Evaluation of WO2017098421: GSK’s benzothiazine compounds as CD73 inhibitor filings

Introduction: There are considerable interests in the development of novel small-molecule CD73 inhibitors for the treatment of cancers, autoimmune diseases, precancerous syndromes, and other diseases associated with CD73 activity.

Areas covered: The application claims novel substituted benzothiadiazine derivatives as CD73 inhibitors for the treatment of cancer, precancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Many of the exemplified compounds have pIC50 values between 5 to 8.4 against CD73.

Expert Opinion: These benzothiadiazine derivatives provide good leads for the discovery of potent CD73 inhibitors for the treatment of cancer and other diseases mediated by adenosine and its action on adenosine receptors.     

Treatment patterns of rheumatoid arthritis in Japanese hospitals and predictors of the initiation of biologic agents

Objective: To describe the usage of different biologic agents for rheumatoid arthritis (RA) in Japan over time and to identify factors that affects the decision to initiate treatment with biologic agents. Determinants of a switch to another biologic agent for patients who are already on biologic treatment were also analyzed.

Research design and methods: We utilized a hospital claims database containing 36,504 Japanese patients with a confirmed RA diagnosis. To analyze the determinants of treatment choices, we applied logistic regression analysis taking into account socio-demographic and medical factors.

Results: Analyses determined that 11.8% of diagnoses and 25.4% of treated patients in Japan receive a biologic agent. Significant factors associated with biologic treatment initiation include younger age, female sex, and a higher comorbidity index. The route of administration plays a major role when it comes to a switch between different biologic agents.

Conclusions: The lower likelihood of elderly patients to be initiated on biologic treatment might be explained by the risk aversion of Japanese physicians’ and patients who are afraid of the potential side effects of biologics. This finding is also consistent with the notion of an age bias that impedes elderly patients from optimal access to biologic treatment. Because claims data does not contain clinical parameters such as disease activity the results should be validated in a clinical context.     

Carbonic anhydrase enzymes for regulating mast cell hematopoiesis and type-2 inflammation: a patent evaluation (WO2017/058370)

Introduction: Activity modulators of carbonic anhydrases hold great potential for several therapeutic applications against ophthalmologic and neurological disease, cancer, and infectious diseases. The involvement of carbonic anhydrase in the regulation of mast cell response opens new ways for the treatment of mastocytosis, allergic inflammation, and parasite infection.

Areas covered: The application claims the use of carbonic anhydrase activity modulators (inhibitors or activators) for treating allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis, or mast cell–mediated inflammation.

Expert opinion: Although there is a lack of essential biological data, this patent proposes a new type of applications for carbonic anhydrase inhibitors and deserves further studies. This may lead to new advances in the field of carbonic anhydrase with potential therapeutic implications in the management of type-2 inflammation.     

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.     

Lidocaine 5% medicated plaster for localized neuropathic pain in thoracic surgical patients

Context: Neuropathic pain is a common and distressing symptom in thoracic surgical patients. When it consistently presents with measurable sensory changes in a circumscribed area, neuropathic pain can be diagnosed as localized neuropathic pain (LNP).

Objective: The purpose of this study was to report the efficacy of lidocaine 5% medicated plaster (Lido5%P) in the treatment of LNP in thoracic surgical patients.

Methods: We retrospectively reviewed the records of sixteen cancer and noncancer thoracic patients treated with Lido5%P for LNP. Patients had been assessed before and during treatment with standardized forms and questionnaires for pain intensity, sleep quality, drug dosages and adverse events.

Results: Treatment with Lido5%P yielded a significant and lasting improvement in pain symptomatology. In oncological patients as an add-on therapy, Lido5%P improved pain intensity and sleep quality, and delayed opioid dose escalation. In non-oncological patients as monotherapy or in association with antineuropathic drugs, Lido5%P attenuated LNP. No local or systemic adverse events were recorded.

Conclusions: Lido5%P was effective in relieving thoracic LNP, and was well tolerated.     

Mulberry leaves and their potential effects against cardiometabolic risks: a review of chemical compositions,biological properties and clinical efficacy

Context: Cardiometabolic risks are regarded as the crucial factors associated with type 2 diabetes (T2DM) and cardiovascular diseases (CVD). Regarding an increased attention to medicinal plants in the current healthcare system, the effects of mulberry (Morus spp., Moraceae) leaves on cardiometabolic risks have been consecutively considered in scientific research.

Objective: The present review compiles and summarizes the chemical compositions, biological properties and clinical efficacy of mulberry leaves that are related to the amelioration of cardiometabolic risks.

Methods: Published English literature from the PubMed, Science Direct and Google Scholar databases was searched by using ‘mulberry leaves’ ‘Morus spp.’, ‘hyperglycemia’, ‘hyperlipidemia’, ‘obesity’, ‘hypertension’, ‘oxidative stress’, ‘atherosclerosis’ and ‘cardiovascular diseases’ as the keywords. The relevant articles published over the past two decades were identified and reviewed.

Results: Mulberry leaves contain numerous chemical constituents. 1-Deoxynojirimycin (DNJ), phenolics and flavonoids are the prominent functional compounds. Preclinical and clinical studies showed that mulberry leaves possessed various beneficial effects against cardiometabolic risks, including antihyperglycaemic, antihyperlipidaemic, antiobesity, antihypertensive, antioxidative, anti-inflammatory, anti-atherosclerotic and cardioprotective effects.

Conclusions: Mulberry leaves could be a promising therapeutic option for modulating cardiometabolic risks. However, further investigations should be performed to substantiate the potential of mulberry leaves in practical uses.     

Recent perspectives on the delivery of biologics to back of the eye

Introduction: Biologics are generally macromolecules, large in size with poor stability in biological environments. Delivery of biologics to tissues at the back of the eye remains a challenge. To overcome these challenges and treat posterior ocular diseases, several novel approaches have been developed. Nanotechnology-based delivery systems, like drug encapsulation technology, macromolecule implants and gene delivery are under investigation. We provide an overview of emerging technologies for biologics delivery to back of the eye tissues. Moreover, new biologic drugs currently in clinical trials for ocular neovascular diseases have been discussed.

Areas covered: Anatomy of the eye, posterior segment disease and diagnosis, barriers to biologic delivery, ocular pharmacokinetic, novel biologic delivery system

Expert opinion: Anti-VEGF therapy represents a significant advance in developing biologics for the treatment of ocular neovascular diseases. Various strategies for biologic delivery to posterior ocular tissues are under development with some in early or late stages of clinical trials. Despite significant progress in the delivery of biologics, there is unmet need to develop sustained delivery of biologics with nearly zero-order release kinetics to the back of the eye tissues. In addition, elevated intraocular pressure associated with frequent intravitreal injections of macromolecules is another concern that needs to be addressed.     

Doxycycline hydrochloride-metronidazole solid lipid microparticles gels for treatment of periodontitis: development,in-vitro and in-vivo clinical evaluation

Objective: To formulate solid lipid microparticles (SLMs) encapsulating doxycycline hydrochloride (DH) and metronidazole (MT) for the treatment of periodontal diseases.

Methods: SLMs were prepared applying hot homogenization method, using different types of lipids and stabilized with various types and concentrations of surfactants. The optimized formula was subjected to freeze-drying followed by incorporation into poloxamer gel. Microbiological and clinical evaluation of the selected SLMs on patients suffering from periodontal diseases was performed.

Results: SLMs could entrap high percentage of both drugs (81.14% and 68.75 % for doxycycline hydrochloride and metronidazole respectively). Transmission electron microscopy images of SLMs showed nearly spherical particles. Freeze-dried SLMs showed satisfactory stability for three months. Combined drugs were molecularly dispersed in SLMs. Incorporation of the freeze-dried SLMs powder in poloxamer gel could control the drugs release for 72 h. In-vivo study revealed effective and safe use of SLMs gel for periodontitis treatment. Significant improvement in both microbiological and clinical parameters was observed as compared to scaling and root planing alone.

Conclusion: The formulated SLMs gel offers an applicable dosage form that can be injected directly into the periodontal pocket as adjunctive to scaling and root planing.     

P2X7 receptor antagonists: a patent review (2010–2015)

Introduction: The P2X7 receptor (P2X7R) is a unique subtype among the family of seven purinergic P2X receptors, which are ATP-gated non-selective cation channels. P2X7R has been reported to have pathological roles in various diseases, including autoimmune diseases such as arthritis and inflammatory bowel disease, neurodegenerative diseases, chronic pain, mood disorders and cancers. Therefore, many pharmaceutical companies have endeavored to develop a clinical candidate targeting P2X7R.

Areas covered: This review provides a summary of various patents on chemicals and biologics and their clinical use published between 2010 and 2015. The reader will gain information on structural claims, representative structures and biological activities of recently developed P2X7R antagonists.

Expert opinion: P2X7R is a fascinating therapeutic target and potential biomarker for inflammation, pain disorders and cancers. Research on the development of P2X7R antagonists has continually increased despite the failure of AstraZeneca and Merck’s compounds in phase II clinical trials. Various scaffolds have been disclosed by several pharmaceutical industries, and some compounds are currently under investigation in clinical trials.     

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.     

Evaluation of WO2017018805: 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors

Introduction: There are great potential in the development of selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine diseases, and other diseases associated with HDAC6 activity.

Areas covered: The application claims 1,3,4-oxadiazole sulfamide derivatives as selective HDAC6 inhibitors for the treatment of infectious diseases, neoplasms, endocrine, nutritional, and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; disease of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities. Many of the exemplified compounds showed nanomole potency against HDAC6 and were more than 5000-fold selectivity for HDAC6 over HDAC1.

Expert opinion: These 1,3,4-oxadiazole sulfamide derivatives have a unique zinc-binding group (ZBG) that provide good leads for the discovery of potent selective HDAC6 inhibitors for the treatment of a variety of diseases associated with HDAC6 activity.     

Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics–small molecule drug interactions

Introduction: Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment.

Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted.

Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.     

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.     

An ethnopharmacological study of aromatic Uyghur medicinal plants in Xinjiang,China

Context: An ethnobotanical survey was completed in a remote village and surrounding country of Xinjiang, where most Uyghur medicinal plants could be collected. This work clarifies and increases ethnobotanical data.

Objectives: We surveyed and organized aromatic medicinal plants that are commonly used in clinical settings to provide a significant reference for studying new medical activities.

Materials and methods: In the survey, informants who have traditional knowledge on aromatic Uyghur medicinal plants were interviewed between March 2014 and September 2014. Aromatic medicinal plant species and pertinent information were collected. Some therapeutic methods and modes of preparation of traditional aromatic medicinal plants were found.

Results: A total of 86 aromatic medicinal plant species belonging to 36 families were included in our study. We identified 34 plant species introduced from different regions such as Europe, India and Mediterranean areas. Fruits and whole plants were the most commonly used parts of plant, and most aromatic medicinal plants could be applied as medicine and food. We assigned the medicinal plants a use value (UV). Knowing the UV of species is useful in determining the use reliability and pharmacological features of related plants.

Conclusions: Xinjiang is an area in which indigenous aromatic medicinal plants are diversely used and has therefore established a sound dimensional medical healthcare treatment system. Some aromatic Uyghur medicinal plants are on the verge of extinction. Hence, further strategies for the conservation of these aromatic medicinal plants should be prioritized.     

Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies

Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients.

Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice.

Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered.

Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05)

Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.     

Safinamide for the treatment of Parkinson’s disease

Introduction: The major unmet needs in the medical treatment of Parkinson disease (PD) are reduction of motor side effects from dopaminergic drugs, management of non-motor symptoms and disease modification.

Areas covered: Motor fluctuations and OFF periods are a significant determinant of quality of life in PD and reducing their duration and severity can significantly improve motor function. This aim may be partly facilitated by the development of effective adjunctive drugs for dopamine replacement. Safinamide (Xadago), which is a first generation anticonvulsant, has pharmacological properties which are of interest in the context of neurodegenerative diseases, leading to research into its potential as an adjunct to levodopa in PD.

Expert opinion: Although its mechanism has not been fully defined, safinamide provides enhanced symptom control of motor function in advanced PD and improves quality of life.     

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.     

First experiences with a tool to measure the level of clinical information present in adverse drug reaction reports

Background: To make a proper causality assessment of an adverse drug reaction (ADR) report, a certain level of clinical information is necessary. A tool was developed to measure the level of clinical information present in ADR reports. The aim of this study was to test the validity and reliability of the clinical documentation tool (ClinDoc) in an international setting.

Methods: The tool was developed by a panel of pharmacovigilance experts. It includes four domains: ADR, chronology of the ADR, suspected drug and patient characteristics. The final score categorizes reports into: excellent, well, moderately or poorly documented.

In two rounds, eight pharmacovigilance assessors of different countries made a total of 224 assessments using the tool, with the expert panels judgement as a standard. Sensitivity and specificity were calculated.

Results: The tool with four outcome-categories demonstrated low sensitivity. A lack of distinctiveness was demonstrated between the categories moderate and well. Results for the second round were re-analysed using three categories. This demonstrated a better validity.

Conclusion: This is the first tool to give insight in the level of relevant clinical information present in ADR reports. It can be used internationally to compare reports coming from different reporting methods and different types of reporters in pharmacovigilance.     

Induction therapy for the management of early relapsing forms of multiple sclerosis. A critical opinion

Introduction: The therapeutic approach in multiple sclerosis (MS) is radically changing. From the early stages of MS, a hard-hitting approach to treatment is taken with strong anti-inflammatory drugs being a possible therapeutic option.

Areas covered: The concept of induction therapy is emerging in the MS therapeutic scenario.

Expert opinion: Not all the MS licensed drugs are suitable candidates for induction therapy. The upcoming challenge will be to identify, after a careful and individual assessment of risk/benefit ratio, the ideal patient who is a candidate to such aggressive therapeutic approach.     

Periodontal disease and women’s health

Background: Periodontal disease (PD) is a multifactorial inflammatory condition in which inappropriate interaction between the host immune response and specific groups of bacterial pathogens leads to destruction of connective and bone tissues supporting the tooth. Dissemination of pathogens, toxins, and immune complexes from and to periodontal lesions is at the basis of the increasingly recognized association between PD and various systemic diseases (SDs). Considering the growing attention of the medical community to “gender medicine”, this review focuses on the association between PD and six systemic conditions heavily impacting women’s health, with the aim of providing evidence in support of a joint effort between physicians and dentists to improve clinical management of these conditions.

Methods: We considered systematic reviews, meta-analyses and narrative reviews evaluating all possible associations between periodontitis, systemic diseases and women.

Results: Gender prevalence for PD is discordant, but the literature strongly supports an association between PD and female infertility and adverse pregnancy outcomes. Moreover, PD is bidirectionally linked to several systemic diseases characterized by an established female gender bias, i.e. osteoporosis (OP), cardiovascular diseases (CVD), autoimmunity, Alzheimer’s disease (AD) and cancer.

Conclusions: Overall, the literature data reviewed here provides a strong foundation for further characterization of molecular and microbial drivers of PD and of several female-prevalent systemic diseases, highlighting the possible importance of a good oral condition in preventing or attenuating women’s systemic diseases.