligand type 5 or RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) plays an important role in the progression of hepatic inflammation and fibrosis. Our objective was to examine the preventive and therapeutic effects of maraviroc (MVC), a C-C chemokine receptor 5 antagonist, on liver pathology in an NAFLD mouse model. A total of 60 male C57BL/6 mice were randomly assigned to 1 of 4 groups: (1) high-fat diet (HFD) group or control group, (2) preventive group (HFD group plus MVC in drinking water since the beginning of the study), (3) early-therapeutic group (HFD group plus MVC in drinking starting at week 24 of the study), and (4) late-therapeutic group (HFD group plus MVC in drinking water starting at week 36 of the study). All mice were sacrificed at week 48. The hepatic triglyceride concentration in the HFD group was significantly higher than that in the groups treated with MVC at any time. Gene expression associated with lipogenesis (diacylglycerol acyltransferase 2 and proliferator-activated receptor-γ), insulin resistance (insulin receptor substrate-2), and ß-oxidation (carnitine palmitoyltransferase 1A and acyl-CoA oxidase) was significantly reduced in all the groups treated with MVC. In summary, the beneficial effect of MVC on hepatic steatosis is maintained throughout the study.

Anti-angiogenic drug loaded liposomes: Nanotherapy for early atherosclerotic lesions in mice.

Fumagillin-loaded liposomes were injected into ApoE-KO mice. The animals were divided into several groups to test the efficacy of this anti-angiogenic drug for early treatment of atherosclerotic lesions. Statistical analysis of the lesions revealed a decrease in the lesion size after 5 weeks of treatment.

Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc.

Residual viremia is common during antiretroviral therapy (ART) and could be caused by ongoing low-level virus replication or by release of viral particles from infected cells. ART intensification should impact ongoing viral propagation but not virion release. Eighteen acutely infected men were enrolled in a randomized controlled trial and monitored for a median of 107 weeks. Participants started ART with (n = 9) or without (n = 9) intensification with maraviroc (MVC) within 90 days of infection. Levels of HIV DNA and cell-free RNA were quantified by droplet digital PCR. Deep sequencing of C2-V3 env, gag, and pol (454 Roche) was performed on longitudinally collected plasma and peripheral blood mononuclear cell (PBMC) samples while on ART. Sequence data were analyzed for evidence of evolution by (i) molecular diversity analysis, (ii) nonparametric test for panmixia, and (iii) tip date randomization within a Bayesian framework. There was a longitudinal decay of HIV DNA after initiation of ART with no difference between MVC intensification groups (-0.08 ± 0.01 versus -0.09 ± 0.01 log10 copies/week in MVC+ versus MVC- groups; P = 0.62). All participants had low-level residual viremia (median, 2.8 RNA copies/ml). Across participants, medians of 56 (interquartile range [IQR], 36 to 74), 29 (IQR, 25 to 35), and 40 (IQR, 31 to 54) haplotypes were generated for env, gag, and pol regions, respectively. There was no clear evidence of viral evolution during ART and no difference in viral diversity or population structure from individuals with or without MVC intensification. Further efforts focusing on elucidating the mechanism(s) of viral persistence in various compartments using recent sequencing technologies are still needed, and potential low-level viral replication should always be considered in cure strategies.IMPORTANCE Residual viremia is common among HIV-infected people on ART. It remains controversial if this viremia is a consequence of propagating infection. We hypothesized that molecular evolution would be detectable during viral propagation and that therapy intensified with the entry inhibitor maraviroc would demonstrate less evolution. We performed a randomized double-blinded treatment trial with 18 acutely infected men (standard ART versus standard ART plus maraviroc). From longitudinally collected blood plasma and cells, levels of HIV DNA and cell-free HIV RNA were quantified by droplet digital PCR, and HIV DNA (env, gag, and pol coding regions) was deep sequenced (454 Roche). Investigating people who started ART during the earliest stages of their HIV infection, when viral diversity is low, provides an opportunity to detect evidence of viral evolution. Despite using a battery of analytical techniques, no clear and consistent evidence of viral propagation for over 90 weeks of observation could be discerned.

Tissue Pharmacologic and Virologic Determinants of Duodenal and Rectal Gastrointestinal-Associated Lymphoid Tissue Immune Reconstitution in HIV-Infected Patients Initiating Antiretroviral Therapy.

Plasma, duodenal, and rectal tissue antiretroviral therapy (ART) drug concentrations, human immunodeficiency virus (HIV) RNA and HIV DNA copy numbers, and recovery of mucosal immunity were measured before and 9 months after initiation of 3 different ART regimens in 26 subjects. Plasma and tissue HIV RNA correlated at baseline and when 9-month declines were compared, suggesting that these compartments are tightly associated. Antiretroviral tissue:blood penetration ratios were above the 50% inhibitory concentration values in almost 100% of cases. There were no correlations between drug concentrations and HIV DNA/RNA. Importantly, no evidence was found for residual viral replication or deficient tissue drug penetration to account for delayed gastrointestinal-associated lymphoid tissue immune recovery.

Effects of Maraviroc versus Efavirenz in Combination with Zidovudine-Lamivudine on the CD4/CD8 Ratio in Treatment-Naive HIV-Infected Individuals.

A low CD4/CD8 ratio during treated HIV infection reflects heightened immune activation and predicts death. The effects of different antiretroviral therapy regimens on CD4/CD8 ratio recovery remains unclear. We performed a post hoc analysis of the MERIT study, a randomized, double-blind trial of maraviroc versus efavirenz in combination with zidovudine-lamivudine in treatment-naive HIV-infected individuals. We found higher rates of CD4/CD8 ratio normalization with efavirenz, which was driven by a greater CD8+ T-cell decline.

Diabetic Hemichorea-hemiballism after Prompt Improvement in Hyperglycemia.

We herein report a case of hemichorea-hemiballism in an 85-year-old man diagnosed with diabetes at 76 years of age. After a one-year interruption in treatment, he was treated with a low-calorie diet, linagliptin, and nateglinide. Over 51 days, his HbA1c level decreased from 15.8% to 7.7%. After a prompt improvement in his hyperglycemia, he began experiencing involuntary movements in the right upper and lower extremities. T1-weighted magnetic resonance imaging showed a high signal intensity in the left lens nucleus. The patient was diagnosed with diabetic hemichorea-hemiballism and received haloperidol (1 mg/day) as treatment.

Penetration and antiviral efficacy of total and unbound maraviroc, raltegravir and rilpivirine in both female and male genital fluids from HIV-positive patients receiving regimens containing these antiretrovirals.

BACKGROUND: Sub-optimal penetration of antiretroviral drugs in genital compartments might promote local HIV persistence and increase the risk of HIV transmission. OBJECTIVES: To describe the penetration of maraviroc, raltegravir, raltegravir glucuronide and rilpivirine in seminal plasma and cervico-vaginal secretions (CVS) and to assess local antiretroviral efficacy in HIV-1-positive patients. METHODS: This was a prospective, multicentre study. Inclusion criteria were HIV-1 positive, age >18 years, receiving regimens containing maraviroc and/or raltegravir and/or rilpivirine for >1 month, and good self-reported adherence. Paired blood and genital samples were collected 12 h (raltegravir and maraviroc) or 24 h (rilpivirine) post-dose. These concentrations were determined (UPLC-MS/MS) in blood and seminal plasma (total and unbound) and CVS (total, dried spots) and HIV-RNA was quantified in paired blood and genital samples. RESULTS: Among the 54 enrolled patients, 15 received maraviroc (6 men), 27 received raltegravir (14 men) and 20 received rilpivirine (10 men), corresponding to 54 total and 52 unbound plasma concentrations, 29 total CVS samples and 23 total and 18 unbound seminal plasma samples. Maraviroc and raltegravir displayed a ratio of genital fluids/plasma concentrations >0.5 in both male and female genital tracts. Conversely, rilpivirine displayed a low ratio. Antiretroviral free fractions were consistent with historical data. Nine patients had blood plasma HIV-RNA >50 copies/mL (2/9 had sub-optimal antiretroviral blood plasma exposure) and two other patients had detectable HIV-RNA in genital fluids. CONCLUSIONS: Maraviroc and raltegravir demonstrated good penetration in genital compartments, yielding good local virological response in genital compartments, whereas rilpivirine presented a low penetration profile but good local response.

Analysis of Clinical HIV-1 Strains with Resistance to Maraviroc Reveals Strain-Specific Resistance Mutations, Variable Degrees of Resistance, and Minimal Cross-Resistance to Other CCR5 Antagonists.

Maraviroc (MVC) is an allosteric inhibitor of human immunodeficiency virus type 1 (HIV-1) entry, and is the only CCR5 antagonist licensed for use as an anti-HIV-1 therapeutic. It acts by altering the conformation of the CCR5 extracellular loops, rendering CCR5 unrecognizable by the HIV-1 envelope (Env) glycoproteins. This study aimed to understand the mechanisms underlying the development of MVC resistance in HIV-1-infected patients. To do this, we obtained longitudinal plasma samples from eight subjects who experienced treatment failure with phenotypically verified, CCR5-tropic MVC resistance. We then cloned and characterized HIV-1 Envs (n = 77) from plasma of pretreatment (n = 36) and treatment failure (n = 41) samples. Our results showed variation in the magnitude of MVC resistance as measured by reductions in maximal percent inhibition of Env-pseudotyped viruses, which was more pronounced in 293-Affinofile cells compared to other cells with similar levels of CCR5 expression. Amino acid determinants of MVC resistance localized to the V3 Env region and were strain specific. We also observed minimal cross-resistance to other CCR5 antagonists by MVC-resistant strains. We conclude that 293-Affinofile cells are highly sensitive for detecting and measuring MVC resistance through a mechanism that is CCR5-dependent yet independent of CCR5 expression levels. The strain-specific nature of resistance mutations suggests that sequence-based diagnostics and prognostics will need to be more sophisticated than simple position scoring to be useful for managing resistance in subjects taking MVC. Finally, the minimal levels of cross-resistance suggests that recognition of the MVC-modified form of CCR5 does not necessarily lead to recognition of other antagonist-modified forms of CCR5.

Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.

BACKGROUND: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). OBJECTIVE: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. DESIGN: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114). SETTING: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. INTERVENTION: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control). MEASUREMENTS: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. RESULTS: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. LIMITATIONS: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. CONCLUSION: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

The novel cannabinoid receptor GPR55 mediates anxiolytic-like effects in the medial orbital cortex of mice with acute stress.

The G protein-coupled receptor 55 (GPR55) is a novel cannabinoid receptor, whose exact role in anxiety remains unknown. The present study was conducted to explore the possible mechanisms by which GPR55 regulates anxiety and to evaluate the effectiveness of O-1602 in the treatment of anxiety-like symptoms. Mice were exposed to two types of acute stressors: restraint and forced swimming. Anxiety behavior was evaluated using the elevated plus maze and the open field test. We found that O-1602 alleviated anxiety-like behavior in acutely stressed mice. We used lentiviral shRNA to selective ly knockdown GPR55 in the medial orbital cortex and found that knockdown of GPR55 abolished the anxiolytic effect of O-1602. We also used Y-27632, a specific inhibitor of ROCK, and U73122, an inhibitor of PLC, and found that both inhibitors attenuated the effectiveness of O-1602. Western blot analysis revealed that O-1602 downregulated the expression of GluA1 and GluN2A in mice. Taken together, these results suggest that GPR55 plays an important role in anxiety and O-1602 may have therapeutic potential in treating anxiety-like symptoms.

Is maraviroc useful in multiple sclerosis patients with natalizumab-related progressive multifocal leukoencephalopathy?

BACKGROUND: Despite the recent advances in the understanding of natalizumab (NTZ) related progressive multifocal leukoencephalopathy (PML) and its associated immune reconstitution inflammatory syndrome (PML-IRIS), the therapeutic options are still under investigated. In this context, the beneficial use of maraviroc is still an anecdotal observation. OBJECTIVE: To evaluate the impact of maraviroc in modifying the course of PML preventing IRIS or blunting IRIS manifestations. METHODS: Three patients with NTZ PML included in the Italian dataset of PML were treated with maraviroc. Their longitudinal clinical and radiological course was described in detail. RESULTS: The three patients were characterized by a steady clinical worsening not controlled by maraviroc. All the three patients manifested PML-IRIS, which emerged, respectively, at 62, 64 and 90days post NTZ withdrawal. This is in accordance with the data of the Italian dataset. Clinical and radiological stabilization of PML-IRIS occurred only after corticosteroids administration. CONCLUSION: In these three cases, maraviroc did not show any clear effect in modulating the clinical course of PML preventing IRIS. Moreover, once PML-IRIS emerged, the clinical stabilization was achieved only with the use of corticosteroids. Thus, the use of maraviroc should be regarded with extreme caution due the potential adverse events associated with its use.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. Results: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period. Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.