Dexmedetomidine promotes biomimetic non-rapid eye movement stage 3 sleep in humans: A pilot study.

Clin Neurophysiol. 2017 Oct 20;129(1):69-78

Authors: Akeju O, Hobbs LE, Gao L, Burns SM, Pavone KJ, Plummer GS, Walsh EC, Houle TT, Kim SE, Bianchi MT, Ellenbogen JM, Brown EN

Abstract
OBJECTIVES: Sleep, which comprises of rapid eye movement (REM) and non-REM stages 1-3 (N1-N3), is a natural occurring state of decreased arousal that is crucial for normal cardiovascular, immune and cognitive function. The principal sedative drugs produce electroencephalogram beta oscillations, which have been associated with neurocognitive dysfunction. Pharmacological induction of altered arousal states that neurophysiologically approximate natural sleep, termed biomimetic sleep, may eliminate drug-induced neurocognitive dysfunction.
METHODS: We performed a prospective, single-site, three-arm, randomized-controlled, crossover polysomnography pilot study (n = 10) comparing natural, intravenous dexmedetomidine- (1-μg/kg over 10 min [n = 7] or 0.5-μg/kg over 10 min [n = 3]), and zolpidem-induced sleep in healthy volunteers. Sleep quality and psychomotor performance were assessed with polysomnography and the psychomotor vigilance test, respectively. Sleep quality questionnaires were also administered.
RESULTS: We found that dexmedetomidine promoted N3 sleep in a dose dependent manner, and did not impair performance on the psychomotor vigilance test. In contrast, zolpidem extended release was associated with decreased theta (∼5-8 Hz; N2 and N3) and increased beta oscillations (∼13-25 Hz; N2 and REM). Zolpidem extended release was also associated with increased lapses on the psychomotor vigilance test. No serious adverse events occurred.
CONCLUSIONS: Pharmacological induction of biomimetic N3 sleep with psychomotor sparing benefits is feasible.
SIGNIFICANCE: These results suggest that α2a adrenergic agonists may be developed as a new class of sleep enhancing medications with neurocognitive sparing benefits.

PMID: 29154132 [PubMed - as supplied by publisher]

Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: A case report and literature review.

World J Gastroenterol. 2017 Nov 07;23(41):7478-7488

Authors: Li CM, Liu ZC, Bao YT, Sun XD, Wang LL

Abstract
Chemotherapy has limited efficacy in the treatment of advanced and metastatic pancreatic cancer (PC), and has serious side effects. The development of novel effective agents, especially targeted therapy, is essential for patients with PC. We present a 58-year-old Chinese woman initially diagnosed with locally advanced PC. As the disease progressed to Stage IV, the patient was unable to tolerate chemotherapy after the fourth-line treatment. She was then treated with apatinib, a novel and highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 and achieved a progression-free-survival of 7 mo. All drug-related side effects were well controlled with medication. To the best of our knowledge, this is the first case of PC which responded to apatinib. Considering this remarkable response, apatinib may be a promising agent in the treatment of PC. We also reviewed the literature on chemotherapy and targeted therapy, especially the anti-angiogenesis therapy for patients with PC, and investigated the effect of apatinib in other solid tumors as well.

PMID: 29151702 [PubMed - in process]

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open-label, Randomized Study.

Clin Pharmacol Ther. 2017 Nov 18;:

Authors: Adkison K, Wolstenholme A, Lou Y, Zhang Z, Eld A, Perger T, Vangerow H, Hayward K, Shaefer M, McCoig C

Abstract
In children aged ≤4 years, the relative bioavailability of lamivudine oral solution was 37% lower than that of a tablet formulation. An open-label, 4-way crossover study was conducted in healthy adults to evaluate the effect of sorbitol, a common liquid excipient, on the pharmacokinetics of lamivudine oral solution (ClinicalTrials.gov identifier, NCT02634073). Sixteen subjects were randomized to 1 of 4 sequences consisting of 4 doses of lamivudine 300 mg (10 mg/mL) alone or with sorbitol 3.2, 10.2, or 13.4 g. Sorbitol 3.2, 10.2, and 13.4 g decreased lamivudine maximum concentration (Cmax) by 28%, 52%, and 55% and area under the concentration-time curve from time 0 to 24 hours (AUC0-24 ) by 20%, 39%, and 44%, respectively. Three subjects (19%) reported 5 non-serious adverse events (1 drug related). The dose-dependent effects of sorbitol on lamivudine Cmax and AUC0-24 reveal an absorption-based interaction that may decrease lamivudine exposure in patients co-administered sorbitol-containing medicines. This article is protected by copyright. All rights reserved.

PMID: 29150845 [PubMed - as supplied by publisher]

Prescribing of NOACs has outnumbered warfarin: exploring how physicians choose anticoagulant treatments.

Eur J Clin Pharmacol. 2017 Nov 17;:

Authors: Eek AK, Øie E, Granas AG

Abstract
PURPOSE: The development of non-vitamin K-dependent oral anticoagulants (NOACs) is a new alternative to treatment with warfarin. The purpose of this study was to explore drug prescription decisions of NOACs or warfarin from hospital physicians in cardiovascular departments.
METHODS: A qualitative study with focus group interviews was conducted in three different hospitals. The interview guide explored the background of prescribing anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and experiences with effect and side-effects they had observed in patients.
RESULTS: The systematic text condensation eluded four main themes: when to prescribe NOACs, concern about side-effects, pharmaceutical properties and patient adherence, and prescribing policy and intra-professional communication. All available anticoagulants were prescribed. However, no specific NOAC was preferred. Factors perceived as contraindications for NOACs varied among the doctors. Most had observed side-effects of NOACs; however, these rarely influenced prescribing decisions due to small differences in safety profiles. Few drug-drug interactions and fixed daily doses made NOACs easy to prescribe; but some doctors had experienced lack of drug effect for some patients. Non-adherence with NOACs was harder to spot. Some different prescribing cultures had evolved between the different hospitals and between general practitioners.
CONCLUSION: The hospital physicians chose anticoagulants based on patient conditions as renal function, bleeding risks, and drug interactions being the most common taken into account. They could not say which NOAC was best, and wish that future studies could compare the different NOACs, and not just compare with warfarin.

PMID: 29149366 [PubMed - as supplied by publisher]

Erlotinib intercalating pemetrexed/cisplatin versus erlotinib alone in Chinese patients with brain metastases from lung adenocarcinoma: a prospective, non-randomised, concurrent controlled trial (NCT01578668).

ESMO Open. 2017;2(Suppl 1):e000112

Authors: Yang H, Deng Q, Qiu Y, Huang J, Guan Y, Wang F, Xu X, Yang X

Abstract
Objective: Erlotinib has a synergistic effect with pemetrexed for treating non-squamous non-small-cell lung cancer. We investigated the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese patients with lung adenocarcinoma with brain metastases.
Design: Patients who were erlotinib-naïve or pemetrexed-naïve were assigned in parallel to receive either E or E-P. The primary endpoint was the intracranial overall response rate (ORRi).
Results: Sixty-nine patients with lung adenocarcinoma with brain metastases received E (n=35) or E-P (n=34) from January 2012 to November 2014. Demographics and patient characteristics were well balanced between the two groups, including epidermal growth factor receptor (EGFR) status, sex, age, smoking status, Eastern Cooperative Oncology Group (ECOG) performance status, brain metastases and number of prior treatments. ORRi in the E-P arm was superior to that in the E arm (79% vs 48%, p=0.008). Compared with E as the first-line treatment, E-P was associated with better intracranial progression-free survival (PFSi, median: 9 vs 2 months, p=0.027) and systemic PFS (median: 8 vs 2 months, p=0.006). The most frequent E-related adverse events were higher in the combination arm. No new safety signals were detected. The side effects were tolerable, and there were no drug-related deaths.
Conclusion: Our study suggests that the E-P combination may be effective in Chinese patients with lung adenocarcinoma with brain metastases, with improved PFS in treatment-naïve patients. Toxicities are tolerable, and there are more E-related side effects.

PMID: 29147576 [PubMed]

A multicenter, open-label, phase III study of Abcertin in Gaucher disease.

Medicine (Baltimore). 2017 Nov;96(45):e8492

Authors: Lee BH, Abdalla AF, Choi JH, Beshlawy AE, Kim GH, Heo SH, Megahed AMH, Elsayed MAL, Barakat TEM, Eid KMAE, El-Tagui MH, Mahmoud MMH, Fateen E, Park JY, Yoo HW

Abstract
BACKGROUND: Gaucher disease (GD) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. Enzyme replacement therapy (ERT) is recommended for clinical improvement.
METHODS: The efficacy and safety of a new imiglucerase, Abcertin, were assessed in 7 Egyptian patients with treatment-naïve type 1 GD. Each patient was administered a biweekly 60 U/kg dose of Abcertin for 6 months. The primary endpoint was the change in hemoglobin concentration. The secondary endpoints were changes from baseline in platelet counts, spleen and liver volumes, biomarker levels, skeletal parameters, and bone mineral density.
RESULTS: The hemoglobin concentration increased by a mean of 1.96 ± 0.91 g/dL (range 1.11-2.80 g/dL) or 20.6% (P = .001). Statistically significant increases in the platelet count and decreases in the spleen volume and biomarker levels were also observed. There were no severe drug-related adverse events. One patient developed anti-imiglucerase antibodies without neutralizing activity.
CONCLUSION: Our study results demonstrate the efficacy and safety of Abcertin in patients with type 1 GD. This suggests that Abcertin can be an alternative ERT option for type 1 GD.

PMID: 29137040 [PubMed - in process]

The effect and safety of anacetrapib in the treatment of dyslipidemia: a systematic review and meta-analysis.

Postgrad Med. 2017 Nov 14;:1-8

Authors: Zhou J, Zhang Q, Wang Y, Gao P, Chen D

Abstract
BACKGROUND: Cardiovascular disease (CVD) is the major cause of morbidity and mortality worldwide. Anacetrapib may be a new treatment option that has a cardiovascular benefit for the management of dyslipidemia.
OBJECTIVE: The aim of our current study was to perform a systematic review and meta-analysis of all randomized controlled trials (RCTs) assessing the effect and safety of anacetrapib in the treatment of dyslipidemia.
METHODS: We systematically searched PubMed, Embase, and Cochrane Library database from their inception to 5 October 2017, with the terms: 'anacetrapib' and 'placebo'. From 287 initial citations, 10 studies including 34781 patients with dyslipidemia were included in the final systematic review and meta-analysis.
RESULTS: Pooled results showed that anacetrapib significantly increased high density lipoprotein cholesterol (HDL-C) [weighted mean differences (WMD) 53.07, 95% confidence interval (95% CI) 46.79 to 59.36] and apolipoprotein AI (ApoAI) (WMD 53.44, 95% CI 45.72 to 61.16). Our study also showed that anacetrapib significantly reduced low density lipoprotein cholesterol (LDL-C) (WMD -32.99; 95% CI -37.13 to -28.86), Non-HDL-C (WMD -39.19; 95% CI -52.22 to -26.16), triglycerides (TG) (WMD -9.97; 95% CI -10.54 to -9.41), apolipoprotein B (ApoB) (WMD -22.55; 95% CI -28.56 to -16.54) and lipoprotein a [LP(a)] (WMD -13.35; 95% CI -18.31 to -8.39). Our results demonstrated that there was no significant difference in all the following adverse events between the anacetrapib group and placebo group: [hepato-toxicity (OR 0.90, 95% CI: 0.75 to 1.07); musculoskeletal injury (OR 1.01, 95% CI: 0.88 to 1.15); drug-related adverse event (OR 1.00, 95% CI: 0.96 to 1.05); drug-related withdrawn (OR 1.01, 95% CI: 0.95 to 1.08)].
CONCLUSIONS: Although further studies are needed, our findings clearly offer support to the use of anacetrapib in the clinical management of patients with dyslipidemia.

PMID: 29135318 [PubMed - as supplied by publisher]

Medical Cannabinoids in Children and Adolescents: A Systematic Review.

Pediatrics. 2017 Nov;140(5):

Authors: Wong SS, Wilens TE

Abstract
CONTEXT: Legalization of medical marijuana in many states has led to a widening gap between the accessibility and the evidence for cannabinoids as a medical treatment.
OBJECTIVE: To systematically review published reports to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.
DATA SOURCES: Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of PubMed, Medline, and the Cumulative Index to Nursing and Allied Health Literature databases was conducted in May 2017.
STUDY SELECTION: Searching identified 2743 citations, and 103 full texts were reviewed.
DATA EXTRACTION: Searching identified 21 articles that met inclusion criteria, including 22 studies with a total sample of 795 participants. Five randomized controlled trials, 5 retrospective chart reviews, 5 case reports, 4 open-label trials, 2 parent surveys, and 1 case series were identified.
RESULTS: Evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy. At this time, there is insufficient evidence to support use for spasticity, neuropathic pain, posttraumatic stress disorder, and Tourette syndrome.
LIMITATIONS: The methodological quality of studies varied, with the majority of studies lacking control groups, limited by small sample size, and not designed to test for the statistical significance of outcome measures. Studies were heterogeneous in the cannabinoid composition and dosage and lacked long-term follow-up to identify potential adverse effects.
CONCLUSIONS: Additional research is needed to evaluate the potential role of medical cannabinoids in children and adolescents, especially given increasing accessibility from state legalization and potential psychiatric and neurocognitive adverse effects identified from studies of recreational cannabis use.

PMID: 29061872 [PubMed - indexed for MEDLINE]

Efficacy and safety of tribendimidine, tribendimidine plus ivermectin, tribendimidine plus oxantel pamoate, and albendazole plus oxantel pamoate against hookworm and concomitant soil-transmitted helminth infections in Tanzania and Côte d'Ivoire: a randomised, controlled, single-blinded, non-inferiority trial.

Lancet Infect Dis. 2017 Nov;17(11):1162-1171

Authors: Moser W, Coulibaly JT, Ali SM, Ame SM, Amour AK, Yapi RB, Albonico M, Puchkov M, Huwyler J, Hattendorf J, Keiser J

Abstract
BACKGROUND: Preventive chemotherapy is the current strategy to control soil-transmitted helminth infections (caused by Ascaris lumbricoides, hookworm, and Trichuris trichiura). But, to improve efficacy and avoid emerging resistance, new drugs are warranted. Tribendimidine has shown good anthelmintic efficacy and is therefore a frontrunner for monotherapy and combination chemotherapy.
METHODS: We did a randomised, controlled, single-blinded, non-inferiority trial on Pemba Island, Tanzania, and in Côte d'Ivoire. We recruited adolescents aged 15-18 years from four primary schools on Pemba, and school attendees and non-schoolers from two districts in Côte d'Ivoire. Only hookworm-positive participants were randomly assigned (1:1:1:1) to single, oral doses of tribendimidine 400 mg plus placebo (tribendimidine monotherapy), tribendimidine 400 mg plus ivermectin 200 μg/kg, tribendimidine 400 mg plus oxantel pamoate 25 mg/kg, or albendazole 400 mg plus oxantel pamoate 25 mg/kg. Randomisation was done via a computer-generated list in block sizes of four or eight. Participants were asked to provide two stool samples on 2 consecutive days at baseline and again 14-21 days at follow-up. The primary outcome was the difference in egg-reduction rates (ERRs; ie, the geometric mean reduction) in hookworm egg counts between treatment groups, measured by the Kato-Katz technique. Differences in coadministrated treatment groups were assessed for non-inferiority with a margin of -3% to albendazole plus oxantel pamoate based on the available-case population, analysed by intention to treat. Safety was assessed 3 h and 24 h after treatment. This study is registered with ISRCTN (number 14373201).
FINDINGS: Between July 26, and Dec 23, 2016, we treated 636 hookworm-positive participants, and outcome data were available for 601 participants (151 assigned to tribendimidine monotherapy, 154 to tribendimidine plus ivermectin, 148 to tribendimidine plus oxantel pamoate, and 148 to albendazole plus oxantel pamoate). Tribendimidine plus ivermectin was non-inferior to albendazole plus oxantel pamoate (ERRs 99·5% [95% CI 99·2-99·7] vs 96·0% [93·9-97·4]; difference 3·52 percentage points [2·05-5·65]). Likewise, tribendimidine plus oxantel pamoate was non-inferior to albendazole plus oxantel pamoate (ERRs 96·5% [95% CI 94·9 to 97·6] vs 96·0% [93·9 to 97·4]; difference 0·48 percentage points [-1·61 to 2·88]). 3 h after treatment, headache (n=50 [8%]) and vertigo (n=37 [6%]) were the most widely reported symptoms; 24 h after treatment, 50 (8%) patients reported vertigo and 41 (7%) reported headache. Mainly mild adverse events were reported with peak numbers (n=111 [18%]) at 24 h after treatment. Three participants had moderate adverse events 3 h after treatment: two (<1%) had vertigo and one (<1%) had headache, and two had moderate adverse events 24 h after treatment: one (<1%) had vomiting and one (<1%) had vomiting plus diarrhoea.
INTERPRETATION: Tribendimidine in combination with either ivermectin or oxantel pamoate had a similar, non-inferior efficacy profile as albendazole plus oxantel pamoate, hence tribendimidine will be a useful addition to the depleted anthelmintic drug armamentarium.
FUNDING: Swiss National Science Foundation.

PMID: 28864027 [PubMed - indexed for MEDLINE]

Do patients with intake of drugs labelled as sleep disturbing really sleep worse? A population based assessment from the Heinz Nixdorf Recall Study.

Br J Clin Pharmacol. 2016 Sep;82(3):869-77

Authors: Lehnich AT, Kowall B, Kuß O, Schmidt-Pokrzywniak A, Weinreich G, Dragano N, Moebus S, Erbel R, Jöckel KH, Stang A

Abstract
AIM: The sleep disturbing effect of many drugs is derived from clinical trials with highly selected patient collectives. However, the generalizability of such findings to the general population is questionable. Our aim was to assess the association between intake of drugs labelled as sleep disturbing and self-reported nocturnal sleep disturbances in a population-based study.
METHODS: We used data of 4221 participants (50.0% male) aged 45 to 75 years from the baseline examination of the Heinz Nixdorf Recall Study in Germany. The interview provided information on difficulties falling asleep, difficulties maintaining sleep and early morning arousal. We used the summary of product characteristics (SPC) for each drug taken and assigned the probability of sleep disturbances. Thereafter, we calculated cumulative probabilities of sleep disturbances per subject to account for polypharmacy. We estimated prevalence ratios (PR) using log Poisson regression models with robust variance.
RESULTS: The adjusted PRs of any regular nocturnal sleep disorder per additional sleep disturbing drug were 1.01 (95% confidence interval (CI) 0.97, 1.06) and 1.03 (95% CI 1.00, 1.07) for men and women, respectively. Estimates for each regular nocturnal sleep disturbance were similarly close to 1. PRs for regular nocturnal sleep disturbances did not increase with rising cumulative probability for drug-related sleep disturbances.
CONCLUSIONS: SPC-based probabilities of drug-related sleep disturbances showed barely any association with self-reported regular nocturnal sleep disturbances. We conclude that SPC-based probability information may lack generalizability to the general population or may be of limited data quality.

PMID: 27279554 [PubMed - indexed for MEDLINE]

In silico methods for drug repurposing and pharmacology.

Wiley Interdiscip Rev Syst Biol Med. 2016 May;8(3):186-210

Authors: Hodos RA, Kidd BA, Shameer K, Readhead BP, Dudley JT

Abstract
Data in the biological, chemical, and clinical domains are accumulating at ever-increasing rates and have the potential to accelerate and inform drug development in new ways. Challenges and opportunities now lie in developing analytic tools to transform these often complex and heterogeneous data into testable hypotheses and actionable insights. This is the aim of computational pharmacology, which uses in silico techniques to better understand and predict how drugs affect biological systems, which can in turn improve clinical use, avoid unwanted side effects, and guide selection and development of better treatments. One exciting application of computational pharmacology is drug repurposing-finding new uses for existing drugs. Already yielding many promising candidates, this strategy has the potential to improve the efficiency of the drug development process and reach patient populations with previously unmet needs such as those with rare diseases. While current techniques in computational pharmacology and drug repurposing often focus on just a single data modality such as gene expression or drug-target interactions, we argue that methods such as matrix factorization that can integrate data within and across diverse data types have the potential to improve predictive performance and provide a fuller picture of a drug's pharmacological action. WIREs Syst Biol Med 2016, 8:186-210. doi: 10.1002/wsbm.1337 For further resources related to this article, please visit the WIREs website.

PMID: 27080087 [PubMed - indexed for MEDLINE]

Rivaroxaban-induced hepatotoxicity: review of the literature and report of new cases.

Eur J Gastroenterol Hepatol. 2017 Nov 08;:

Authors: Licata A, Puccia F, Lombardo V, Serruto A, Minissale MG, Morreale I, Giannitrapani L, Soresi M, Montalto G, Almasio PL

Abstract
AIM/OBJECTIVE/BACKGROUND: Direct-acting oral anticoagulant drugs are marketed worldwide for the primary and secondary prevention and treatment of thromboembolic disorders. Rivaroxaban, an oral, direct factor Xa inhibitor, is one of the most used. Rivaroxaban-induced hepatotoxicity is unusual, although a number of adverse reports have recently been reported. Here, we report two new cases of rivaroxaban-induced hepatitis.
METHODS: A systematic search of case reports on the MEDLINE database encompassing the years 2008-2016 was carried out.Additional references were obtained following a manual search of the retrieved papers. We report two new cases of adverse events occurred in patients treated with rivaroxaban (20 mg/die) to prevent systemic embolism, who presented with hepatocellular liver injury with onset at 8 weeks after initiation of the drug intake.
RESULTS: Twenty-six cases were retrieved from MEDLINE (57.7% female, 42.3% male). Using the Roussel Uclaf Causality Assessment Method (RUCAM) scale, liver injury was classified as hepatocellular (42.3%), cholestatic (26.9%), or mixed (15.4%). Older age (≥65 years) was present as a risk factor in 57.7%. The time lapse between initiation of treatment and onset of hepatic injury ranged from 2 to 180 days (median: 15 days). Our two new patients were diagnosed with drug-induced liver injury (hepatocellular pattern) using the 'consensus criteria', for drug-induced liver injury. Their RUCAM scores were calculated and assessed as highly probable and probable, respectively. A clinical recovery after rivaroxaban withdrawal was observed.
CONCLUSION: Direct-acting oral anticoagulants have been commonly prescribed, even if safety issues regarding the use of these drugs are still an ongoing concern, especially in patients experiencing chronic liver disease. Dedicated postauthorization safety studies should be undertaken to better define rivaroxaban-induced drug-induced liver injury.

PMID: 29120909 [PubMed - as supplied by publisher]

Drug-induced nephrotoxicity: pathogenic mechanisms, biomarkers and prevention strategies.

Curr Drug Metab. 2017 Nov 08;:

Authors: Huang J, Wu H

Abstract
Overdosing of the drugs, drug-drug interaction or drug related adverse effects are the risk factors of drug-induced nephrotoxicity. Since the use of some nephrotoxic drugs is still unavoidable in clinic, to understand the pathogenic mechanisms of nephrotoxicity of these drugs is critical to decrease the incidence of kidney injury. Early detection of drug-induced nephrotoxicity and reduce the therapeutic side effects are still accessible approaches to avoid the end stage of renal failure. Therefore, the discovery or development of the early and accurate diagnostic biomarkers is an effective prevention strategy for drug-induced kidney impairment. In the present review, we summarized the mechanisms and prevention strategies for some common used drugs in clinic that induced acute and chronic kidney injury. We discussed the pros and cons of the biomarkers available nowadays. In addition, the in vitro and pre-clinical in vivo models to assess the nephrotoxicity during the drug development stages are also discussed.

PMID: 29119923 [PubMed - as supplied by publisher]

Decreased 5-HT2cR and GHSR1a interaction in antipsychotic drug-induced obesity.

Obes Rev. 2017 Nov 09;:

Authors: Huang XF, Weston-Green K, Yu Y

Abstract
Second generation antipsychotics (SGAs), notably atypical antipsychotics including olanzapine, clozapine and risperidone, can cause weight gain and obesity side effects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin receptor type 1a (GHSR1a) signalling have been identified as a main cause of SGA induced obesity. Here we review the pivotal regulatory role of the 5-HT2cR in ghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to inhibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization and increases GHSR1a-induced food intake. Dimerization is specific to the unedited 5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibitory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and its interaction with the GHSR1a could serve as the basis for discovering novel approaches to preventing and treating SGA-induced obesity.

PMID: 29119689 [PubMed - as supplied by publisher]

Older People's Preferences for Side Effects Associated with Antimuscarinic Treatments of Overactive Bladder: A Discrete-Choice Experiment.

Drugs Aging. 2017 Aug;34(8):615-623

Authors: Decalf VH, Huion AMJ, Benoit DF, Denys MA, Petrovic M, Everaert KCMM

Abstract
INTRODUCTION: Understanding the importance older people attribute to the different side effects associated with oral antimuscarinic treatments for overactive bladder (OAB) could help inform prescribers, healthcare policy makers and the drug industry.
OBJECTIVE: Our objective was to quantify the importance of the most prevalent cognitive and side effects of oral antimuscarinic treatments for OAB in older people.
METHODS: We conducted a discrete-choice experiment (DCE) with the assistance of an interviewer with community-dwelling and hospitalized older people aged >65 years. The DCE involved two hypothetical drugs for imaginary OAB, with three levels of four side effects for each drug, and the International Consultation on Incontinence Questionnaire-Overactive Bladder and EuroQol 5-Dimensions (EQ-5D) questionnaire were also administered. Data were analysed using a conditional logit model.
RESULTS: In total, 276 older people participated in the study. The median age was 75 years (interquartile range [IQR] 69-80), 63% were women and 21% had OAB syndrome. The most unwanted side effect in the choice of antimuscarinics for OAB was severe cognitive effects, followed by severe constipation, severe blurred vision, severe dry mouth, moderate cognitive effects and moderate constipation. Severe cognitive effects were at least 1.7 times as important as severe constipation. Exploratory subgroup analysis showed that none of the attributes was found to be significant in people who scored as anxious or depressed on the EQ-5D, and preferences about cognitive effects, constipation and blurred vision were equal in people with and without OAB.
CONCLUSION: Older people attribute more importance to loss of cognitive function as a possible side effect of antimuscarinic treatment than to the three most prevalent possible side effects of this treatment.

PMID: 28656509 [PubMed - indexed for MEDLINE]

Tolerability, Safety, and Effectiveness of Oxycodone DETERx in Elderly Patients ≥65 Years of Age with Chronic Low Back Pain: A Randomized Controlled Trial.

Drugs Aging. 2017 Aug;34(8):603-613

Authors: Kopecky EA, Vaughn B, Lagasse S, O'Connor M

Abstract
TRIAL DESIGN: This was a phase III, randomized withdrawal, double-blind, placebo-controlled, enriched enrollment, parallel-group, multicenter study intended to demonstrate the safety, tolerability, and analgesic efficacy of oxycodone DETERx(®) (Xtampza™ ER) compared with matching placebo.
METHODS: This post hoc analysis was performed using data from a subpopulation of enrolled patients who were ≥65 years of age. The study enrolled male and female patients with a clinical diagnosis of moderate-to-severe chronic low back pain for a minimum of 6 months prior to screening who required around-the-clock opioid therapy. To be eligible for enrollment, patients were required to have an average 24-h pain intensity score of ≥5 and ≤9 on an 11-point (0-10) Pain Intensity-Numerical Rating Scale at the screening visit. The study enrolled both opioid-experienced and opioid-naïve patients. The study consisted of an open-label titration phase followed by a 12-week double-blind maintenance phase. The dose range was 40-160 mg oxycodone hydrochloride equivalent per day. This post hoc analysis evaluated the safety, tolerability, and effectiveness of oxycodone DETERx among patients ≥65 years of age. The effectiveness of oxycodone DETERx was evaluated based on average pain intensity scores, Patient Global Impression of Change, responder analysis, and Kaplan-Meier survival analysis. The safety and tolerability of oxycodone DETERx were also evaluated. Patients were randomized to either oxycodone DETERx or placebo using a blocked randomization scheme in a 1:1 ratio. Randomization was stratified by previous opioid use (naïve or experienced). The study drug was coded in a manner that maintained the blinding. Study personnel and patients remained blinded to the assigned treatments throughout the study.
RESULTS: For this post-hoc analysis, the intent-to-treat and randomized safety populations included 52 patients ≥65 years old, 26 each in the oxycodone DETERx and placebo groups, who participated in the study during the titration phase and were randomized to the double-blind maintenance phase. Clinically important pain reduction from screening was achieved with oxycodone DETERx, with the median pain intensity score decreasing from 7.50 at screening to 2.69 at Week 12. A clinically meaningful treatment difference of -0.9 in pain score between oxycodone DETERx and placebo was observed. All 18 elderly patients who completed the study reported improvement in pain, with 62% showing ≥30% improvement and 54% showing ≥50% improvement in pain intensity compared with patients on placebo (p = 0.0128 and p = 0.0501, respectively). Patients on oxycodone DETERx remained in the study longer than those on placebo. Of the 26 patients ≥65 years old randomized to continue oxycodone DETERx during the double-blind maintenance phase, 18 (69%) completed the study; only two patients (8%) in the oxycodone DETERx group discontinued due to adverse events. The safety and tolerability profiles showed no new or unexpected safety concerns. The adverse event profiles were similar between the titration and double-blind maintenance phases.
CONCLUSIONS: Oxycodone DETERx was efficacious and generally well tolerated in patients ≥65 years old.
TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (NCT01685684).

PMID: 28600725 [PubMed - indexed for MEDLINE]

[Causality assessment in reports on adverse drug reactions. Algorithm of Spanish pharmacovigilance system].

Med Clin (Barc). 2016 Nov 18;147(10):461-464

Authors: Aguirre C, García M

PMID: 27450163 [PubMed - indexed for MEDLINE]

Long-term safety of long-acting octreotide in patients with diabetic retinopathy: results of pooled data from 2 randomized, double-blind, placebo-controlled phase 3 studies.

Endocrine. 2017 Nov 07;:

Authors: Pivonello R, Muscogiuri G, Holder G, Paul M, Sarp S, Lesogor A, Jordaan P, Eisinger J, Colao A

Abstract
PURPOSE: Octreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.
METHODS: Two studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.
RESULTS: Median duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61-2.03]; OCT30, RR = 1.09 [95% CI, 0.70-1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28-3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69-3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.
CONCLUSIONS: The results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.

PMID: 29116540 [PubMed - as supplied by publisher]

Self-administered Versus Directly Observed Once-Weekly Isoniazid and Rifapentine Treatment of Latent Tuberculosis Infection: A Randomized Trial.

Ann Intern Med. 2017 Nov 07;:

Authors: Belknap R, Holland D, Feng PJ, Millet JP, Caylà JA, Martinson NA, Wright A, Chen MP, Moro RN, Scott NA, Arevalo B, Miró JM, Villarino ME, Weiner M, Borisov AS, TB Trials Consortium iAdhere Study Team

Abstract
Background: Expanding latent tuberculosis treatment is important to decrease active disease globally. Once-weekly isoniazid and rifapentine for 12 doses is effective but limited by requiring direct observation.
Objective: To compare treatment completion and safety of once-weekly isoniazid and rifapentine by self-administration versus direct observation.
Design: An open-label, phase 4 randomized clinical trial designed as a noninferiority study with a 15% margin. Seventy-five percent or more of study patients were enrolled from the United States for a prespecified subgroup analysis. (ClinicalTrials.gov: NCT01582711).
Setting: Outpatient tuberculosis clinics in the United States, Spain, Hong Kong, and South Africa.
Participants: 1002 adults (aged ≥18 years) recommended for treatment of latent tuberculosis infection.
Intervention: Participants received once-weekly isoniazid and rifapentine by direct observation, self-administration with monthly monitoring, or self-administration with weekly text message reminders and monthly monitoring.
Measurements: The primary outcome was treatment completion, defined as 11 or more doses within 16 weeks and measured using clinical documentation and pill counts for direct observation, and self-reports, pill counts, and medication event-monitoring devices for self-administration. The main secondary outcome was adverse events.
Results: Median age was 36 years, 48% of participants were women, and 77% were enrolled at the U.S. sites. Treatment completion was 87.2% (95% CI, 83.1% to 90.5%) in the direct-observation group, 74.0% (CI, 68.9% to 78.6%) in the self-administration group, and 76.4% (CI, 71.3% to 80.8%) in the self-administration-with-reminders group. In the United States, treatment completion was 85.4% (CI, 80.4% to 89.4%), 77.9% (CI, 72.7% to 82.6%), and 76.7% (CI, 70.9% to 81.7%), respectively. Self-administered therapy without reminders was noninferior to direct observation in the United States; no other comparisons met noninferiority criteria. A few drug-related adverse events occurred and were similar across groups.
Limitation: Persons with latent tuberculosis infection enrolled in South Africa would not routinely be treated programmatically.
Conclusion: These results support using self-administered, once-weekly isoniazid and rifapentine to treat latent tuberculosis infection in the United States, and such treatment could be considered in similar settings when direct observation is not feasible.
Primary Funding Source: Centers for Disease Control and Prevention.

PMID: 29114781 [PubMed - as supplied by publisher]

Muscadine Grape Skin Extract in Men with Biochemically Recurrent Prostate Cancer: A Randomized, Multicenter, Placebo-Controlled Clinical Trial.

Clin Cancer Res. 2017 Nov 07;:

Authors: Paller CJ, Zhou XC, Heath EI, Taplin ME, Mayer T, Stein MN, Bubley GJ, Pili R, Hudson T, Kakarla R, Abbas MM, Anders NM, Dowling D, King S, Bruns AB, Wagner WD, Drake CG, Antonarakis ES, Eisenberger MA, Denmeade SR, Rudek MA, Rosner GL, Carducci MA

Abstract
PURPOSE: MPX, a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer (PCa) wishing to defer androgen deprivation therapy.
EXPERIMENTAL DESIGN: This was a 12-month, multi-center, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR PCa, powered to detect a prostate specific antigen doubling time (PSADT) difference of 6 months (low-dose) and 12 months (high-dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500mg MPX (low), 4000mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation and polyphenol pharmacokinetics.
RESULTS: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (p=0.81): control 0.9 months (n=20, range -6.7 to 83.1), low-dose 1.5 months (n=52, range: -10.3 to 87.2), high-dose 0.9 months (n=40, range: -27.3 to 88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms) (6.4 months, p=0.02), but not in control (1.8 months, p=0.25).
CONCLUSIONS: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study.

PMID: 29113986 [PubMed - as supplied by publisher]