Brimonidine tartrate for the treatment of glaucoma

Introduction: Brimonidine tartrate is a commonly used eyedrop for short- and long-term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine’s role in the treatment algorithm of ocular hypertension and glaucoma.

Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed.

Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine’s adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance.     

Dosing strategies to optimize currently available anti-MRSA treatment options (Part 2: PO options)

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a problematic pathogen in both outpatient and inpatient settings. Research to optimize the dosing of these agents is needed to slow the development of antimicrobial resistance and to decrease the likelihood of clinical failure.

Areas covered: This review summarizes the available data for orally administered antimicrobials routinely used as monotherapy for MRSA infections. We make recommendations and highlight the current gaps in the literature. A PubMed (1966 – Present) search was performed to identify relevant literature for this review.

Expert commentary: There is a vast divide in the amount of pharmacokinetic/pharmacodynamic data to guide dosing decisions for older MRSA agents compared with the oxazolidenones.

Five-year view: Additional retrospective data will become available for the older MRSA agents in severe MRSA infections.     

Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma

Introduction: Among the intraocular pressure (IOP)-lowering drugs used in a clinical setting, Rho kinase (ROCK) inhibitors lower IOP by a unique mechanism, namely the depolymerization of intracellular actin in the conventional outflow tissues: the trabecular meshwork (TM) and Schlemm’s canal (SC). Furthermore, ROCK inhibitors suppress the production of extracellular matrix by TM cells, which represents a potential alternative method of lowering IOP. Considering that conventional outflow is a dominant pathway in humans, IOP-lowering ROCK inhibitors, delivered in conjunction with other drugs, may be able to treat the glaucomatous eye.

Areas covered: Ripasudil hydrochloride hydrate is the first ROCK inhibitor approved for clinical use in Japan (and worldwide) against glaucoma and ocular hypertension. The efficacy of ripasudil, as monotherapy and as an adjunctive medication to prostaglandin analogs and/or adrenergic β-receptor antagonists, has been confirmed in clinical trials.

Expert opinion: Considering the unique ROCK-inhibiting mechanism by which ripasudil lowers IOP via its actions on TM and SC endothelial cells, it may be an ideal adjunctive medication for treating glaucoma in the clinic.     

Olopatadine hydrochloride ophthalmic solution for the treatment of allergic conjunctivitis

Introduction: Olopatadine hydrochloride is an antihistamine and mast cell stabilizer available as oral, intranasal and ocular preparations. Most of the practical applications of olopatadine therapy focus on the treatment of allergic rhinoconjunctivitis via intranasal and ocular routes.

Areas covered: This article was created from a comprehensive literature search with information taken from meta-analyses, systematic reviews, and clinical trials of children and adults. The articles that have been selected, evaluate the use of intranasal and ocular antihistamines and their role in allergic rhinoconjunctivitis.

Expert opinion: Olopatadine is significantly more effective than placebos in relieving the symptoms of allergic rhinoconjunctivitis. It can function both as a viable alternative or addition to first line therapies such as intranasal steroids and oral antihistamines.     

Trabecular meshwork ECM remodeling in glaucoma: could RAS be a target?

Introduction: Disturbances of extracellular matrix (ECM) homeostasis in trabecular meshwork (TM) cause increased aqueous outflow resistance leading to elevated intraocular pressure (IOP) in glaucomatous eyes. Therefore, restoration of ECM homeostasis is a rational approach to prevent disease progression. Since renin-angiotensin system (RAS) inhibition positively alters ECM homeostasis in cardiovascular pathologies involving pressure and volume overload, it is likely that RAS inhibitors reduce IOP primarily by restoring ECM homeostasis.

Areas covered: Current evidence showing the presence of RAS components in ocular tissue and its role in regulating aqueous humor dynamics is briefly summarized. The role of RAS in ECM remodeling is discussed both in terms of its effects on ECM synthesis and its breakdown. The mechanisms of ECM remodeling involving interactions of RAS with transforming growth factor-β, Wnt/β-catenin signaling, bone morphogenic proteins, connective tissue growth factor, and matrix metalloproteinases in ocular tissue are discussed.

Expert opinion: Current literature strongly indicates a significant role of RAS in ECM remodeling in TM of hypertensive eyes. Hence, IOP-lowering effect of RAS inhibitors may primarily be attributed to restoration of ECM homeostasis in aqueous outflow pathways rather than its vascular effects. However, the mechanistic targets for RAS inhibitors have much wider distribution and consequences, which remain relatively unexplored in TM.     

Clinical trial transparency update: an assessment of the disclosure of results of company-sponsored trials associated with new medicines approved in Europe in 2012

Background:

The objective of this study was to assess the timely disclosure of results of company-sponsored clinical trials related to all new medicines approved by the European Medicines Agency (EMA) during 2012. This is an extension of the previously reported study of trials related to all new medicines approved in Europe in 2009, 2010 and 2011, which found that over three-quarters of all these trials were disclosed within 12 months and almost 90% were disclosed by the end of the study.

Methods:

The methodology used was exactly as previously reported. Various publicly available information sources were searched for both clinical trial registration and disclosure of results. All completed company-sponsored trials related to each new medicine approved for marketing by the EMA in 2012, carried out in patients and recorded on a clinical trials registry and/or included in an EMA European Public Assessment Report (EPAR), were included. Information sources were searched between 1 May and 31 July 2014.

Outcome measures and results:

The main outcome measure was the proportion of trials for which results had been disclosed on a registry or in the scientific literature either within 12 months of the later of either first regulatory approval or trial completion, or by 31 July 2014 (end of survey). Of the completed trials associated with 23 new medicines licensed to 17 different companies in 2012, results of 90% (307/340) had been disclosed within 12 months, and results of 92% (312/340) had been disclosed by 31 July 2014.

Conclusions:

The disclosure rate within 12 months of 90% suggests the industry is now achieving disclosure in a timely manner more consistently than before. The overall disclosure rate at study end of 92% indicates that the improvement in transparency amongst company-sponsored trials has been maintained in the trials associated with new medicines approved in 2012.     

Treatment patterns of rheumatoid arthritis in Japanese hospitals and predictors of the initiation of biologic agents

Objective: To describe the usage of different biologic agents for rheumatoid arthritis (RA) in Japan over time and to identify factors that affects the decision to initiate treatment with biologic agents. Determinants of a switch to another biologic agent for patients who are already on biologic treatment were also analyzed.

Research design and methods: We utilized a hospital claims database containing 36,504 Japanese patients with a confirmed RA diagnosis. To analyze the determinants of treatment choices, we applied logistic regression analysis taking into account socio-demographic and medical factors.

Results: Analyses determined that 11.8% of diagnoses and 25.4% of treated patients in Japan receive a biologic agent. Significant factors associated with biologic treatment initiation include younger age, female sex, and a higher comorbidity index. The route of administration plays a major role when it comes to a switch between different biologic agents.

Conclusions: The lower likelihood of elderly patients to be initiated on biologic treatment might be explained by the risk aversion of Japanese physicians’ and patients who are afraid of the potential side effects of biologics. This finding is also consistent with the notion of an age bias that impedes elderly patients from optimal access to biologic treatment. Because claims data does not contain clinical parameters such as disease activity the results should be validated in a clinical context.     

Osmolyte taurine induction in UVA exposed human retinal pigment epithelial cells

Aim: To explore the osmolytes expression in ultraviolet (UVA) stressed human retinal pigment epithelial cells.

Methods: Osmolyte transporters and vascular endothelial growth factor (VEGF) messenger RNA (mRNA) were determined by real time polymerase chain reaction (PCR). Osmolyte uptake was measured by radioimmunoassay. VEGF concentrations were determined by immunoassay and enzyme-linked immunosorbent assay (ELISA). Osmolyte taurine transporter (TAUT) were silenced by siRNA technology.

Results: Hypertonicity accelerated osmolyte betaine uptake, myoinositol uptake, and taurine uptake, compared to normotonic stress. UVA irradiation also accelerated osmolyte transporters expression and osmolytes uptake. Especially, osmolyte taurine remarkably inhibited VEGF release induced by UVA irradiation. VEGF in the UVA stressed retinal pigment epithelial cell supernatant was accumulated slow after taurine preincubation. VEGF expression increased significantly in UVA-stressed cells after TAUT silencing. Moreover, taurine reduced the VEGF level in human ocular aqueous humor.

Conclusion: The inhibition of VEGF by osmolyte taurine plays the crucial role in retina adaption to UVA irradiation.     

From benzalkonium chloride-preserved Latanoprost to Polyquad-preserved Travoprost: a 6-month study on ocular surface safety and tolerability

Background: To evaluate the safety and tolerability of Polyquad-preserved Travoprost (PQ-Travoprost) in patients previously treated with benzalkonium chloride (BAK)-preserved Latanoprost.

Methods: Cohort 6-month study on open-angle glaucoma or ocular hypertension patients. Complete ophthalmic examination, intraocular pressure (IOP) measurement and ocular surface status (tear film break-up time [TF-BUT], corneal staining and ocular surface disease index [OSDI]) were evaluated at baseline and 6 months later.

Results: A total of 44 patients were enrolled. Median (interquartile range [IQR]) baseline IOP was 18 (15.5 – 21) and 16 (14 – 17) mmHg (p < 0.0001) after 6 months. At baseline, 18 (40.9%) patients presented an IOP of < 18 mmHg, 11 (25%) < 16 mmHg, 2 (4.3%) < 14 mmHg and 1 (2.3%) < 12 mmHg; 6 months later the proportions were 36 (81.8%) (p < 0.0001), 21 (47.7%) (p = 0.00075), 8 (18.2%) (p = 0.0143) and 6 (13.6%) (p = 0.0253). Concerning safety, TF-BUT improved from 8 [IQR 6 – 10] to 10 [IQR 8 – 12] s (p < 0.0001). No eye developed corneal staining; punctate keratitis was absent in 13 (29.5%) patients at baseline and in 31 (70.4%) after 6 months (p < 0.001). OSDI changed from 16 (10 – 30) to 9 (2 – 20).

Conclusions: No patient treated with PQ-Travoprost developed ocular surface disease after 6 months of monotherapy, whereas many patients reached a good IOP control with lower IOP values. Ocular surface status statistically improved when examined by TF-BUT and corneal staining.     

Topical treatment of glaucoma: established and emerging pharmacology

Introduction: Glaucoma is a collection of optic neuropathies consisting of retinal ganglion cell death and corresponding visual field loss. Glaucoma is the leading cause of irreversible vision loss worldwide and is forecasted to precipitously increase in prevalence in the coming decades. Current treatment options aim to lower intraocular pressure (IOP) via topical or oral therapy, laser treatment to the trabecular meshwork or ciliary body, and incisional surgery. Despite increasing use of trabecular laser therapy, topical therapy remains first-line in the treatment of most forms of glaucoma.

Areas covered: Novel glaucoma therapies are a long-standing focus of investigational study. More than two decades have passed since the last United States Food and Drug Administration (FDA) approval of a topical glaucoma drug. Here, the authors review established topical glaucoma drops as well as those currently in FDA phase 2 and 3 clinical trial, nearing clinical use.

Expert opinion: Current investigational glaucoma drugs lower IOP, mainly through enhanced trabecular meshwork outflow. Although few emerging therapies show evidence of retinal ganglion cell and optic nerve neuroprotection in animal models, emerging drugs are focused on lowering IOP, similar to established medicines.     

Cognitive defusion versus experiential avoidance in the reduction of smoking behaviour: an experimental and preliminary investigation

Background: Brief procedures that reduce smoking behaviour may be useful in reaching the many people that do not seek help for smoking addiction.

Objectives: The current study aimed to determine if one component of Acceptance and Commitment Therapy (ACT), cognitive defusion, could be useful in reducing smoking behaviour in a sample of students.

Methods: The study employed a between-subjects three-arm design. For one week, participants were asked to reduce their cigarette consumption. To aid them in their reduction, participants were randomly allocated to one of three conditions: the first received a defusion procedure, the second received an experiential avoidance procedure and a control condition received no procedure. For a second week, the instruction to reduce cigarette consumption was lifted. During both weeks participants were required to monitor their smoking behaviour via a tally diary system.

Results: The defusion condition smoked significantly less than the control condition during week one and significantly less than the control and experiential avoidance conditions during week two.

Conclusion: Results are discussed in terms of the potential utility of defusion in this domain, and the limitations of this preliminary research that would need to be addressed in future investigations.     

Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid

Introduction: Topical corticosteroids are an important pharmacotherapy for the management of various inflammatory conditions affecting the anterior segment of the eye. However, medications in this class are associated with well-known risks including increased intraocular pressure (IOP) and development of cataracts. The topical corticosteroid loteprednol etabonate (LE) was developed with the specific intention of minimizing these side effects.

Areas covered: The focus of this review is to examine published efficacy and safety data for LE, a drug engineered to undergo rapid metabolism to inactive metabolites with the goal of improved safety. Two decades of clinical research focused on LE formulations are reviewed, including the use of LE in combination with tobramycin. The cumulative body of experience affirms the concept that the molecular design of LE confers certain safety benefits without compromising the desired anti-inflammatory efficacy of a topical corticosteroid.

Expert opinion: Loteprednol etabonate is a mainstay for topical therapy of a wide variety of commonplace and niche conditions of the ocular surface and the anterior segment, including in the healing post-operative patient. Its versatility and safety allow eye care providers to recommend both acute induction as well as chronic maintenance therapy with appropriate follow-up.     

Pharmacological interventions for stress ulcer prophylaxis in critically ill patients: a mixed treatment comparison network meta-analysis and a recursive cumulative meta-analysis

Background: Proton pump inhibitors (PPI), histamine-2 receptor antagonists (H2RA), sucralfate and antacids are the commonly administered agents for stress ulcer prophylaxis (SUP) in critically ill patients. The authors of this paper have conducted a network meta-analysis to compare the efficacy of these agents in SUP.

Methods: Electronic databases were searched for randomized controlled trials, cohort studies and conference abstracts for studies comparing a SUP agent in critically ill patients to another active SUP agent or placebo. Overt, occult and clinically significant upper gastro-intestinal (UGI) bleeding, all-cause mortality, pneumonia, gastric colonization and ICU length of stay were considered as the outcome measures. A random effects model was used to generate pooled estimates.

Results: A total of 53 studies (4258 participants) were included. The pooled estimates were in favor of PPI and sucralfate for the overt UGI bleeding. PPI and H2RA bolus were associated with increased risk of gastric colonization and pneumonia.

Conclusions: SUP in critically ill patients was not associated with any benefit with regard to clinically significant bleeding episodes. However, PPI and sucralfate significantly reduces overt UGI bleeding. On the contrary, PPI and H2RA bolus are associated with an increased risk of gastric colonization and pneumonia.     

Lidocaine 5% medicated plaster for localized neuropathic pain in thoracic surgical patients

Context: Neuropathic pain is a common and distressing symptom in thoracic surgical patients. When it consistently presents with measurable sensory changes in a circumscribed area, neuropathic pain can be diagnosed as localized neuropathic pain (LNP).

Objective: The purpose of this study was to report the efficacy of lidocaine 5% medicated plaster (Lido5%P) in the treatment of LNP in thoracic surgical patients.

Methods: We retrospectively reviewed the records of sixteen cancer and noncancer thoracic patients treated with Lido5%P for LNP. Patients had been assessed before and during treatment with standardized forms and questionnaires for pain intensity, sleep quality, drug dosages and adverse events.

Results: Treatment with Lido5%P yielded a significant and lasting improvement in pain symptomatology. In oncological patients as an add-on therapy, Lido5%P improved pain intensity and sleep quality, and delayed opioid dose escalation. In non-oncological patients as monotherapy or in association with antineuropathic drugs, Lido5%P attenuated LNP. No local or systemic adverse events were recorded.

Conclusions: Lido5%P was effective in relieving thoracic LNP, and was well tolerated.     

Overcoming platinum resistance in ovarian cancer treatment: from clinical practice to emerging chemical therapies

Introduction: The objective of this review is to summarize results from clinical trials that tested cytotoxic drugs and target strategies for the treatment of platinum resistant (PR) recurrent ovarian cancer (ROC) with particular attention to Phase III and ongoing trials.

Areas covered: Since platinum free interval (PFI) represents the most important predictive factor for response to platinum re-treatment in ROC, non-platinum regimens are conventionally considered the most appropriate approaches.

Impressive progress has been made in recent decades, resulting in the identification of most effective cytotoxic agents and in the development of new target strategies.

However, the efficacy of most of these drugs for the treatment of PR disease is still limited.

Expert opinion: The most favorable benefit for the treatment of PR disease, has been described by the AURELIA trial that showed a 3.3 months increase in progression free survival (PFS) when bevacizumab was combined with non-platinum single agent chemotherapy in bevacizumab-naïve patients.

Nevertheless, the use of novel agents is associated to important costs for just little gains in survival.

Thus, in our opinion the economic evaluation, such as the incorporation of quality of life into the clinical studies is crucial for the development of future trials for PR-ROC.     

Echinacea biotechnology: advances,commercialization and future considerations

Context: Plants of the genus Echinacea (Asteraceae) are among the most popular herbal supplements on the market today. Recent studies indicate there are potential new applications and emerging markets for this natural health product (NHP).

Objective: This review aims to synthesize recent developments in Echinacea biotechnology and to identify promising applications for these advances in the industry.

Methods: A comprehensive survey of peer-reviewed publications was carried out, focusing on Echinacea biotechnology and impacts on phytochemistry. This article primarily covers research findings since 2007 and builds on earlier reviews on the biotechnology of Echinacea.

Results: Bioreactors, genetic engineering and controlled biotic or abiotic elicitation have the potential to significantly improve the yield, consistency and overall quality of Echinacea products. Using these technologies, a variety of new applications for Echinacea can be realized, such as the use of seed oil and antimicrobial and immune boosting feed additives for livestock.

Conclusions: New applications can take advantage of the well-established popularity of Echinacea as a NHP. Echinacea presents a myriad of potential health benefits, including anti-inflammatory, anxiolytic and antibiotic activities that have yet to be fully translated into new applications. The distinct chemistry and bioactivity of different Echinacea species and organs, moreover, can lead to interesting and diverse commercial opportunities.     

Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions,biological properties and clinical efficacy

Context: Cardiometabolic risks are regarded as the crucial factors associated with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Regarding an increased attention to medicinal plants in the current healthcare system, the effects of mulberry (Morus spp., Moraceae) leaves on cardiometabolic risks have been consecutively considered in scientific research.

Objective: The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.

Methods: Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using ‘mulberry leaves’ ‘Morus spp.’, ‘hyperglycemia’, ‘hyperlipidemia’, ‘obesity’, ‘hypertension’, ‘oxidative stress’, ‘atherosclerosis’ and ‘cardiovascular diseases’ as the keywords. The relevant articles published over the past two decades were identified and reviewed.

Results: Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.

Conclusions: Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses.     

Expanded access to investigational drugs: balancing patient safety with potential therapeutic benefits

Introduction: Expanded access is the use of an investigational product by patients with serious medical conditions without participation in a clinical trial. It is a complicated process involving the collaboration of many parties and pharmaceutical companies. Ongoing efforts focus on accelerating expanded access procedures in the best interest of patients with cancer.

Areas covered: We review the regulatory and ethical challenges encountered in efforts to optimize expanded access.

Expert opinion: In the era of personalized medicine, patients may benefit from novel therapeutic agents that demonstrate encouraging results in early studies. However, drug approval is a lengthy and cumbersome procedure that might exceed the time frame of a life-threatening disease. Expanded access provides options to patients with unmet needs. It may provide informative safety and efficacy data to the manufacturers and the scientific and regulatory organizations.

Ongoing efforts are being made by global governmental and scientific committees, regulatory agencies, and patient organizations to address the ethical and regulatory issues and to optimize the expanded access process. Their goal is to expand access to promising novel drugs for individual patients and to accelerate the necessary procedures while preserving patient safety.     

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.

Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented.

In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.

Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.

Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.     

Incarceration history,social network composition,and substance use among homeless youth in Los Angeles

Background: Homeless youth in the United States have high rates of substance use. Existing research has identified social network composition and street-associated stressors as contributing factors. Incarceration is a highly prevalent stressor for homeless youth. Its effect on youth’s social network composition and substance use, however, has been neglected.

Aims: This study investigated the direct and indirect associations between incarceration history and substance use (through social networks) among homeless youth in Los Angeles, California.

Methods: A sample of 1047 homeless youths were recruited between 2011 and 2013. Computerized self-administrated surveys and social network interviews were conducted to collect youth’s sociodemographic characteristics, incarceration history, social network composition, and substance use. Bootstrapping was used to identify the direct and indirect associations between youth’s incarceration history and substance use.

Results: Incarceration history was positively associated with youth’s cannabis, methamphetamine, and injection drug use. The percentage of cannabis-using peers partially mediated the associations between incarceration history and youth’s cannabis, cocaine, and heroin use. The percentage of methamphetamine-using peers partially mediated the associations between incarceration history and youth's methamphetamine, cocaine, and injection drug use. The percentage of heroin-using peers partially mediated the association between incarceration history and youth’s heroin use. Moreover, the percentage of peers who inject drugs partially mediated the associations between incarceration history and youth’s methamphetamine, heroin, and injection drug use.

Discussion: Incarceration history should be taken to a more central place in future research and practice with homeless youth in the United States.