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.     

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.     

Investigational therapies for squamous cell lung cancer: from animal studies to phase II trials

Introduction: It remains challenging to treat squamous cell lung cancer (SCC) with limited therapeutic options. However, recent breakthroughs in targeted therapies and immunotherapies have shed some light on the management of this deadly disease.

Areas covered: The article first reviews the current treatment options for advanced SCC, especially recent FDA approved molecular agents (afatinib, ramucirumab and necitumumab) and immunotherapies (nivolumab, pembrolizumab and atezolimumab). We then provide an overview on investigational therapies with data ranging from preclinical to phase II studies, focusing on new cytotoxic agents, emerging molecularly targeted agents (including a PARP inhibitor for Homologous Recombinant Deficiency positive SCC) and novel immunotherapeutic strategies.

Expert opinion summary: Identification of potential therapeutic targets, development of novel clinical trials and the rapid approvals of immune checkpoint inhibitors have shifted the management paradigm for squamous cell lung cancer. On the other hand, continued efforts are needed to identify the predictive biomarkers and to investigate novel mechanistically-driven mono- and combination therapies. We need to learn more about the biology behind immune checkpoint blockade and tumor genomics in SCC for better patient selection and future trial design.     

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

Introduction: Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer.

Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer.

Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.     

Osimertinib for the treatment of non-small cell lung cancer

Introduction: The T790 M mutation of the epidermal growth factor receptor (EGFR) gene is the most common mechanism underlying resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Osimertinib, a third-generation EGFR TKI, shows robust clinical efficacy in patients with T790 M-mutated lung cancer.

Areas covered: We analyzed and reviewed clinical data for which patients who experienced acquired resistance to first- or second-generation EGFR TKIs. In addition, we briefly reviewed the potential role of osimertinib as a first-line therapy.

Expert opinion: Osimertinib was recently licensed for use in NSCLC patients with acquired resistance to other EGFR TKIs due to a T790 M mutation. However, unresolved issues surrounding the optimal application of osimertinib remain, specifically the development of a plasma-based mutation test to overcome the difficulty of repeat biopsy, the efficacy of osimertinib for brain or leptomeningeal metastases, the development of resistance to osimertinib, and the use of osimertinib therapy as a first-line treatment. Many ongoing studies are currently exploring these issues.     

Clinacanthus nutans: a review on ethnomedicinal uses,chemical constituents and pharmacological properties

Context: Medicinal plants have attracted global attention for their hidden therapeutic potential. Clinacanthus nutans (Burm.f) Lindau (Acanthaceae) (CN) is endemic in Southeast Asia. CN contains phytochemicals common to medicinal plants, such as flavonoids. Traditionally, CN has been used for a broad range of human ailments including snake bites and cancer.

Objectives: This article compiles the ethnomedicinal uses of CN and its phytochemistry, and thus provides a phytochemical library of CN. It also discusses the known pharmacological and biological effects of CN to enable better investigation of CN.

Methods: This literature review was limited to articles and websites published in the English language. MEDLINE and Google Scholar databases were searched from December 2014 to September 2016 using the following keywords: "Clinacanthus nutans" and "Belalai gajah". The results were reviewed to identify relevant articles. Information from relevant selected studies was systematically analyzed from contemporary ethnopharmacological sources, evaluated against scientific literature, and extracted into tables.

Results: The literature search yielded 124 articles which were then further scrutinized revealing the promising biological activities of CN, including antimicrobial, antiproliferative, antitumorigenic and anti-inflammatory effects. Few articles discussed the mechanisms for these pharmacological activities. Furthermore, CN was beneficial in small-scale clinical trials for genital Herpes and aphthous stomatitis.

Conclusion: Despite the rich ethnomedicinal knowledge behind the traditional uses of CN, the current scientific evidence to support these claims remains scant. More research is still needed to validate these medicinal claims, beginning by increasing the understanding of the biological actions of this plant.     

Role of osteopontin as a predictive biomarker for anti-EGFR therapy in triple-negative breast cancer

Objective: Effective targeted therapies for patients with triple-negative breast cancer (TNBC) present an unmet clinical need. There is evidence that TNBCs often have increased expression of the epidermal growth factor receptor (EGFR) and of osteopontin (OPN). OPN-mediated signaling can activate EGFR-dependent signaling pathways. Here, we assessed OPN as a potential predictive biomarker for response to anti-EGFR therapy in TNBC.

Research design and methods: Using two different TNBC cell lines, MDA-MB-468 and MDA-MB-231, we investigated the impact of stable expression of OPN on efficacy of the EGFR inhibitor erlotinib in vitro.

Results: We observed that breast cancer cells engineered to overexpress OPN are more sensitive to growth inhibition by erlotinib than control cells. The level of response was related to the level of OPN expression, possibly due to increased phosphorylation status of EGFR Tyr1068.

Conclusions: These results indicate that OPN expression levels are related to sensitivity of TNBC cells to growth inhibition by erlotinib. OPN thus is a promising predictive biomarker for anti-EGFR therapy in breast cancer.     

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.     

Modulation of sensitivity and resistance to multikinase inhibitors by microenvironmental platelet factors in HCC

Introduction: Response of a tumor to chemotherapy or multikinase inhibitor therapy has been traditionally thought to be a reflection of the sum of the characteristics of both the drug and of the tumor cell resistance mechanisms. More recently, there has been a growing awareness of the role of non-tumor factors-both cellular and humoral-in the tumor microenvironment that can increase or decrease the tumor cellular responses to the therapy. This article focuses on platelet factors in clinical HCC and experimental evidence that they provide growth stimulants that can antagonize the growth inhibitory effects of therapy.

Areas covered: Review of the mechanisms of multikinase cancer growth inhibitors and of the role of platelets in providing growth factors that can antagonize their effects.

Expert opinion: These new ideas and data show that the response of a tumor to multikinase inhibitors or chemotherapy may be strongly influenced by microenvironmental factors. Conversely, antagonists to these environmental factors, such as EGFR inhibitors and IGF1-R inhibitors, might be expected to augment the anti-tumor effect of both chemotherapy and multikinase inhibitors.     

Conservative treatment of pelvic congestion syndrome: indications and opportunities

Introduction: This brief review describes conservative treatment methods for pelvic venous congestion.

Therapy options: The authors present an analysis of the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs), ergot alkaloid derivatives, hormonal agents, venoprotective agents, and compression therapy in the treatment of pelvic congestion syndrome (PCS) as well as indications for medical therapy.

Conclusion: The paucity of studies addressing this topic and the need for large multidisciplinary studies to explore the opportunities for non-surgical treatment of PCS are highlighted.     

Ethno-medicinal documentation of polyherbal medicines used for the treatment of tuberculosis in Amathole District Municipality of the Eastern Cape Province,South Africa

Context: Tuberculosis (TB) has remained a devastating global public health problem. In the continuing search for effective treatment, polyherbal remedies used as alternative medicines in the Eastern Cape Province of South Africa were surveyed.

Objective: The survey collected information and documents the list of ingredients such as the name of the plants used including the non-herbal inclusions, type and dosage of polyherbal formulations used for the treatment of TB.

Materials and methods: The survey was conducted over a period of 6 months using semi-structured questionnaires amidst informal conversations with the traditional healers in five communities in the study area. The chosen study area is the third infected Province with TB in South Africa.

Results: A total of nine polyherbal preparations were collected. Information on the parts of the plant used, mode of preparation and the dosage used were documented. In total, the herbs belong to 20 families of which Apiaceae, Liliaceae, Strychnaceae, Rutaceae and Hypoxidaceae are the most prominent. However, members of Apiaceae were commonly mentioned for the preparation of the remedies. The two most frequently used plants were Allium sativum L. (Liliaceae) and Strychnos decussata (Pappe) Gilg. (Strychnaceae). Rhizome was the commonest parts used, followed by the roots and barks.

Conclusions: This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in the study area. The therapeutic claims made on medicinal plants used for the preparations are well supported by the literature, with many of the species having antimicrobial properties.     

Can binimetinib,encorafenib and masitinib be more efficacious than currently available mutation-based targeted therapies for melanoma treatment?

Introduction: Historically, there were few effective and durable treatments for metastatic melanoma. Recently, mutation based targeted therapies have revolutionized treatment and outcomes for patients with metastatic melanoma. Specifically, inhibitors aimed at BRAF, NRAS, and C-KIT mutations are now commonly used in treatment for patients harboring the specific mutations.

Areas covered: A brief review of current BRAF, NRAS, and C-KIT inhibitors provides background for a thorough review of newly developed agents namely binimetinib, a MEK inhibitor, encorafenib a BRAF inhibitor, and masitinib which inhibits C-KIT.

Expert opinion: While the 3 novel agents reviewed here have potential for use in melanoma, optimal utilization will occur once a more personalized approach incorporating genomic, proteomic, and immunologic data guides therapeutic decisions.     

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.     

Empirical antifungal treatment for diagnosed and undiagnosed invasive fungal disease in patients with hematologic malignancies

Background: Empirical antifungal therapy is effective in some patients with risk factors for invasive fungal disease (IFD) who do not qualify for the EORTC/MSG criteria for IFD, but who fail to respond to anti-bacterial and anti-viral therapy.

Objective: This retrospective single-center study investigated the epidemiology of IFD and empirical antifungal therapy in patients with hematological malignancies.

Methods: This study recruited 893 patients with hematologic malignancies who had failed to respond to anti-bacterial and anti-viral treatment and received antifungal therapy, but not for antifungal prophylaxis. Antifungal therapy regimens included amphotericin B, voriconazole, itraconazole and caspofungin. A total of 689 patients were diagnosed with proven, probable, or possible IFD, while 159 patients did not meet the EORTC/MSG criteria for IFD diagnosis but recovered with antifungal treatment, and 45 were excluded from having IFD. Effective treatment was defined as the disappearance or resolution of clinical symptoms of IFD.

Results: Patients diagnosed with IFD underwent chemotherapy at a higher proportion, and had significantly higher neutrophil counts compared to those who did not qualify for the EORTC/MSG criteria for IFD but responded to antifungals. The mortality due to all causes within 3 months was significantly higher for patients diagnosed with proven IFD, compared with those who did not qualify for the EORTC/MSG criteria for IFD. There was no discontinuation reported due to adverse events of caspofungin.

Conclusion: Empirical antifungal treatment could help save the lives of some patients with severe infections who are strongly suspected of having IFD.     

Evaluation of the quality of life in patients with arsenic keratosis

Background: Chronic exposure to inorganic arsenic is an important public health problem and leads to hyperpigmentation, hyperkeratosis, Bowen’s disease and non-melanoma skin cancers in humans. Arsenic keratosis is the most common skin change that is associated with arsenic exposure. It may be an indicator of arsenic induced health hazards.

Objective: To determine the needs of patients with arsenic keratosis by evaluating the impact of disease on the quality of life with respect to treatment and provide rehabilitation services.

Methods: A total of 47 subjects with arsenic hyperkeratosis, were enrolled in this crossover study. The demographics, smoking status and the presence of chronic diseases diagnosed by the physician were recorded. Weight and height of the subjects were measured and BMI was calculated. The patients were asked to respond the visual analogue scale and EuroQoL-5D scales for assessing the pain and quality of life impairment associated with arsenic hyperkeratosis.

Results: In the study group, moderate to severe problems were reported in 78.7% of patients for pain/uncomfortable condition domains and in 91.5% in anxiety/depression domains. Lower quality of life was reported in those with associated chronic disorders, at an advanced age, in thin patients and in those with severe lesions.

Conclusion: According to our knowledge, our study is the first one measuring the quality of life in patients with arsenic keratosis in the literature. By this study, we tried to underline the guidance of health services to be developed towards the needs of patients and the need for the development of new health policies by determining the requirements of these patients.     

COPD-treating nurses’ preferences for inhaler attributes – a discrete choice experiment

Objective: To assess nurses’ preferences for various attributes of chronic obstructive pulmonary disease (COPD) inhalation devices in order to obtain information about the relative importance of the different attributes and their assigned levels.

Methods: Data from a web-based questionnaire among Danish nurses who treat patients with COPD (accomplished in the spring/summer of 2015) was used. A total of 222 nurses completed the questionnaire which was based on discrete choice experiment (DCE) methodology. The probability of choosing an alternative from a number of choices in a discrete choice game was estimated by means of the conditional logit model.

Results: The two most important attributes according to the COPD-treating nurses were “Indicator when empty” and “Inspiratory flow rate”. In addition, the nurses considered the attribute “Obvious that dose is given” important. The three least-valued attributes were frequency of doses, whether the inhaler requires fine motor skills and whether it requires hand strength.

Conclusion: Inhalation devices can be classified into five categories, where the soft mist inhaler (SMI) includes the three most important attributes among its characteristics.

Limitations: The study sample size does not allow for subgroup analysis, which would have been valuable. The questionnaire design gives an indication of nurses’ preferences and it is assumed that these are similar to real life choices, but the current study cannot conclude on the nurses’ actual choices.     

Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy

Introduction: Cancer cells have increased glycolysis and glutaminolysis. Their third feature is increased de novo lipogenesis. As such, fatty acid (FA) synthesis enzymes are over-expressed in cancer and their depletion causes antitumor effects. As fatty acid synthase (FASN) plays a pivotal role in this process, it is an attractive target for cancer therapy.

Areas covered: This is a review of the lipogenic phenotype of cancer and how this phenomenon can be exploited for cancer therapy using inhibitors of FASN, with particular emphasis on orlistat as a repurposing drug.

Expert opinion: Disease stabilization only has been observed with a highly selective FASN inhibitor used as a single agent in clinical trials. It is too early to say whether the absence of tumor responses other than stabilization results because even full inhibition of FASN is not enough to elicit antitumor responses. The FASN inhibitor orlistat is a ‘dirty’ drug with target-off actions upon at least seven targets with a proven role in tumor biology. The development of orlistat formulations suited for its intravenous administration is a step ahead to shed light on the concept that drug promiscuity can or not be a virtue.     

Multiple sclerosis as an adverse drug reaction: clues from the FDA Adverse Event Reporting System

Background: Possible relationship between drug exposure and multiple sclerosis (MS) development is insufficiently investigated, and further challenged by the incomplete understanding of MS etiopathogenesis. The study aims to investigate whether drug exposure could contribute to MS, by analyzing worldwide spontaneous reporting archives of adverse drug reaction (ADRs).

Research design and methods: We retrieved information from the US Food and Drug Administration Adverse Event Reporting System (FAERS) over a 13-year period. Reporting odds ratio (ROR) for MS was calculated for each single substance. Disproportionality signals were considered when at least 10 cases were retrieved with a lower limit of the 95% confidence interval (CI) >1.

Results: After a customized data-mining process, 3,226 reports of MS were retrieved. ‘Antineoplastic and immunomodulating drugs’ (33% of total reports) were the most frequently reported, with 10 disproportionality signals, including etanercept (445 cases; ROR: 2.48; 95% Cl: 2.24–2.74), adalimumab (329; 2.05; 1.83–2.30), and infliximab (119; 2.25; 1.87–2.70). We also observed signals for drugs acting on hormone balance, bone density, and central nervous system.

Conclusion: Our findings suggest that immunomodulatory drugs increase the risk of MS and point out that some other drug classes should be further investigated for this risk.     

Dronedarone and renal impairment: evaluation of Spanish postmarketing reports and review of literature

Background: Renal impairment associated with dronedarone use is hardly known. Our aim is to describe the characteristics of spontaneous reports involving renal adverse reactions with use of dronedarone.

Methods: In the Spanish Pharmacovigilance database, reports with renal reactions and dronedarone until May 2014 were retrieved and analyzed. Also, a review of case reports of renal failure and dronedarone was conducted in MEDLINE.

Results: Dronedarone was found as a suspected drug in 192 reports, 10 (5.2%) of these reports described renal reactions. Renal reactions appeared until 3 months after the onset of dronedarone treatment. In 5 out of 10 cases, dronedarone was withdrawn and the patient recovered. The Reporting Odds Ratio was 2.88 [95% CI 1.52 – 5.46; p < 0.05]. Additionally, eight cases were found in the medical literature. In five of them, the patient outcome was described as recovered. One patient had to undergo hemodialysis for the treatment of their renal impairment.

Conclusions: The effect of dronedarone on the renal function is supported by limited information; therefore, the cases from spontaneous reporting system and those from the medical literature could give relevant additional information. Our analysis shows a potential relationship between dronedarone use and renal impairment. Further studies are needed to confirm these findings.     

Active and passive surveillance of enoxaparin generics: a case study relevant to biosimilars

Objective: This retrospective analysis assessed the capability of active and passive safety surveillance systems to track product-specific safety events in the USA for branded and generic enoxaparin, a complex injectable subject to immune-related and other adverse events (AEs).

Methods: Analysis of heparin-induced thrombocytopenia (HIT) incidence was performed on benefit claims for commercial and Medicare supplemental-insured individuals newly treated with enoxaparin under pharmacy benefit (1 January 2009 – 30 June 2012). Additionally, spontaneous reports from the FDA AE Reporting System were reviewed to identify incidence and attribution of enoxaparin-related reports to specific manufacturers.

Results: Specific, dispensed products were identifiable from National Drug Codes only in pharmacy-benefit databases, permitting sensitive comparison of HIT incidence in nearly a third of patients treated with brand or generic enoxaparin. After originator medicine’s loss of exclusivity, only 5% of spontaneous reports were processed by generic manufacturers; reports attributable to specific generics were approximately ninefold lower than expected based on market share.

Conclusions: Claims data were useful for active surveillance of enoxaparin generics dispensed under pharmacy benefits but not for products administered under medical benefits. These findings suggest that the current spontaneous reporting system will not distinguish product-specific safety signals for products distributed by multiple manufacturers, including biosimilars.