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  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 653 journals)
Showing 1 - 200 of 253 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 35)
AAPS Open     Open Access   (Followers: 5)
AAPS PharmSciTech     Hybrid Journal   (Followers: 10)
AboutOpen     Open Access  
ACS Pharmacology & Translational Science     Hybrid Journal   (Followers: 4)
Acta Pharmaceutica     Open Access   (Followers: 7)
Acta Pharmaceutica Indonesia     Open Access   (Followers: 2)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 4)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 5)
Acta Physiologica Hungarica     Full-text available via subscription   (Followers: 4)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 7)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 214)
Advanced Herbal Medicine     Open Access   (Followers: 8)
Advanced Therapeutics     Hybrid Journal   (Followers: 1)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Drug Research     Full-text available via subscription   (Followers: 27)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 22)
Advances in Pharmacoepidemiology & Drug Safety     Open Access   (Followers: 5)
Advances in Pharmacological and Pharmaceutical Sciences     Open Access   (Followers: 9)
Advances in Pharmacology     Full-text available via subscription   (Followers: 18)
Advances in Pharmacology and Pharmacy     Open Access   (Followers: 11)
Advances in Traditional Medicine     Hybrid Journal   (Followers: 8)
Adverse Drug Reaction Bulletin     Full-text available via subscription   (Followers: 6)
African Journal of Pharmacy and Pharmacology     Open Access   (Followers: 9)
AJP : The Australian Journal of Pharmacy     Full-text available via subscription   (Followers: 17)
Alternatives to Laboratory Animals     Full-text available via subscription   (Followers: 10)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 21)
American Journal of Drug Discovery and Development     Open Access   (Followers: 5)
American Journal of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 13)
American Journal of Health-System Pharmacy     Full-text available via subscription   (Followers: 66)
American Journal of Pharmaceutical Education     Open Access   (Followers: 13)
American Journal of Pharmacological Sciences     Open Access   (Followers: 2)
American Journal of Pharmacology and Toxicology     Open Access   (Followers: 24)
American Journal of Therapeutics     Hybrid Journal   (Followers: 15)
Analytical Methods     Full-text available via subscription   (Followers: 13)
Annales de Toxicologie Analytique     Open Access  
Annales Pharmaceutiques Francaises     Full-text available via subscription   (Followers: 3)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 35)
Anti-Infective Agents     Hybrid Journal   (Followers: 6)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibiotiques     Full-text available via subscription  
Antibody Therapeutics     Open Access   (Followers: 1)
Antiviral Chemistry and Chemotherapy     Open Access   (Followers: 2)
Antiviral Research     Hybrid Journal   (Followers: 8)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal   (Followers: 2)
Applied Clinical Trials     Full-text available via subscription   (Followers: 7)
Arabian Journal of Medicinal and Aromatic Plants     Open Access   (Followers: 4)
Archiv der Pharmazie     Hybrid Journal   (Followers: 3)
Archives of Drug Information     Hybrid Journal   (Followers: 5)
Archives of Pharmacal Research     Full-text available via subscription   (Followers: 2)
Archives of Pharmacy and Pharmaceutical Sciences     Open Access   (Followers: 7)
Archives of Pharmacy Practice     Open Access   (Followers: 12)
Archives of Razi Institute     Open Access  
Archivos Venezolanos de Farmacología y Terapéutica     Open Access  
Ars Pharmaceutica     Open Access   (Followers: 1)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 2)
Asian Journal of Pharmaceutical Research and Health Care     Open Access   (Followers: 4)
Asian Journal of Pharmaceutical Sciences     Open Access   (Followers: 3)
Asian Journal of Pharmaceutics     Open Access   (Followers: 4)
Asian Journal of Research in Medical and Pharmaceutical Sciences     Open Access   (Followers: 1)
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 4)
Australian Journal of Herbal Medicine     Full-text available via subscription   (Followers: 5)
Australian Pharmacist     Full-text available via subscription   (Followers: 6)
Autonomic & Autacoid Pharmacology     Hybrid Journal  
Avicenna Journal of Phytomedicine     Open Access   (Followers: 1)
Bangladesh Journal of Pharmacology     Open Access  
Bangladesh Journal of Physiology and Pharmacology     Open Access  
Bangladesh Pharmaceutical Journal     Full-text available via subscription   (Followers: 3)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 13)
Behavioural Pharmacology     Hybrid Journal   (Followers: 3)
Bioanalysis     Full-text available via subscription   (Followers: 12)
Biochemical Pharmacology     Hybrid Journal   (Followers: 11)
Biochemistry & Pharmacology : Open Access     Open Access   (Followers: 5)
BioDrugs     Full-text available via subscription   (Followers: 10)
Biological & Pharmaceutical Bulletin     Full-text available via subscription   (Followers: 6)
Biomedical and Environmental Sciences     Full-text available via subscription   (Followers: 3)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 3)
Biometrical Journal     Hybrid Journal   (Followers: 10)
Biopharm International     Full-text available via subscription   (Followers: 19)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 11)
Biotemas     Open Access  
BMC Pharmacology     Open Access   (Followers: 3)
BMC Pharmacology & Toxicology     Open Access   (Followers: 7)
Botanics : Targets and Therapy     Open Access   (Followers: 6)
Brazilian Journal of Pharmaceutical Sciences     Open Access   (Followers: 2)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 33)
British Journal of Pharmacology     Hybrid Journal   (Followers: 20)
British Journal of Pharmacy (BJPharm)     Open Access   (Followers: 6)
Bulletin of Faculty of Pharmacy, Cairo University     Open Access   (Followers: 8)
CADTH Technology Overviews     Free  
Canadian Journal of Pain     Open Access   (Followers: 2)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
Canadian Pharmacists Journal / Revue des Pharmaciens du Canada     Hybrid Journal   (Followers: 3)
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal   (Followers: 1)
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 7)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 16)
Cardiovascular Therapeutics     Open Access   (Followers: 2)
Cephalalgia Reports     Open Access   (Followers: 4)
Chemical and Pharmaceutical Bulletin     Full-text available via subscription   (Followers: 3)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 25)
ChemMedChem     Hybrid Journal   (Followers: 11)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Chinese Herbal Medicines     Full-text available via subscription   (Followers: 1)
Chinese Journal of Pharmaceutical Analysis     Full-text available via subscription  
Ciencia e Investigación     Open Access  
Ciência Equatorial     Open Access   (Followers: 1)
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 8)
Clinical and Translational Science     Open Access   (Followers: 5)
Clinical Cancer Drugs     Hybrid Journal   (Followers: 2)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 8)
Clinical Immunology, Endocrine & Metabolic Drugs     Hybrid Journal  
Clinical Medicine Insights : Therapeutics     Open Access   (Followers: 1)
Clinical Neuropharmacology     Hybrid Journal   (Followers: 4)
Clinical Pharmacist     Partially Free   (Followers: 11)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 30)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 48)
Clinical Pharmacology in Drug Development     Hybrid Journal   (Followers: 6)
Clinical Pharmacology: Advances and Applications     Open Access   (Followers: 6)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 17)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
Clinical Toxicology     Hybrid Journal   (Followers: 21)
Clinical Trials     Hybrid Journal   (Followers: 21)
CNS & Neurological Disorders - Drug Targets     Hybrid Journal   (Followers: 3)
CNS Drug Reviews     Open Access   (Followers: 5)
CNS Drugs     Full-text available via subscription   (Followers: 8)
Combination Products in Therapy     Open Access  
Consultant Pharmacist     Full-text available via subscription   (Followers: 3)
Consumer Drugs     Full-text available via subscription  
Contract Pharma     Full-text available via subscription  
Cosmetics     Open Access   (Followers: 5)
CPT : Pharmacometrics & Systems Pharmacology     Open Access   (Followers: 9)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 19)
Critical Reviews in Therapeutic Drug Carrier Systems     Full-text available via subscription   (Followers: 5)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Current Bioactive Compounds     Hybrid Journal  
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 6)
Current Clinical Pharmacology     Hybrid Journal   (Followers: 4)
Current Computer-Aided Drug Design     Hybrid Journal   (Followers: 1)
Current Drug Delivery     Hybrid Journal   (Followers: 9)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Current Drug Safety     Hybrid Journal   (Followers: 9)
Current Drug Targets     Hybrid Journal   (Followers: 7)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 2)
Current Issues in Pharmacy and Medical Sciences     Open Access   (Followers: 6)
Current Medical Science     Hybrid Journal   (Followers: 3)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 14)
Current Metabolomics     Hybrid Journal   (Followers: 6)
Current Molecular Pharmacology     Hybrid Journal  
Current Nanomedicine     Hybrid Journal   (Followers: 1)
Current Nanoscience     Hybrid Journal  
Current Neuropharmacology     Hybrid Journal   (Followers: 2)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 10)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 3)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 11)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 13)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Current Pharmacology Reports     Hybrid Journal   (Followers: 1)
Current Protocols in Pharmacology     Hybrid Journal  
Current Psychopharmacology     Hybrid Journal   (Followers: 1)
Current Radiopharmaceuticals     Hybrid Journal   (Followers: 1)
Current Research in Drug Discovery     Open Access   (Followers: 1)
Current Therapeutic Research     Open Access   (Followers: 10)
Current trends in Biotechnology and Pharmacy     Open Access   (Followers: 10)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 5)
DARU Journal of Pharmaceutical Sciences     Open Access   (Followers: 4)
Dhaka University Journal of Pharmaceutical Sciences     Open Access   (Followers: 4)
Die Pharmazie - An International Journal of Pharmaceutical Sciences     Full-text available via subscription   (Followers: 10)
Discovery Phytomedicine     Open Access   (Followers: 4)
Dose-Response     Open Access  
Drug Analytical Research     Open Access  
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 16)
Drug and Therapeutics Bulletin     Hybrid Journal   (Followers: 9)
Drug Delivery     Open Access   (Followers: 12)
Drug Delivery and Translational Research     Hybrid Journal   (Followers: 2)
Drug Delivery Letters     Hybrid Journal  
Drug Design, Development and Therapy     Open Access   (Followers: 4)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 34)
Drug Development Research     Hybrid Journal   (Followers: 19)
Drug Discovery Today     Full-text available via subscription   (Followers: 191)
Drug Discovery Today: Disease Mechanisms     Full-text available via subscription   (Followers: 8)
Drug Discovery Today: Disease Models     Full-text available via subscription   (Followers: 10)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 13)
Drug Discovery Today: Therapeutic Strategies     Full-text available via subscription   (Followers: 12)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 17)
Drug Metabolism and Personalized Therapy     Hybrid Journal   (Followers: 3)
Drug Metabolism and Pharmacokinetics     Full-text available via subscription   (Followers: 6)
Drug Metabolism Letters     Hybrid Journal   (Followers: 4)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 10)
Drug Research     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Drug Safety     Full-text available via subscription   (Followers: 191)
Drug Safety - Case Reports     Open Access   (Followers: 3)
Drug Target Insights     Open Access  
Drug, Healthcare and Patient Safety     Open Access   (Followers: 12)
Drugs     Full-text available via subscription   (Followers: 234)

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CNS Drugs
Journal Prestige (SJR): 1.635
Citation Impact (citeScore): 4
Number of Followers: 8  
  Full-text available via subscription Subscription journal
ISSN (Print) 1172-7047 - ISSN (Online) 1179-1934
Published by Adis Homepage  [21 journals]
  • Expanding the Treatment Landscape for Lennox-Gastaut Syndrome: Current and
           Future Strategies
    • Abstract: Abstract Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient’s lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%–68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%–78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat–OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a ‘one size fits all’ approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.
      PubDate: 2021-01-21
  • Correction to: Siponimod: A Review in Secondary Progressive Multiple
    • Abstract: The article Siponimod: A Review in Secondary Progressive Multiple Sclerosis
      PubDate: 2021-01-18
  • Correction to: OnabotulinumtoxinA in Chronic Migraine: A Profile of Its
    • Abstract: The article OnabotulinumtoxinA in Chronic Migraine: A Profile of Its Use, written by James E. Frampton, was originally published electronically on SpringerLink on 11 December 2020 without open access. After publication in volume 34, issue 12, page 1287–1298, AbbVie requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by AbbVie. Therefore, the copyright of the article has been changed to © Springer Nature Switzerland AG 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
      PubDate: 2021-01-16
  • Opicapone: A Review in Parkinson’s Disease
    • Abstract: Abstract Oral opicapone (Ongentys®), a potent third-generation, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive therapy to preparations of levodopa/dopa-decarboxylase inhibitor (L-dopa/DDCI) in adults with Parkinson’s disease (PD) and end-of dose (EoD) motor fluctuations. In pivotal global trials (BIPARK 1 and BIPARK 2; 14–15 weeks’ duration), open-label extensions (OLEs) of BIPARK, and in the real-world setting (OPTIPARK; 3–6 months), opicapone 50 mg once daily was an effective and generally well tolerated adjunctive therapy to L-dopa/DDCI plus other PD therapy in adults with PD and EoD motor fluctuations. Adjunctive opicapone provided better efficacy than placebo for improvements in ON- and OFF-state time and fulfilled noninferiority to adjunctive entacapone for improvements in OFF time in BIPARK 1. These beneficial effects of adjunctive opicapone on motor fluctuations were maintained during 1 year of treatment in OLE studies. Given its efficacy and safety profile, adjunctive opicapone remains an important option in the management of adults with PD and EoD motor fluctuations who cannot be stabilized on preparations of L-dopa/DDCI.
      PubDate: 2021-01-11
  • Safety and Efficacy of Sovateltide (IRL-1620) in a Multicenter Randomized
    • Abstract: Background Sovateltide (IRL-1620, PMZ-1620), an endothelin-B receptor agonist, has been previously shown to increase cerebral blood flow, have anti-apoptotic activity and produce neurovascular remodeling when administered intravenously following acute cerebral ischemic stroke in rats. Its safety and tolerability were confirmed in healthy human volunteers (CTRI/2016/11/007509). Objective Our objective was to determine the safety, tolerability and efficacy of sovateltide as an addition to standard of care (SOC) in patients with acute cerebral ischemic stroke. Methods A prospective, multicentric, randomized, double-blind, placebo-controlled study was conducted to compare the safety (primary objective) and efficacy (secondary objective) of sovateltide in patients with acute cerebral ischemic stroke. Adult males or females aged 18–70 years who had experienced a radiologically confirmed ischemic stroke within the last 24 h were included in the study. Patients with intracranial hemorrhage and those receiving endovascular therapy were excluded. Patients randomized to the sovateltide group received three doses of sovateltide (each dose 0.3 µg/kg) administered as an intravenous bolus over 1 min at an interval of 3 ± 1 h on day 1, day 3 and day 6 (total dose of 0.9 µg/kg/day). Patients randomized to the placebo group received an equal volume of saline. Every patient in both groups received SOC for stroke. Efficacy was evaluated using neurological outcomes based on National Institute of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS) and Barthel Index (BI) scores from day 1 through day 90. Quality of life was measured using the EuroQoL-5 Dimensions (EQ-5D) and Stroke-Specific Quality of Life (SSQoL) at 60 and 90 days of follow-up. Results A total of 40 patients with acute cerebral ischemic stroke were enrolled in this study, of whom 36 completed the 90-day follow-up. Patients received saline (n = 18; 11 male and 7 female) or sovateltide (n = 18; 15 male and 3 female) within 24 h of onset of stroke. The number of patients receiving investigational drug within 20 h of onset of stroke was 14/18 in the saline group and 10/18 in the sovateltide group. The baseline characteristics and SOC in both cohorts was similar. Sovateltide was well-tolerated, and all patients received complete treatment with no incidence of drug-related adverse events. Hemodynamic, biochemical or hematological parameters were not affected by sovateltide. Sovateltide treatment resulted in improved mRS and BI scores on day 6 compared with day 1 (p < 0.0001), an effect not seen in the saline group. Sovateltide increased the frequency of favorable outcomes at 3 months. An improvement of ≥ 2 points on the mRS was observed in 60 and 40% of patients in the sovateltide and saline groups, respectively (p = 0.0519; odds ratio [OR] 5.25). An improvement on the BI of ≥ 40 points was seen in 64 and 36% of the sovateltide and saline groups, respectively (p = 0.0112; OR 12.44). An improvement of ≥6 points on the NIHSS was seen in 56% of patients in the sovateltide group versus 43% in the saline group (p = 0.2714; OR 2.275). The number of patients with complete recovery (defined as an NIHSS score of 0 and a BI of 100) was significantly greater (p < 0.05) in the sovateltide group than in the saline group. An assessment of complete recovery using an mRS score of 0 did not show a statistically significant difference between the treatment groups. Sovateltide treatment resulted in improved quality of life as measured by the EQ-5D and SSQoL on day 90. Conclusion Sovateltide was safe and well-tolerated and resulted in improved neurological outcomes in patients with acute cerebral ischemic stroke 90 days post-treatment. Trial Registration The study is registered at CTRI/2017/11/010654 and NCT04046484.
      PubDate: 2021-01-11
  • Efficacy and Safety of Ibuprofen Plus Paracetamol in a Fixed-Dose
           Combination for Acute Postoperative Pain in Adults: Meta-Analysis and a
           Trial Sequential Analysis
    • Abstract: Background Ibuprofen and paracetamol (acetaminophen) are very commonly used for analgesia and pain. In 2020, the US FDA gave its first approval of a fixed-dose combination (FDC) of the two drugs in the same tablet for postoperative pain. There has been no quantitative, summative analysis of the FDC effect size measures against postoperative pain in adults. Similar analyses exist, but only in pediatric patients. Objective This was the first meta-analysis to compare the efficacy and safety outcomes of the ibuprofen/paracetamol FDC against placebo, administered postoperatively, for moderate to severe pain relief in adults. Methods The MEDLINE, EMBASE, and Cochrane CENTRAL databases, in addition to the grey literature, were searched for clinical trials until April 2020, to identify comparative literature studies of the ibuprofen/paracetamol FDC in acute postoperative pain in adults. No restrictions on doses, formulations (oral, intravenous), and underlying type of surgery were applied. Independent reviewers performed the study selection, data extraction, and the risk-of-bias and quality-of-evidence assessments based on the Cochrane criteria. The outcome measures of interest in the meta-analysis were ≥ 50% pain relief , need for rescue medications, and occurrence of adverse drug events. Statistical analyses using a random-effects model were performed, at a statistical significance of p < 0.05. The RevMan software was used for analysis. A trial sequential analysis (TSA) was conducted to assess how precise and conclusive the meta-analysis outcomes are. Results Seven double-blind, randomized controlled trials with 2947 participants were included. The FDC dose was at three different levels: 75–100 mg ibuprofen/250 mg paracetamol, 150–200 mg ibuprofen/500 mg paracetamol (FDA-approved dose level), and 292.5–400 mg ibuprofen/975–1000 mg paracetamol. The ≥ 50% pain relief outcome was more achieved with the FDC compared to placebo (risk ratio [RR] 2.60, 95% confidence interval [CI] 2.11–3.20, p < 0.00001), as was the reduced need for rescue medications (RR 0.51, 95% CI 0.37–0.71, p < 0.0001). While inconclusive based on TSA, the FDC was at the highest doses at least as well tolerated as placebo regarding the occurrence of adverse events, including severe, common, and treatment-related adverse events, as well as those that lead to discontinuation, but it was also significantly associated with lower rates of headache and nausea. Subgroup analyses confirmed that the efficacy and safety of the FDC were maintained regardless of doses and formulations. The sensitivity analysis confirmed outcomes against potential publication bias and identified sources of heterogeneity in analyses. Conclusion The ibuprofen plus paracetamol FDC is conclusively an effective analgesic against placebo in acute postoperative, moderate to severe pain in adults. It is also superiorly well tolerated, including at the higher dose of 292.5–400 mg ibuprofen/975–1000 mg paracetamol; however, safety outcomes were inconclusive. Future studies need to confirm the safety of FDC and its benefits against other marketed analgesics in postoperative pain.
      PubDate: 2021-01-11
  • OnabotulinumtoxinA in Chronic Migraine: A Profile of Its Use
    • Abstract: Abstract OnabotulinumtoxinA (Botox®; a formulation of botulinum toxin type A (BoNT/A)] is indicated for the prevention of headaches in adults with chronic migraine (CM) in numerous countries, including those of Europe. In clinical trials, intramuscular administration of BoNT/A (155–195 units at 12-week intervals) to patients with CM was generally well tolerated and associated with sustained and clinically meaningful improvements in multiple assessments of headache symptoms, headache-related impact and/or disability and migraine-specific health-related quality of life over a period of 1 year (in the pivotal PREEMPT 1 and 2 studies) and 2 years (in the phase IV COMPEL study). The efficacy and safety of BoNT/A therapy have been confirmed in a number of large, prospective, real-world studies conducted in Europe, including the 2-year REPOSE study. Intramuscular BoNT/A has also demonstrated greater clinical utility than the oral prophylactic medication topiramate in a clinical practice setting (FORWARD study).
      PubDate: 2020-12-11
  • Evaluation of Prescription Practices of Domperidone in Parkinson’s
           Disease: A Cross Sectional Study Among French Neurologists
    • Abstract: Background Domperidone is used to treat gastrointestinal symptoms in patients with Parkinson’s disease. Because of an increased risk of cardiac adverse events, the European Medicines Agency has issued recommendations restricting its use mainly in terms of age, dose, and treatment duration. Objective The aim of this study was to investigate current prescription practices of domperidone in Parkinson’s disease among French neurologists. Methods A cross-sectional study based on a questionnaire was conducted among French neurologists from Parkinson’s disease expert centers from the French NS-Park/FCRIN network, general hospitals, and private practice. Results Among the 253 neurologists who completed the questionnaire, 86 (34%) were physicians from expert centers and 167 (66%) were from other healthcare settings; 209 (83%) were aware of recommendations restricting domperidone use. The majority of neurologists (92%) declared prescribing domperidone regardless of the age of the patients. Sixty-one percent of neurologists prescribed domperidone beyond 7 days in newly diagnosed patients, 33% in patients with orthostatic hypotension, and 79% in patients receiving continuous apomorphine treatment. They did not follow the recommendation on posology in newly diagnosed patients (7% of neurologists), patients with orthostatic hypotension (10%), and patients receiving continuous apomorphine therapy (25%). Finally, only 58% of neurologists declared taking specific precautions before prescribing domperidone. Conclusions These findings show most French neurologists who responded to our questionnaire do not fully follow the restrictions on domperidone use, particularly in terms of treatment duration, and in patients receiving continuous apomorphine treatment. This may reflect the unmet need to prevent nausea in patients with Parkinson’s disease treated with dopaminergic drugs, particularly continuous apomorphine therapy.
      PubDate: 2020-12-05
  • Effects of Antipsychotic Drugs: Cross Talk Between the Nervous and Innate
           Immune System
    • Abstract: Abstract Converging lines of evidence suggest that activation of microglia (innate immune cells in the central nervous system [CNS]) is present in a subset of patients with schizophrenia. The extent to which antipsychotic drug treatment contributes to or combats this effect remains unclear. To address this question, we reviewed the literature for evidence that antipsychotic exposure influences brain microglia as indexed by in vivo neuroimaging and post-mortem studies in patients with schizophrenia and experimental animal models. We found no clear evidence from clinical studies for an effect of antipsychotics on either translocator protein (TSPO) radioligand binding (an in vivo neuroimaging measure of putative gliosis) or markers of brain microglia in post-mortem studies. In experimental animals, where drug and illness effects may be differentiated, we also found no clear evidence for consistent effects of antipsychotic drugs on TSPO radioligand binding. By contrast, we found evidence that chronic antipsychotic exposure may influence central microglia density and morphology. However, these effects were dependent on the dose and duration of drug exposure and whether an immune stimulus was present or not. In the latter case, antipsychotics were generally reported to suppress expression of inflammatory cytokines and inducible inflammatory enzymes such as cyclooxygenase and microglia activation. No clear conclusions could be drawn with regard to any effect of antipsychotics on brain microglia from current clinical data. There is evidence to suggest that antipsychotic drugs influence brain microglia in experimental animals, including possible anti-inflammatory actions. However, we lack detailed information on how these drugs influence brain microglia function at the molecular level. The clinical relevance of the animal data with regard to beneficial treatment effects and detrimental side effects of antipsychotic drugs also remains unknown, and further studies are warranted.
      PubDate: 2020-12-01
  • Cannabinoids in the Treatment of Insomnia Disorder: A Systematic Review
           and Meta-Analysis
    • Abstract: Background Insomnia is associated with significant comorbidity, disability and impact on quality of life and, despite advances in pharmacotherapy and psychotherapy, remains a significant burden to society. Cannabinoids are gaining acceptance for use as medicines in the treatment of insomnia disorder. Objective We conducted a systematic review and meta-analysis to evaluate the efficacy of cannabinoids in the treatment of insomnia disorder. Methods We performed a systematic review of the PubMed, Cochrane Library, MEDLINE, and Cumulative Index to Nursing and Allied Health Literature Complete databases from inception to 5 December 2019, and again prior to data abstraction, for studies of cannabis-based products for the treatment of insomnia disorder in adults. Inclusion criteria were (1) clinical studies, (2) participants aged ≥ 18 years, (3) insomnia disorder either formally diagnosed against contemporaneous diagnostic criteria or quantified with validated instruments and (4) compared cannabis-based products with the standard of care, placebo or a sedative. No language restrictions were imposed. Non-primary research, animal studies and studies of cannabis-induced insomnia were excluded. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials (RCTs) and Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I) tool for non-randomized trials. Heterogeneity was assessed with the I2 statistic. Results A total of five studies (two RCTs and three non-randomised studies) with 219 study participants were included, of which three could be combined. The three non-randomised studies contributed data on the Pittsburgh Sleep Quality Index Questionnaire score, showing a favourable effect of cannabinoids at ≤ 4 weeks of follow-up (mean difference − 1.89 [95% confidence interval {CI} − 2.68 to − 1.10]; n = 176) and at 8 weeks of follow-up (mean difference − 2.41 [95% CI − 3.36 to − 1.46]; n = 166). One double-blind crossover RCT (n = 32) reported that, compared with amitriptyline, nabilone—a synthetic analogue to tetrahydrocannabinol (THC)—improved Insomnia Severity Index scores after 2 weeks of treatment (adjusted difference − 3.25 [95% CI − 5.26 to − 1.24]) and resulted in a more restful sleep as a sub-measure of the Leeds Sleep Evaluation Questionnaire (LSEQ) (difference 0.48 [95% CI 0.01–0.95]) but with no effect on overall sleep quality as measured by the LSEQ. In a single ascending-dose RCT (n = 9), THC reduced sleep-onset latency compared with placebo at 10 mg, 20 mg and 30 mg doses (mean difference − 43.00 min [95% CI − 82.76 to − 3.24], − 62.00 [95% CI − 103.60 to − 20.40] and − 54.00 [95% CI − 103.93 to − 4.07], respectively). All the included studies were assessed as poor quality, mainly due to small sample sizes, short treatment periods, uncertain clinical significance and high risk of bias. Conclusions Few studies have examined the efficacy of cannabinoids in the treatment of insomnia disorder. Despite some possible signals for efficacy, the heterogeneity of participants, interventions, efficacy outcomes and results, and the high risk of bias across included trials, do not reliably inform evidence-based practice. This review highlights shortcomings in the existing literature, including lack of diagnostic clarity, poorly defined participant groups, non-standardised interventions and studies of inappropriate design, duration and power to detect clinically meaningful outcomes. Further research in the form of high-quality RCTs are required before drawing any conclusions about the efficacy of cannabinoids in the treatment of insomnia disorder. Trial Registration PROSPERO registration number, CRD42020161043.
      PubDate: 2020-11-26
  • Three-Year Effectiveness of Dimethyl Fumarate in Multiple Sclerosis: A
           Prospective Multicenter Real-World Study
    • Abstract: Background Dimethyl fumarate (DMF) has demonstrated efficacy in phase III studies. However, real-world data are still limited. Objective The objective of this study was to describe the profile of patients who receive DMF and to assess the effectiveness of DMF regarding relapses, disability progression, magnetic resonance imaging activity, and NEDA (No Evidence Disease Activity)-3 status in a Spanish population in a real-world setting. Methods We conducted a multicenter prospective study of patients who started DMF between 2014 and 2019 in Spain. Three subgroups were considered: naïve, switch to DMF because of inefficacy, and switch to DMF because of adverse effects. The effects of DMF on clinical and radiological measures were evaluated. Results Among 886 patients, 25.3% were naïve, 28.8% switched because of adverse effects, and 45.9% because of inefficacy. Median follow-up was 38.9 (interquartile range 22.6–41.8) months. Annualized relapse rates were 0.15, 0.10, and 0.10 at 12, 24, and 36 months respectively, and 77.7% of patients were relapse free at month 42. At 12, 24, and 42 months, 96.1%, 87.4%, and 79.7% of patients were progression free, respectively. The number of T1 gadolinium-enhancement (T1Gd+) lesions was 0.19, 0.14, and 0.18 at 12, 24, and 36 months. NEDA-3 status at month 42 was maintained by 49.8% of patients. Relapsing was associated with higher annualized relapse rates the year before (hazard ratio 1.34, p < 0.001) and to the inefficacy switch vs naïve group (hazard ratio 1.76, p = 0.003). A higher baseline Expanded Disability Status Scale score was associated with disability progression (hazard ratio 1.15, p = 0.003) and more T1Gd+ lesions (hazard ratio 1.07, p < 0.001) with radiological progression. A higher baseline Expanded Disability Status Scale score, a larger number of T1Gd+ lesions, and a switch because of inefficacy (vs adverse events) were all risk factors for losing NEDA-3 status. DMF was discontinued in 29.9% of patients, in 13.5% because of inefficacy. Conclusions Our findings confirm the sustained effectiveness of DMF on the clinical and radiological activity of multiple sclerosis in a real-world setting, both in naïve patients and in those switching from other multiple sclerosis therapies.
      PubDate: 2020-11-23
  • Pharmacological Interactions between the Dual Orexin Receptor Antagonist
           Daridorexant and Ethanol in a Double-Blind, Randomized,
           Placebo-Controlled, Double-Dummy, Four-Way Crossover Phase I Study in
           Healthy Subjects
    • Abstract: Background Daridorexant (ACT-541468) is a potent dual orexin receptor antagonist under development for the treatment of sleep disorders. Concomitant intake of ethanol and hypnotics has been shown to result in additive/supra-additive depression of the central nervous system, resulting in pronounced sedation. Objective The aim of this study was to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) interactions between ethanol and daridorexant. Method This was a single-center, double-blind, placebo-controlled, randomized, four-way crossover study conducted in 19 healthy male/female subjects. Subjects received the following four treatments: ethanol with daridorexant, daridorexant alone, ethanol alone, and placebo. Daridorexant 50 mg and the matching placebo were administered as single oral tablets. Ethanol was infused intravenously and clamped at a level of 0.6 g/L for 5 h. The PK of ethanol and daridorexant were assessed and a battery of PD tests performed. Results Concomitant administration of ethanol prolonged the time to reach maximum plasma concentrations (tmax) of daridorexant (median difference 1.25 h). No other relevant PK interactions were observed. Coadministration with ethanol produced a numerically greater impairment on saccadic peak velocity, body sway, visual analog scale (VAS) alertness, VAS alcohol intoxication, smooth pursuit, and adaptive tracking compared with daridorexant alone. All treatments were generally well tolerated without serious adverse events (AEs). The most commonly reported treatment-emergent AEs following coadministration of daridorexant and ethanol included somnolence, headache, fatigue, sudden onset of sleep, and dizziness. Conclusions Apart from a shift in tmax, no relevant changes in PK parameters were observed following coadministration of daridorexant and ethanol. The coadministration led to reinforced drug actions that were, at most, indicative of infra-additive effects on certain PD markers. Patients will be advised not to consume ethanol with daridorexant. Clinical Trials Registration number: NCT03609775 (ClinicalTrials.gov Identifier)
      PubDate: 2020-11-18
  • Acknowledgement to Referees
    • PubDate: 2020-11-13
  • Improving the Delivery of Levodopa in Parkinson’s Disease: A Review of
           Approved and Emerging Therapies
    • Abstract: Abstract Levodopa is the most effective drug for the treatment of Parkinson’s disease, but its use as an oral medication is complicated by its erratic absorption, extensive metabolism and short plasma half-life. On long-term use and with disease progression, there is a high incidence of motor and non-motor complications, which remain a major clinical and research challenge. It is widely accepted that levodopa needs to be administered using formulations that result in good and consistent bioavailability and the physiologically relevant and continuous formation of dopamine in the brain to maximise its efficacy while avoiding and reversing ‘wearing off’ and dyskinesia. However, the physicochemical properties of levodopa along with its pharmacokinetic and pharmacodynamic profile make it difficult to deliver the drug in a manner that fulfils these criteria. In this review, we examine the problems associated with the administration of levodopa in Parkinson’s disease and how the use of novel technologies and delivery devices is leading to a more consistent and sustained levodopa delivery with the aim of controlling motor function as well as non-motor symptoms.
      PubDate: 2020-11-04
  • Adjunctive Cenobamate for Focal-Onset Seizures in Adults: A Systematic
           Review and Meta-Analysis
    • Abstract: Background Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. This drug can enhance the inactivated state of voltage-gated sodium channels, preferentially inhibiting the persistent component of the sodium channel current, and acts as a positive allosteric modulator of GABAA receptors, binding at a non-benzodiazepine site. Objective We assessed the efficacy and safety of adjunctive cenobamate for the treatment of focal-onset seizures in adult patients with epilepsy using meta-analytical techniques. Methods We systematically searched (May, week 4, 2020) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials.gov). There were no date limitations or language restrictions. Randomized, placebo-controlled, single or double-blinded, add-on trials of cenobamate in adult patients with uncontrolled focal-onset seizures were identified. Main outcomes included the proportion of patients with ≥ 50 and 100% reduction in seizure frequency during the maintenance treatment period compared with baseline and the incidence of treatment withdrawal and adverse events (AEs). Risk ratio (RR) with 95% confidence interval (CI) was estimated for each outcome. Results Two trials were included, overall enrolling 659 patients (442 for the add-on cenobamate group and 217 for the add-on placebo group). Seizure frequency reduction by at least 50% occurred during the maintenance phase in 50.1% of the patients randomized to cenobamate and 23.5% of the placebo-treated participants (RR 2.18, 95% CI 1.67–2.85; p < 0.001). The pooled estimated RR to achieve seizure freedom for the cenobamate group in comparison with placebo was 3.71 (95% CI 1.93–7.14; p < 0.001). Withdrawal from randomized treatment occurred in 16.7 and 11.1% of participants receiving cenobamate and placebo, respectively (RR 1.34, 95% CI 0.85–2.09; p = 0.205). Treatment was discontinued due to AEs in 12.2 and 4.1% of the patients in the active and control arms (RR 2.27, 95% CI 1.08–4.79; p = 0.031). AEs were reported in 76.9 and 66.8% of the patients during treatment with cenobamate and placebo (RR 1.14, 95% CI 1.02–1.26; p = 0.021). The cenobamate-associated AEs included somnolence, dizziness, fatigue, balance disorder, and diplopia. Conclusions Adjunctive cenobamate in adult patients with uncontrolled focal-onset seizures is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.
      PubDate: 2020-11-01
  • Siponimod: A Review in Secondary Progressive Multiple Sclerosis
    • Abstract: Abstract Oral siponimod (Mayzent®), a next-generation, selective sphingosine 1-phosphate receptor (S1PR) 1 and 5 modulator, is approved in several countries for the treatment of secondary progressive multiple sclerosis (SPMS), with specific indications varying between individual countries. In the pivotal EXPAND trial (median duration double-blind treatment 18 months) in a broad spectrum of patients with SPMS, once-daily oral siponimod 2 mg (initial dose titration over 6 days) was significantly more effective than placebo in reducing clinical and MRI-defined outcomes of disease activity and disability progression, including 3-month confirmed disability progression on the Expanded Disability Status Scale (EDSS), and was generally well tolerated in the core phase of the study. These beneficial effects of siponimod appeared to be sustained during up to 5 years of treatment in the ongoing open-label extension phase of EXPAND. The safety profile of siponimod is similar to that of other agents in its class, including adverse events of special interest (i.e. those known to be associated with S1PR modulators). No new safety signals were identified during up to 5 years’ treatment in the open-label extension phase. Albeit further long-term efficacy and safety data from the real-world setting are required to fully define its role, given the paucity of current treatment options and its convenient dosage regimen, siponimod represents an important emerging option for the treatment of adult patients with SPMS with active disease evidenced by relapses or imaging-features of inflammatory activity.
      PubDate: 2020-10-27
  • Levetiracetam versus Phenytoin for the Pharmacotherapy of
           Benzodiazepine-Refractory Status Epilepticus: A Systematic Review and
           Meta-Analysis of Randomized Controlled Trials
    • Abstract: Background Recent studies have shown conflicting results regarding the effectiveness of levetiracetam for treating benzodiazepine-refractory status epilepticus (SE) compared with phenytoin. Therefore, a meta-analysis was carried out to assess the value of levetiracetam versus phenytoin in the pharmacotherapy of benzodiazepine-refractory SE. Objective The aim of this systematic review and meta-analysis was to compare the efficacy and safety of levetiracetam and phenytoin in the treatment of benzodiazepine-refractory SE. Methods The MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that had been conducted to evaluate levetiracetam versus phenytoin for benzodiazepine-refractory SE, to April 2020. The data were assessed using Review Manager 5.3 software. The risk ratio (RR) was analyzed using dichotomous outcomes, and calculated using a random-effect model. Results We pooled 1850 patients from 12 RCTs. Patients in the levetiracetam group had a significantly higher rate of clinical seizure cessation than in the phenytoin group (75.2% vs. 67.8%; RR 1.14, 95% confidence interval [CI] 1.05–1.25, p = 0.003). Moreover, less adverse events were observed in the levetiracetam group than in the phenytoin group (17.8% vs. 21.4%; RR 0.82, 95% CI 0.70–0.97, p = 0.02). In subgroup analysis, clinical seizure cessation was achieved more frequently with a higher dose of levetiracetam (> 30 mg/kg) [RR 1.15, 95% CI 1.00–1.32, p = 0.05]. Furthermore, in the subgroup of children, levetiracetam showed a higher rate of clinical seizure cessation than phenytoin (RR 1.13, 95% CI 1.02–1.25, p = 0.02). Conclusion Pharmacotherapy for BZD-refractory SE by LEV is superior to PHT in efficacy and safety outcomes.
      PubDate: 2020-10-27
  • Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A
           Population-Based Cohort and Case-Crossover Study
    • Abstract: Background Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. Objectives The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. Methods We did a population-based study using data from the Hong Kong Hospital Authority’s Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91–120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. Results 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42–18.69), 5.88 (2.46–14.04), and 4.77 (1.95–11.66). Conclusions Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded.
      PubDate: 2020-10-03
  • Efficacy and Safety of Low Doses of Trazodone in Patients Affected by
           Painful Diabetic Neuropathy and Treated with Gabapentin: A Randomized
           Controlled Pilot Study
    • Abstract: Background Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy. Objective This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy. Methods This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient’s improvement, and safety. Results One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were − 3.1, − 2.6, and − 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval − 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval − 1.54, − 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders. Conclusions All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ. Clinical Trial Registration NCT03202979, date of registration: 29/06/2017.
      PubDate: 2020-09-16
  • Neurobiology, Functions, and Relevance of Excitatory Amino Acid
           Transporters (EAATs) to Treatment of Refractory Epilepsy
    • Abstract: Abstract Epilepsy is one of the most prevalent and devastating neurological disorders characterized by episodes of unusual sensations, loss of awareness, and reoccurring seizures. The frequency and intensity of epileptic fits can vary to a great degree, with almost a third of all cases resistant to available therapies. At present, there is a major unmet need for effective and specific therapeutic intervention. Impairments of the exquisite balance between excitatory and inhibitory synaptic processes in the brain are considered key in the onset and pathophysiology of the disease. As the primary excitatory neurotransmitter in the central nervous system, glutamate has been implicated in the process, with the glutamatergic system holding center stage in the pathobiology as well as in developing disease-modifying therapies. Emerging data pinpoint impairments of glutamate clearance as one of the key causative factors in drug-resistant disease forms. Reinstatement of glutamate homeostasis using pharmacological and genetic modulation of glutamate clearance is therefore considered to be of major translational relevance. In this article, we review the neurobiological and clinical evidence suggesting complex aberrations in the activity and functions of excitatory amino acid transporters (EAATs) in epilepsy, with knock-on effects on glutamate homeostasis as a leading cause for the development of refractory forms. We consider the emerging data on pharmacological and genetic manipulations of EAATs, with reference to seizures and glutamate dyshomeostasis, and review their fundamental and translational relevance. We discuss the most recent advances in the EAATs research in human and animal models, along with numerous questions that remain open for debate and critical appraisal. Contrary to the widely held view on EAATs as a promising therapeutic target for management of refractory epilepsy as well as other neurological and psychiatric conditions related to glutamatergic hyperactivity and glutamate-induced cytotoxicity, we stress that the true relevance of EAAT2 as a target for medical intervention remains to be fully appreciated and verified. Despite decades of research, the emerging properties and functional characteristics of glutamate transporters and their relationship with neurophysiological and behavioral correlates of epilepsy challenge the current perception of this disease and fit unambiguously in neither EAATs functional deficit nor in reversal models. We stress the pressing need for new approaches and models for research and restoration of the physiological activity of glutamate transporters and synaptic transmission to achieve much needed therapeutic effects. The complex mechanism of EAATs regulation by multiple factors, including changes in the electrochemical environment and ionic gradients related to epileptic hyperactivity, impose major therapeutic challenges. As a final note, we consider the evolving views and present a cautious perspective on the key areas of future progress in the field towards better management and treatment of refractory disease forms.
      PubDate: 2020-09-14
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
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