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.     

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.     

A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.     

Taurine reduces blue light-induced retinal neuronal cell apoptosis in vitro

Background: The massive uptake of organic compatible osmolytes is a self-protective response to multiple stressors.

Objective: This study aimed to determine the protective effects of the osmolyte taurine against blue light-induced apoptosis in retinal neuronal cells in vitro.

Methods: Real-time PCR was used to measure osmolyte transport. Radioimmunoassays were performed to measure osmolyte uptake. Cell Counting Kit-8 assays were conducted to measure cellular viability. Flow cytometry analysis was used to measure apoptosis.

Results: Compared with normotonic stress, hypertonic stress-induced uptake of osmolytes, including betaine, myoinositol, and taurine, into the retinal neuronal cells. Blue light increased osmolyte transporter mRNA expression together with osmolyte uptake. Furthermore, taurine significantly suppressed blue light-induced retinal neuronal cell apoptosis.

Conclusion: The compatible osmolyte taurine may have an important role in cell resistance to blue light and cell survival.     

Taurine prevents ultraviolet B induced apoptosis in retinal ganglion cells

Background: Compatible osmolytes accumulation is an active resistance response in retina under ultraviolet (UV) radiation and hypertonicity conditions.

Objective: The purpose of this research is to investigate the protective role of taurine on retina under UVB radiation.

Methods: Osmolytes transporters were measured by quantitative realtime PCR. Osmolytes uptake was estimated by radioimmunoassay. Cell viability was calculated by MTT assay. Cell apoptosis was measured by flow cytometry analysis.

Results: Hypertonicity accelerated osmolytes uptake into retinal ganglion cells (RGCs) including taurine, betadine, and myoinositol. UVB radiation increased osmolytes transporter expression and osmolytes uptake. In addition, osmolyte taurine remarkably prevented UVB radiation induced cell apoptosis in RGCs.

Conclusions: The effect of compatible osmolyte taurine on cell survival rate may play an important role in cell resistance and adaption to UVB exposure.     

Inflammation in Heart Failure: known knowns and unknown unknowns

Introduction: The review deals with inflammation in heart failure (HF). Many data show that systemic inflammation is frequent in HF and implicate that inflammation contributes to damage and dysfunction of the cardiovascular system.

Areas Covered: Experimental data have been mainly obtained in acute laboratory animal models. It is questionable whether animals’ data can be translated into clinical settings with patients with chronic HF who have concomitant pathologies.

The idea of a common inflammatory pathway that characterizes all different forms of clinical HF is unrealistic. It seems realistic that inflammation differs in non-cardiac and cardiac diseases.

Research therapeutic options address the use of inhibitors of cytokines, of agents antagonizing oxidative stress, of MMP and of PI3K signaling pathways.

Expert Opinion: Considering the many unknowns in our knowledge it is not surprising that early trials aimed to antagonize inflammation in HF have been disappointing. We are far away from having solid therapeutic schedules to use immunomodulation in all subtypes of HF. However, modern trials on HF due to virus infections have proven that immunomodulation is therapeutically effective.

We should wisely use the known facts and accept that we have many unknowns. By appropriate selection of the subtypes of HF we may be able to find the appropriate therapy against inflammation in HF.     

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review

Context: Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis.

Objectives: To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically.

Methods: Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded.

Results: Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies.

Conclusion: This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.     

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy

Background: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM.

Methods: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov.

Results: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia.

Conclusions: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).     

Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly.

Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site-related. Their cost is the main limitation to use.

Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetes

Expert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits.     

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.     

A review on phytochemical and pharmacological properties of Litsea coreana

Context: Litsea coreana H. Lév. (Lauraceae) is used as an ethnic herb or beverage in China. Substantial studies indicate that it contains a variety of compounds and shows diverse bioactivities with no toxicity.

Objective: This review analyzes and summarizes the ethnopharmacological applications, phytochemistry, and pharmacological activities and molecular mechanisms of L. coreana.

Methods: Related literature (from 1998 to 2016) was obtained and compiled via searching databases including Scopus, Web of Science, Google Scholar, CNKI and PubMed. Keywords (Litsea coreana, hawk tea, eagle tea and laoying cha) were used to select the articles.

Results: Studies indicate that L. coreana contains characteristic polysaccharides, polyphenols, essential oils, and numerious flavonoids, which exhibit remarkable bioactivities, such as hepatoprotection, hyperglycaemia, anti-inflammation, antioxidation and antibacterial, through multiple molecular mechanisms.

Conclusion: This paper provides a systematic review on the phytochemicals and pharmacological activities of L. coreana which should be useful for further study and application of this medicinal herb.     

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.     

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.     

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.     

Inhibitors of α-glucosidase and α-amylase from Cyperus rotundus

Context: A methanol extract of Cyperus rotundus L. (Cyperaceae) rhizomes showed inhibitory activity against α-glucosidase and α-amylase, two enzymes involve in carbohydrate digestion.

Objective: Identification of compounds from C. rotundus rhizomes responsible for the inhibition of α-glucosidase and α-amylase.

Materials and methods: Compounds were identified by a phytochemical investigation using combined chromatographic and spectroscopic methods. α-glucosidase and α-amylase inhibitory activities were evaluated by in vitro enzyme inhibition assays.

Results: A new (2RS,3SR)-3,4′,5,6,7,8-hexahydroxyflavane (1), together with three known stilbene dimers cassigarol E (2), scirpusin A (3) and B (4) were isolated. Compound 2 inhibited both α-glucosidase and α-amylase activities while the flavane 1 only showed effect on α-amylase, and compounds 3 and 4 were active on α-glucosidase. All four compounds showed significant 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity.

Discussion: The inhibitory activities against α-amylase and α-glucosidase of the C. rotundus rhizomes were reported for the first time. Stilbene dimers are considered as potent inhibitors of α-glucosidase and promising antihyperglycemic agents.

Conclusion: The isolated compounds may contribute to the antidiabetic property of C. rotundus.     

Influence of route of administration/drug formulation and other factors on adherence to treatment in rheumatoid arthritis (pain related) and dyslipidemia (non-pain related)

Objectives: A comprehensive review was performed to investigate the effect of route of administration on medication adherence and persistence in rheumatoid arthritis (RA) and to compare adherence/persistence with oral medications between RA and a non-painful disease (dyslipidemia).

Research design and methods: Comprehensive database searches were performed to identify studies investigating medication adherence and/or persistence in adults with RA receiving conventional synthetic or biologic agents. Similar searches were performed for studies of patients with dyslipidemia receiving statins. Studies had to be published after 1998 in English and involve ≥6 months’ follow up.

Main outcome measures: Adherence and persistence were compared between the different routes of drug administration in RA, and between the two diseases for oral medications.

Results: A total of 35 and 28 papers underwent data extraction for RA and dyslipidemia, respectively. Within the constraints of the analysis, adherence and persistence rates appeared broadly similar for the different routes of drug administration in RA. Adherence to oral medications was also broadly similar across the two diseases, but persistence was lower in dyslipidemia. Poor adherence has clinical consequences in both diseases: greater disease activity and risk of flare in RA, and increased serum cholesterol levels and risk of heart and cerebrovascular disease in dyslipidemia. Over 1–3 years, poor adherence to biologic RA medications led to increased resource use and medical costs but lower total direct costs due to reduced biologic drug costs. Conversely, poor adherence to dyslipidemia medications resulted in increased total direct costs. In both diseases, adherence improved with patient education/support.

Conclusions: The route of drug administration and the symptomatic (pain) nature of the disease do not appear to be dominant factors for drug adherence or persistence in RA.

Limitation: The wide range of adherence and persistence values and definitions across studies made comparisons between drug formulations and diseases difficult.     

Corneal perforation: another side effect of nicorandil

Context: Nicorandil is an antianginal drug used for 20 years in Japan and introduced in France in 1994. Since 1997, side effects such as mucocutaneous ulcerations have regularly been reported.

Objective: To describe the first case of a patient with a spontaneous corneal perforation associated with mucocutaneous ulcerations while taking Nicorandil.

Materials and methods: A 81-year-old patient, with no past history of ocular disease but a long past history of cardiovascular disease, presented with a spontaneous paracentral corneal perforation. This was consecutive to 5 months of recurrent keratoconjunctivitis and mucocutaneous ulcerations resistant to conventional therapy. (He was taking nicorandil for 5 years.) A penetrating keratoplasty was performed in emergency.

Results: Inflammatory and infectious causes of spontaneous corneal perforation were ruled out. After initial uneventful post-operative wound healing, an epithelial ulcer appeared on the graft. Dermatologists suggested the iatrogenic role of nicorandil and the drug was discontinued. Both mucocutaneous and corneal ulcerations resolved rapidly.

Discussion: Although mucocutaneous ulcerations have been attributed several times to nicorandil, this is, to our knowledge, the first major corneal damage due to this antianginal drug. Timing, pattern of illness, absence of other aetiology, recurrence of epithelial ulceration on the corneal graft and its spontaneous healing after nicorandil discontinuation make it highly apparent probable that nicorandil was directly involved in this corneal perforation.

Conclusion: Ophthalmologists and dermatologists should be aware of the risk of severe but reversible corneal ulcerations in patients treated with nicorandil. A pharmacovigilance warning statement should be compulsory.     

Compound glycyrrhizin plus conventional therapy for psoriasis vulgaris: a systematic review and meta-analysis of randomized controlled trials

Background: Psoriasis vulgaris is a chronic skin condition affecting patients’ quality of life. Long-term use of conventional therapy increases risk of unwanted side effects. Compound glycyrrhizin in conjunction with conventional therapy has been used in clinical practice, but the evidence for such practice has not been evaluated systematically.

Objective: This review aims to evaluate the efficacy and safety of compound glycyrrhizin in combination with conventional therapy for psoriasis vulgaris.

Methods: PubMed, Excerpta Medica dataBASE (Embase), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials, Allied and Complementary Medicine Database (AMED), CiNii, Chinese Biomedical Literature, China National Knowledge Infrastructure, Chinese Scientific Journals Full Text Database and Wanfang Data were searched from their respective inceptions to July 2015. Randomized controlled trials comparing compound glycyrrhizin plus conventional therapy to conventional therapy alone for psoriasis vulgaris were included. Data analysis was performed using Review Manager 5.3.

Results: Eleven randomized controlled trials were included in this review. Meta-analysis of the 11 randomized controlled trials indicated that the addition of compound glycyrrhizin increased the number of patients achieving Psoriasis Area and Severity Index (PASI) 60 (RR: 1.30 [1.21, 1.40], I² = 6%), when compared with conventional therapy alone. Comparable numbers of patients experienced adverse events in the two groups.

Conclusions: Compound glycyrrhizin in conjunction with conventional therapy enhances clinical response, and compound glycyrrhizin as add-on therapy does not appear to pose any additional risk in the treatment of psoriasis vulgaris. However, the findings should be interpreted with caution of methodological flaws in the included studies.

PROSPERO registration number: CRD42015027763.     

Can apps and calendar methods predict ovulation with accuracy?

Objective: The accuracy of prediction of ovulation by cycle apps and published calendar methods was determined by comparing to true probability of ovulation.

Methods: A total of 949 volunteers collected urine samples for one entire menstrual cycle. Luteinizing hormone was measured to assign surge day, enabling probability of ovulation to be determined across different cycle lengths. Cycle-tracking apps were downloaded. As none provided their methodology, four published calendar-based methods were also examined: standard days, rhythm, alternative rhythm and simple calendar method. The volunteer ovulation data was applied to the app/calendar methods to determine their accuracy.

Results: Mean cycle length was 28 days (range: 23–35); 34% of women believed they had a 28-day cycle, but only 15% did. No LH surge was seen for 99 women. Most likely day of ovulation for a 28-day cycle was day 16 (21%). Accuracy of ovulation prediction was no better than 21% by the apps. The standard days and rhythm methods were most likely to predict ovulation (70% and 89%, respectively) but had very low accuracy.

Conclusions: Ovulation day varies considerably for any given menstrual cycle length, thus it is not possible for calendar/app methods that use cycle-length information alone to accurately predict the day of ovulation.

National Clinical Trial Code: NCT01577147. Registry website: www.clinicaltrials.gov.     

Safety considerations surrounding use of treatment options for nausea and vomiting in pregnancy

Introduction: Nausea and vomiting of pregnancy (NVP) is the most prevalent medical condition during gestation, affecting up to 85% of pregnant women. Many of them hesitate to use medications due to perceived fetal risks.

Areas covered: There are two main aspects to medication safety in NVP: The fetal safety of drugs used to treat NVP symptoms, and the risks of untreated NVP.

While mild and moderate NVP are not associated with major increase in fetal or maternal risks, and may render protective fetal effects, they have major impact on the quality of life of the mother. In contrast, severe NVP and hyperemesis gravidarum (HG) are associated with increased maternal and fetal risks, from in utero growth restriction to developmental delay.

For the doxylamine/pyridoxine combination, H1blockers and metoclopramide there are large studies documenting fetal safety. There are also large reassuring studies on the fetal safety of ondansetron, but they are contrasted by some studies claiming increased fetal risk.

Expert opinion: Fetal safety of the doxylamine/pyridoxine combination, H1blockers and for metoclopramide has been documented. Reassuring studies on the fetal safety of ondansetron, are contrasted by some studies claiming increased teratogenicity. More studies are needed to quantify fetal risks of HG.