Loretta Piccenna

Pharmacotherapies for Obesity: Past, Current, and Future Therapies

Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs.

Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice

Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75NTR) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte‐derived nerve growth factor (NGF) was linked to p75NTR‐expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF‐dependent p75NTR‐mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75NTR ligand binding by using neurotrophin‐stimulated cell death assays and transgenic ALS mice. Murine motor neuron‐like (NSC‐34) cell cultures expressed full‐length and truncated p75NTR, tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog‐2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose‐dependent cell death, which was significantly blocked by the cyclic decapeptide p75NTR antagonist. Application of brain‐derived neurotrophic factor, neurotrophin‐3, or neurotrophin‐4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K‐252a. Systemic administration of a modified cyclic decapeptide p75NTR antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1G93A mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF‐p75NTR interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand‐independent pathways of p75NTR activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice.

Smoking Cessation–Recent Advances

BackgroundSmoking continues to be a major contributor to the burden of disease across the world although there has been a decrease in some developed countries such as USA and Australia. In countries of South-East Asia with a high prevalence of smoking, the incidence of tobacco-related diseases will continue to increase.MethodsWe reviewed the literature in relation to the pharmacology of nicotine, the measures used to determine the efficacy of anti-smoking therapies, and the randomised controlled trials and systematic reviews of pharmacotherapies published between 2004 and 2010. We focused primarily on the three first line therapies that are currently available: nicotine replacement therapy (NRT), bupropion and varenicline.ResultsRandomised controlled trials and meta-analyses have demonstrated that single therapy with either NRT, bupropion or varenicline are all more effective than placebo for smoking cessation. Abstinence rates for monotherapies varies from 13.3% to 19% for NRT compared to 7.5% to 14% for placebo, 19% to 19.7% for bupropion versus 10.9% to 11% for placebo and 25.5% to 25.6% for varenicline versus 11.2% to 14.8% for placebo. Of current therapies varenicline appears to be more effective at achieving abstinence. Some combination therapies with one or two formulations of NRT or NRT plus bupropion have demonstrated superior results to monotherapy. To date there are no randomised controlled trials of varenicline in combination with NRT or bupropion.ConclusionFurther studies are required to address the uncertainty that exists on the most appropriate duration of therapy as well as the effectiveness and safety of combination pharmacotherapy. Post-marketing surveillance continues to play an important role in monitoring the adverse effects events associated with these therapies.

Relaxin family peptides and receptors in mammalian brain

As a foundation for regulatory and functional studies of central relaxin family peptide receptor systems, we are mapping the distribution of the different receptors in the brain of rat, mouse, and nonhuman primates, attempting to identify the nature of the receptor‐positive neurons in key circuits and establish the complementary distribution of the respective ligands in these species. Here we review progress in mapping RXFP1, RXFP2, and RXFP3 (mRNAs and proteins) and their respective ligands and discuss some of the putative functions for these peptides and receptors that are being explored using receptor‐selective agonist and antagonist peptides and receptor and peptide gene deletion mouse strains. Comparative studies reveal an association of RXFP1 and RXFP2 with excitatory neurons but a differential regional or cellular distribution, in contrast to the association of RXFP3 with inhibitory neurons. These studies also reveal differences in the distribution of RXFP1 and RXFP2 in rat and mouse brain, whereas the distribution of RXFP3 is more conserved across these species. Enrichment of RXFP1/2/3 in olfactory, cortical, thalamic, limbic, hypothalamic, midbrain, and pontine circuits suggests a diverse range of modulatory actions for these receptors. For example, experimental evidence in the rat reveals that RXFP1 activation in the amygdala inhibits memory consolidation, RXFP2 activation in striatum produces sniffing behavior, and RXFP3 modulation has effects on feeding and metabolism, the activity of the septohippocampal pathway, and spatial memory. Further studies are now required to reveal additional details of these and other functions linked to relaxin family peptide receptor signaling in mammalian brain and the precise mechanisms involved.

Quality of guidelines for cognitive rehabilitation following traumatic brain injury.

Introduction:Cognitive rehabilitation following traumatic brain injury can aid in optimizing function, independence, and quality of life by addressing impairments in attention, executive function, cognitive communication, and memory. This study aimed to identify and evaluate the methodological quality of clinical practice guidelines for cognitive rehabilitation following traumatic brain injury. Methods:Systematic searching of databases and Web sites was undertaken between January and March 2012 to identify freely available, English language clinical practice guidelines from 2002 onward. Eligible guidelines were evaluated using the validated Appraisal of Guidelines for Research and Evaluation II instrument. Results:The 11 guidelines that met inclusion criteria were independently rated by 4 raters. Results of quality appraisal indicated that guidelines generally employed systematic search and appraisal methods and produced unambiguous, clearly identifiable recommendations. Conversely, only 1 guideline incorporated implementation and audit information, and there was poor reporting of processes for formulating, reviewing, and ensuring currency of recommendations and incorporating patient preferences. Intraclass correlation coefficients for agreement between raters showed high agreement (intraclass correlation coefficient > 0.80) for all guidelines except for 1 (moderate agreement; intraclass correlation coefficient = 0.76). Conclusion:Future guidelines should address identified limitations by providing implementation information and audit criteria, along with better reporting of guideline development processes and stakeholder engagement.

Localization of LGR7 Gene Expression in Adult Mouse Brain Using LGR7 Knock-out/LacZ Knock-in Mice: Correlation with LGR7 mRNA Distribution

Abstract: Knowledge of the distribution of the relaxin receptor, LGR7, in the brain provides a basis for studies of the physiologic actions of relaxin. LGR7 knock‐out (KO) mice were produced by the in‐frame replacement of LGR7 exon 10 and 11 with a LacZ‐reporter cassette (knock‐in [KI]), and in this study we used LGR7‐KO/LacZ‐KI mice to determine the regional/cellular distribution of LGR7 gene expression in adult mouse brain by assessing β‐galactosidase activity in perfusion‐fixed sections. High densities of β‐galactosidase‐positive neurons were detected in anterior olfactory and claustrum/endopiriform nuclei, deep layers of cortex (particularly somatosensory), and the subiculum. Low to moderate densities were detected in olfactory bulb (periglomerular layer), cingulate cortex, subfornical organ, hippocampal CA2/dentate hilus, amygdala, hypothalamus, and thalamus. This LGR7/LacZ expression appears to recapitulate that of native LGR7 in wild‐type mice and provides a model to further investigate the phenotype of LGR7‐responsive neurons in the brain and to help reveal functions associated with central relaxin signaling.

The Value of Patient-Centred Registries in Phase IV Drug Surveillance

In the past, postmarketing surveillance of drugs relied mainly on the spontaneous reporting of adverse drug reactions. There are now several other approaches used, including databases with individual prescription data (or prescription event monitoring systems), electronic health records and record linkage between health databases. The recent drug withdrawals have continued to highlight the inadequacies of current postmarketing surveillance and the need for better strategies to monitor the safety of new drugs. One such strategy is the use of drug registries.Drug registries facilitate a special form of prospective observational cohort study of patients exposed to a particular drug. They are particularly useful in establishing the safety of orphan drugs and ascertaining the safety of drugs in specific populations. To minimize bias, patient eligibility is defined and data capture is standardized. All patients are followed up systematically over a pre-defined time period, either manually or using electronic record linkage to other health databases. To establish the incidence of any adverse events using a drug registry, there should be complete follow-up of all patients.Drug registries may play an important role in postmarketing surveillance of new drugs. Unlike spontaneous reporting systems they have the benefit of being able to determine the incidence of one or more outcomes in the patient population. Drug registries do, however, have some limitations, including a potential for bias and confounding, long periods of follow-up and high cost.

Management of post-traumatic epilepsy: An evidence review over the last 5 years and future directions

Post‐traumatic epilepsy (PTE) is a relatively underappreciated condition that can develop as a secondary consequence following traumatic brain injury (TBI). The aim of this rapid evidence review is to provide a synthesis of existing evidence on the effectiveness of treatment interventions for the prevention of PTE in people who have suffered a moderate/severe TBI to increase awareness and understanding among consumers. Electronic medical databases (n = 5) and gray literature published between January 2010 and April 2015 were searched for studies on the management of PTE. Twenty‐two eligible studies were identified that met the inclusion criteria. No evidence was found for the effectiveness of any pharmacological treatments in the prevention or treatment of symptomatic seizures in adults with PTE. However, limited high‐level evidence for the effectiveness of the antiepileptic drug levetiracetam was identified for PTE in children. Low‐level evidence was identified for nonpharmacological interventions in significantly reducing seizures in patients with PTE, but only in a minority of cases, requiring further high‐level studies to confirm the results. This review provides an opportunity for researchers and health service professionals to better understand the underlying pathophysiology of PTE to develop novel, more effective therapeutic targets and to improve the quality of life of people with this condition.

Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part I: rapid review of SCI prioritisation literature

Study design:This is a rapid evidence review.Objectives:The objective of this study was to gain an overview of the volume, nature and findings of studies regarding priorities for spinal cord injury (SCI) research.Setting:A worldwide literature search was conducted.Methods:Six medical literature databases and Google Scholar were searched for reviews in which the primary aim was to identify SCI research priorities.Results:Two systematic reviews were identified—one of quantitative and one of qualitative studies. The quality of the reviews was variable. Collectively, the reviews identified 31 primary studies; 24 quantitative studies totalling 5262 participants and 7 qualitative studies totalling 120 participants. Despite the difference in research paradigms, there was convergence in review findings in the areas of body impairments and relationships. The vast majority of literature within the reviews focused on the SCI patient perspective.Conclusion:The reviews inform specific research topics and highlight other important research considerations, most notably those pertaining to SCI patients’ perspectives on quality of life, which may be of use in determining meaningful research outcome measures. The views of other SCI research stakeholders such as researchers, clinicians, policymakers, funders and carers would help shape a bigger picture of SCI research priorities, ultimately optimising research outputs and translation into clinical practice and health policy change. Review findings informed subsequent activities in developing a regional SCI research strategy, as described in two companion papers.Sponsorship:This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand SCI Network.

Developing a spinal cord injury research strategy using a structured process of evidence review and stakeholder dialogue. Part II: Background to a research strategy.

Study design:Literature review/semi-structured interviews.Objective:To develop a spinal cord injury (SCI) research strategy for Australia and New Zealand.Setting:Australia.Methods:The National Trauma Research Institute Forum approach of structured evidence review and stakeholder consultation was employed. This involved gathering from published literature and stakeholder consultation the information necessary to properly consider the challenge, and synthesising this into a briefing document.Results:A research strategy ‘roadmap’ was developed to define the major steps and key planning questions to consider; next, evidence from published SCI research strategy initiatives was synthesised with information from four one-on-one semi-structured interviews with key SCI research stakeholders to create a research strategy framework, articulating six key themes and associated activities for consideration. These resources, combined with a review of SCI prioritisation literature, were used to generate a list of draft principles for discussion in a structured stakeholder dialogue meeting.Conclusion:The research strategy roadmap and framework informed discussion at a structured stakeholder dialogue meeting of 23 participants representing key SCI research constituencies, results of which are published in a companion paper. These resources could also be of value in other research strategy or planning exercises.Sponsorship:This project was funded by the Victorian Transport Accident Commission and the Australian and New Zealand Spinal Cord Injury Network.