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.     

Impact of bodyweight/body mass index on the effectiveness of emergency contraception with levonorgestrel: a pooled-analysis of three randomized controlled trials

Objective:

A pooled analysis of two randomized controlled trials (RCTs) suggested that increased bodyweight and body mass index (BMI) may be associated with a greater probability of pregnancy. To address this issue we investigated whether higher bodyweight and/or BMI negatively impacted the risk of pregnancy in women receiving LNG-EC (levonorgestrel – emergency contraception) after unprotected sexual intercourse in a pooled analysis of three large multinational RCTs conducted by the World Health Organization (WHO).

Methods:

A pooled analysis of three double-blind, multinational RCTs conducted by the WHO to investigate the efficacy of LNG-EC in the general population. All analyses were done on the per-protocol set (PPS) which included 5812 women who received LNG-EC within 72 hours following unprotected sexual intercourse. The analysis was based on logistic regression, with pregnancy as the outcome. BMI and weight were represented in the same model.

Results:

A total of 56 pregnancies were available for analysis in the PPS. Increasing bodyweight and BMI were not correlated with an increased risk of pregnancy in the studied population. A limitation of this study is that despite the large study population in the pooled analysis there were relatively small numbers of women in the high-BMI and high-bodyweight subgroups.

Conclusion:

LNG-EC is effective for preventing pregnancy after unprotected intercourse or contraceptive failure and no evidence was found to support the hypothesis of a loss of EC efficacy in subjects with high BMI or bodyweight. Therefore, access to LNG-EC should not be limited only to women of lower bodyweight or BMI.     

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.     

Shaving effects on percutaneous penetration: clinical implications

Context: Human/animal shaving biology.

Objective: To assess the effect of shaving on percutaneous penetration and skin function.

Methods: We screened 500+publications in Pub Med, Scopus, Cochrane Library and pertinent journals out of which only 17 were deemed relevant. Terms for searches included shaving and skin, percutaneous penetration and shaving, skin absorption and shaving, absorption of dyes and shaving, skin penetration, effects of shaving and absorption, shave and dyes, axillary shaving and stratum corneum, shaving and breast cancer, shaving and infections, etc.

Result: Shaving appears to have an exaggerated effect on percutaneous absorption; however, some studies do not support this evidence.

Conclusion: Shaving enhances percutaneous penetration of some chemicals; however this effect is species and chemical specific. Further investigations of chemicals of varying physio-chemical properties are mandated before a generalized theory can be promulgated.     

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.     

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.     

Bilateral diffuse iris atrophy after the use of oral clarithromycin

Purpose: To report a newly recognised advert event of clarithromycin.

Methods: Retrospective, case report.

Results: A 30-year old female referred to our centre with bilateral diffuse iris atrophy after the use of oral clarithromycin for a pulmonary infection.

Conclusions: Bilateral acute depigmentation of the iris is a new clinical entity. Iris transillumination and sphincter paralysis are recognised adverse effects of oral antibiotic therapy, but to our knowledge no other publication has referred to uveitis-like syndrome due to oral administration of clarithromycin.     

Anti-inflammatory potential of zootherapeutics derived from animals used in Brazilian traditional medicine

Context: Animals are used for the treatment of diseases caused by inflammatory processes, although few studies evaluate their potential for these purposes.

Objectives: To evaluate the anti-inflammatory potential of zootherapeutic products derived from vertebrates used in Brazilian traditional medicine.

Material and methods: The species analyzed were Tupinambis merianae, Iguana iguana, Crotalus durissus, Boa constrictor, and Euphractus sexcinctus. The methods used in anti-inflammatory assays were ear edema (topical) and paw (systemic).

Results: With regard to topical anti-inflammatory activity, the fat from T. merianae, C. durissus, I. iguana, B. constrictor, and E. sexcinctus reduced inflammation, while for systemic anti-inflammatory activity, only the fat and the skin of C. durissus, the skin of I. iguana and the fat from B. constrictor reduced inflammation.

Conclusions: Studies should be conducted to evaluate the mechanisms of action for each product that demonstrated anti-inflammatory activity as well as against other inflammatory processes.     

Cancer-free survival of psoriasis patients treated with methotrexate and cyclosporine combination

Context: Combination of methotrexate and cyclosporine was used and reported to be effective for recalcitrant psoriasis patients. Also each agent is accused for development of malignancies.

Objective: To evaluate the cancer-free survival of psoriasis patients who received methotrexate and cyclosporine treatment at the same time.

Methods: Psoriasis patients who had been treated with combination of cyclosporine and methotrexate between March 2000 and April 2005 were questioned in 2011. A diagnosis of new cancer during follow-up period was asked and also each patient was evaluated by a questionnaire.

Results: Seventeen psoriasis patients were not treated due to a diagnosis of new cancer during the follow-up period. Also none of them complained of possible symptoms of skin or lymphoproliferative malignancies. The median follow-up time was 76 months.

Conclusion: Psoriasis patients who had been treated with methotrexate and cyclosporine combination did not report a detected malignant disease.     

Vitamin E: A potential therapy for gastric mucosal injury

Context: Many scientific reports have shown the involvement of oxidative stress and inflammation as well as diminished gastroprotective substances in the pathogenesis of gastric lesions using various models. Therefore, treatment with antioxidants like tocopherol and tocotrienol may afford beneficial effects in attentuating the formation of the gastric lesions.

Objective: The aim of this work was to summarize documented reports on the effects of vitamin E on various models of gastric lesion.

Methods: A literature search was performed from databases in Medline (PubMed), Web of Science, ScienceDirect, and Googlescholar from June to December 2013.

Results and conclusion: The potential roles of tocopherol and tocotrienol in modifying the effects of ulcerogenic agents are discussed in this review. The protective effects of the vitamin E might involve ameliorating oxidative stress and inflammation as well as restoration of endogenous gastroprotective substances. This vitamin has the potential to be used as a therapy for gastric mucosal injury.     

Nine years of a single referral center management of Stevens–Johnson syndrome and toxic epidermal necrolysis (Lyell’s syndrome)

Context: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) corresponds to a rare and acute life-threatening mucocutaneous reactions characterized by extensive necrosis and epidermal detachment. There are no efficacious pharmaceutical interventions proven through large clinical trials.

Objective: We sought to study clinical cases admitted in our institution in order to determine which drugs and medical comorbidities or treatments impacted the mortality.

Material and methods: In a retrospective study over 9 years we evaluated all patients presenting biopsy-proven SJS or TEN for age, gender, total body surface area involved, causing agents, SCORTEN score, blood transfusion, steroid administration, intubation, length of intensive care stay and death rate. Statistical analysis was done using SPSS statistical software.

Results: The highest incidence of SJS and TEN was in age group of 71–80 years. Of the 30 patients, 30% died from SJS/TEN, mainly due sepsis. For each subgroup SJS/TEN overlap had the highest mortality. The highest mortality was from antibiotic treatment as causing agent. Step-wise regression analysis identified mechanical ventilation requirement and age over 65 years as mortality high-risk factors.

Discussion: The most crucial interventions are discontinuation of the offending drug and prompt referral to a burn unit, which helps in early diagnosis and decrease mortality in these diseases.

Conclusion: When SJS/TEN is caused by antibiotics suspicion of developing fatal sepsis should be high, independently of patients’ medical condition.     

Development and Validation of a Brief Measure of Eating Compulsivity (MEC)

Food addiction is increasingly being recognised as a contributory factor in overweight and obesity. Management of eating compulsivity, a key component of food addiction, may assist greatly in the successful treatment of obesity.

Measurement of food addiction and its core characteristic of eating compulsivity is fundamental to increasing understandings of the concept of food addiction, its prevalence among people with and without obesity and its utility within a treatment context.

The current study describes the development and initial validation of a brief measure of eating compulsivity that can be used within clinical and research settings to establish a person's level of eating compulsivity.

Sixty five participants with a BMI ≥30 (mean BMI 38.1) were recruited from a general population sample within Christchurch, New Zealand. Participants completed the test version of the Measure of Eating Compulsivity (MEC) and the Yale Food Addiction Scale (YFAS) as well as providing self-reported measures of height and weight.

The 10-item MEC was developed. This measure was shown to have excellent internal consistency (Cronbach's alpha =.946), based on a single factor accounting for 67.4% of the variance and excellent test-retest reliability (r =.923). MEC10 score was strongly predictive of being categorised as having food addiction based on the YFAS, although not associated with BMI.

This brief tool is likely to have high utility in clinical and research settings and requires further validation with a range of populations including those with and without obesity, binge eating disorder and other eating disorders.     

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.     

Systematic literature review of the health economic implications of early detection by screening populations at risk for type 2 diabetes

Background: Undetected/uncontrolled diabetes is associated with substantial morbidity and mortality and consequent costs. Early detection through screening identifies patients at risk, allowing for earlier treatment initiation.

Objectives: To determine the economic impact of screening for type 2 diabetes (T2DM).

Data sources: We systematically reviewed health economic analyses of screening programs for T2DM/pre-diabetes.

Study eligibility criteria: Published between 2000 and 2015 in any language. Articles must have reported costs of screening, test/patient outcomes and cost-effectiveness.

Participants and interventions: Any type of screening (universal, targeted, opportunistic) was accepted.

Methods: Data were extracted from Scopus/Medline/Embase, then tabulated.

Results: There were 137 studies identified, 108 rejected; 29 were analyzed. Screening types included 18 universal, 8 targeted and 8 opportunistic. One study screened for pre-diabetes, 16 for T2DM and 12 examined both. Fourteen (48%) reported costs of screening only, 9 (31%) costs of screening combined with interventions and 6 (21%) presented all costs separately. Screening was compared to no screening in 13 studies (45%); screening was cost-effective in 8 (62%), not cost-effective in 4 (31%) and neither in 1 (8%). When comparing different screening methods, 6 found targeted screening was cost-effective compared with universal screening (none found the opposite), 2 found opportunistic superior to universal. Sensitivity analyses generally confirmed primary findings. Cost drivers included prevalence of T2DM/pre-diabetes, type of blood test used and uptake of testing. For optimal cost-effectiveness, screening for both T2DM and pre-diabetes should be initiated around age 45–50, with repeated testing every 5 years.

Conclusions/implications: Targeted screening appears to be cost-effective compared to universal screening.     

Accelerated sample preparation and formation of astragaloside IV in Astragali Radix

Context: Astragali Radix (Huangqi; Astragalus mongholicus BUNGE, Fabaceae) is used in herbal medicinal products as well as in many food supplements. In traditional Chinese medicine, the roots are used for its Qi tonifying, immunostimulant, cardioprotective, hepatoprotective and hypoglycemic effects.

Objective: Astragaloside IV (AGS-IV), a cycloartane-type triterpene glycoside is used as a marker compound for the quality control of Astragali Radix in various pharmacopoeias.

Materials and methods: In this study, we analyzed the content of AGS-IV and other astragalosides in various commercial samples of Huangqi by reversed-phase HPLC using evaporative light scattering detection.

Results: The analyses revealed that AGS-IV is formed during sample preparation from acylated astragalosides like astragaloside I and astragaloside II, when using the assay method of the European Pharmacopoeia.

Discussion and conclusion: For consistent assay results, the extraction methods of the pharmacopoeias should be re-evaluated and optimized. Alternatively, the hydrolysis by ammonia could be omitted and the genuine compounds like astragaloside I, II and malonyl-AGS-I could be considered for the quality control of Astragali Radix.     

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.     

Pharmaceutical properties of calycosin,the major bioactive isoflavonoid in the dry root extract of Radix astragali

Context: Radix astragali (Fabaceae astragalus propinquus Schischkin) is a Chinese medicinal herb traditionally used for the treatment of several diseases. Calycosin is the major bioactive chemical in the dry root extract of this medical plant.

Objective: This work presents a brief overview of recent reports on the potential effects of calycosin on several diseases and the possible mechanisms of action of this chemical.

Materials and methods: This review gathers information from the scientific literature (before 1 June 2013) that was compiled from various databases, such as Science Direct, PubMed, Google Scholar, and Scopus.

Results: The potential pharmaceutical properties of calycosin in the treatment of tumors, inflammation, stroke, and cardiovascular diseases have gained increasing attention in the recent years. The literature survey showed that calycosin exhibits promising effects for the treatment of several diseases and that these effects may be due to its isoflavonoid and phytoestrogenic properties. The effects of calycosin most likely result from its interaction with the ER receptors on the cell membrane and the modulation of the MAPK signaling pathway.

Conclusion: Calycosin exhibits great potential as a therapeutic drug and may be a successful example of the standardization and modernization of traditional Chinese herbal medicine.     

Fibromyalgia as a cause of uncontrolled asthma: a case–control multicenter study

Background: Fibromyalgia can affect the control of asthma when both diseases are present in a single patient.

Objectives: To characterize asthma in patients with concomitant fibromyalgia to assess whether fibromyalgia is an independent factor of asthma severity that influences poor asthma control. We also evaluated how dyspnea is perceived by patients in order to demonstrate that alterations in the perception of airway obstruction may be responsible for poor asthma control.

Methods: This was a cross-sectional case–control multicenter study, in which 56 patients in the asthma and fibromyalgia group were matched to 36 asthmatics by sex, approximate age, and asthma severity level. All patients were women. Study variables included the Asthma Control Test (ACT), the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), the Nijmegen hyperventilation syndrome questionnaire, the Hospital Anxiety and Depression Scale, and perception of dyspnea after acute bronchoconstriction.

Results: Although patients in both study groups showed similar asthma severity and use of anti-asthmatic drugs, patients in the asthma and fibromyalgia group showed lower scores on the ACT and MiniAQLQ questionnaires, and higher scores of anxiety and depression as well as hyperventilation compared to asthma patients without fibromyalgia. All these differences were statistically significant.

Conclusions: Fibromyalgia in patients with asthma influences poor control of the respiratory disease and is associated with altered perception of dyspnea, hyperventilation syndrome, high prevalence of depression and anxiety, and impaired quality of life.

Clinical implications: Fibromyalgia may be considered a risk factor for uncontrolled asthma in patients suffering from asthma and fibromyalgia concomitantly.     

Human factors and usability engineering in the development of SMT-101 for the treatment of pulmonary arterial hypertension

Background: SMT-101, a novel, proprietary, water-resistant wearable infusion pump prefilled with a preset dosage of treprostinil, was designed to address many of the administration-related shortcomings of existing parenteral therapy for pulmonary arterial hypertension (PAH). The objective of the human factors (HF) program was to demonstrate that the SMT-101 system is safe and effective when used by patients with PAH, their caregivers, or healthcare providers.

Methods: The HF program for SMT-101 consisted of 8 studies (148 participants): an ethnographic study, an online survey of patients with PAH, 4 formative studies, a study of the instructions for use (IFU), and a summative study for validation. The pump and IFU were iteratively modified using observational data and participant feedback to inform subsequent improvements throughout the HF program to optimize safe use of SMT-101 before the final study.

Results: The results of the summative study demonstrated that the design of the SMT-101 wearable, pre-filled infusion pump and IFU are safe and effective for use.

Conclusions: In accordance with regulatory guidelines, the usability and HF aspects of SMT-101 were developed and refined through a rigorous HF program in patients with PAH and healthcare providers, which culminated in a summative study that validated the usability and use-safety of SMT-101.