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.     

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.     

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.     

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.     

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.     

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.     

Treatment options and considerations for hypertensive patients to prevent dementia

Introduction: Dementia is a worldwide health concern, which leads to loss of autonomy. To date no curative treatment is available so focus on modifiable risk factors is of particular interest. Hypertension, particularly midlife high blood pressure, has been associated with an increased risk for cognitive decline and dementia including vascular dementia (VAD) and Alzheimer disease (AD). In this context, antihypertensive treatments might have a preventive effect.

The objective of this review was to examine the relationship between antihypertensive therapy and cognitive decline or dementia.

Areas covered: A literature search was conducted using PUBMED and the COCHRANE LIBRARY for publications from 1990 onwards mentioning cognitive decline, AD, Vad, mixed dementia, vascular cognitive impairment, hypertension and antihypertensive therapy. Thirty-nine relevant publications including 20 longitudinal studies, 10 randomized-controlled trials and 9 meta-analyses were taken into account.

Expert opinion: Most observational studies have suggested a potential preventive effect of antihypertensive therapies on cognitive decline and dementia, particularly calcium channel blockers and renin-angiotensin system blockers. Randomized clinical trials and meta-analyses provided more conflicting results potentially due to methodological issues.

In conclusion, antihypertensive therapies may reduce cognitive decline and incidence of dementia. Further randomized clinical trials conducted in populations at higher risk of cognitive decline, with longer periods of follow-up and cognition as the primary outcome are still needed.     

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.     

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.     

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.     

A systematic review on biological activities of prenylated flavonoids

Context: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant’s self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized.

Objective: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids.

Methods: PubMed and WEB OF KNOWLEDGE® were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure–activity relationship between prenylated flavonoids and their bioactivities.

Results: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids.

Conclusion: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure–activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.     

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.     

A systematic review of the Alcohol norms literature: A focus on context

Objective: To proffer a theoretically driven assessment of the validity of research which examines alcohol-related normative beliefs.

Methods: A systematic review of 68 articles matching the inclusion criteria, published between 1970 and 2013.

Results: Potential causes of deviations in research findings are identified and compelling gaps in our knowledge with regards to the influence of participant gender, age and contextual factors are highlighted and discussed in relation to the broader literature.

Conclusions: It is proposed that a standardization of research approaches and alcohol intake measures are required in order to increase the validity of present research and enable useful comparisons between studies. Further attention to key, potentially mediatory variables is also highlighted as important for increasing research validity with a view to facilitating the improvement of interventions.     

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.     

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.     

Investigation of thiol-disulphide balance in patients with acute urticaria and chronic spontaneous urticaria

Background: Thiol–disulphide balance plays a major role in health and diseases. This balance may be disrupted by various diseases. We aimed to determine status of the effect of thiol–disulphide balance in urticaria.

Objectives: We aimed to investigate the thiol–disulphide balance in patients with acute urticaria (AUP) and chronic spontaneous urticaria (CSU).

Methods: Study included 53 AUP and 47 healthy controls plus 57 patients with chronic spontaneous urticaria (CSUP) and 57 healthy controls. Levels of native thiols, disulphides and total thiols were evaluated in plasma using a new and automated spectrophotometric method. Ratios of disulphides/total thiols, disulphides/native thiols and native thiols/total thiols were calculated.

Results: For AU, there was no statistical difference compared to control group in levels of native thiols, disulphides and total thiols. For CSU, however, there was an increase in levels of native thiols, disulphides and total thiols and the ratio of thiol/disulphide in favour of disulphide.

Conclusion: Thiol–disulphide balance was not affected by AU but shifted towards to disulphide in CSU indicating the presence of oxidative stress (OS).     

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.     

Taurine inhibits interleukin-6 expression and release induced by ultraviolet B exposure to human retinal pigment epithelium cells

Background: The massive uptake of compatible osmolytes is a self-protective response shared by retina exposed to hypertonic stress and ultraviolet stress.

Objective: This study aimed to investigate the protective effects of taurine against ultraviolet damage in human retinal pigment epithelium cells.

Methods: Real-time PCR, radioimmunoassay, ELISA and immunoassay were used to measure osmolyte uptake and IL-6 expression.

Results: Compared with normotonic stress, hypertonic stress led to an induction of osmolyte uptake including betaine, myoinositol and taurine. UVB exposure upregulated osmolyte transporter mRNA expression and increased osmolyte uptake respectively. Especially, taurine suppressed UVB-induced IL-6 mRNA expression significantly. The accumulation of IL-6 in UVB-exposed human retinal pigment epithelial cells supernatant was much slower when the cells were preincubated with taurine. Moreover, taurine suppressed IL-6 concentration in aqueous humour.

Conclusion: The effect of compatible osmolyte taurine on IL-6 expression and release may play an important role in cell resistance and adaption to UVB exposure.