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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Computational analysis of benzofuran-2-carboxlic acids as potent Pim-1 kinase inhibitors

Context: The three Pim serine/threonine kinases (Pim-1, Pim-2, and Pim-3) belong to a small family of kinases that regulate numerous signaling pathways fundamental to the development of tumors. Pim kinases’ overexpression has been reported in numerous solid and hematological tumors and, in particular, prostate cancer (Pim-1).

Objectives: This study investigated the binding modes of benzofuran-2-carboxlic acids against Pim-1 kinase, hence providing useful information for the active inhibition of it.

Materials and methods: In present study, molecular docking approach via MOE-Dock program was applied to predict the binding interactions of some known Pim-1 kinase inhibitors. First validation of the docking protocol was carried out by calculating RMSD for the co-crystallized and docked ligands. Using the same protocol, all the compounds were docked into the active site of Pim-1 kinase.

Results: All the compounds showed significant interactions and good correlation with the experimental data. The results illustrate that compounds with optimum basicity and relevant distance between the acidic and basic groups showed optimum interactions with the active site residues of Pim-1 kinase.

Conclusion: We hope that this study will be helpful in designing new, structurally diverse and more potent compounds for the active treatment of prostate cancer and other related diseases caused by deregulation of Pim-1 kinase.     

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.     

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 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.     

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.     

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.     

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).