Systematic review and technological prospection: ethyl ferulate,a phenylpropanoid with antioxidant and neuroprotective actions

Introduction: Ethyl ferulate is a phenylpropanoid with anti-inflammatory, antioxidant and neuroprotective activities of natural and synthetic origin with potential uses in the nutraceutical and pharmaceutical industry. Therefore, the aim of this study was to investigate the current scenario regarding patents and scientific articles available involving the substance in question, regarding aspects such as quantity, areas of knowledge and depositor countries.

Areas covered: To do so, we conducted technological and scientific prospecting on the WIPO, EPO, USPTO and INPI and scientific databases in PubMed, Web of Science and Lilacs databases using the keywords ‘ferulic acid ethyl ester’ and ‘ethyl ferulate’ in English and Portuguese. A total of 16 articles and 17 patents of which 10 were Chinese and 11 claimed the use of ethyl ferulate or for the synthesis of other substances or synthetic methods of the same. Five of the patents selected claimed therapeutic applications related to the treatment of mycobacterial infections, use as a cosmetic and neuroprotective activity. The systematic review of the literature revealed antioxidant, neuroprotective, anti-inflammatory, antimutagenic, antiapoptotic, antimutagenic and antiproliferative activities.

Expert opinion: The technological and scientific prospection highlighted ethyl ferulate, despite its known pharmacological activities, is little explored by the pharmaceutical and nutraceutical industries.     

Safety and efficacy of rivaroxaban for thromboprophylaxis following lower limb surgery: an update

Introduction: Thromboprophylaxis in orthopedic surgery remains a controversial issue despite recent changes to NICE guidelines, particularly with the addition of oral factor Xa inhibitors. The healthcare burden of venous thromboembolism is substantial and needs frequent academic and clinical appraisal.

Areas covered: The authors review the available relevant literature on the use of rivaroxaban in orthopedic surgery, identified using an EMBASE (1980 – 2010) and Ovid MEDLINE (1950 – 2010) search of published articles up to August 2010. This includes clinical studies, case reports and experimental studies where applicable. Search terms include: ‘rivaroxaban’, ‘safety’, ‘efficacy’, ‘bleeding’, ‘toxicity’, ‘tolerability’ and ‘complication’.

Expert opinion: Rivaroxaban is a safe and effective choice of thromboprophylactic agent following lower limb arthroplasty surgery. More research is required to expand the application of this novel agent to other areas of orthopedic surgery.     

Pharmacological and biotechnological advances with Rosmarinus officinalis L

Introduction: Rosmarinus officinalis L. is an aromatic plant with a number of biological properties. Recently, has been studied regarding its therapeutic potential. The objective of this study was to perform a systematic review on R. officinalis essential oil for its pharmacological properties and biotechnological applications.

Areas covered: The databases were searched for articles (Science Direct, Pub Med and Web of Science) and patents (INPI, WIPO and EPO) with publications on R. officinalis and associations with essential oil (EO-Ro), cardiovascular system, hypertension and cyclodextrin. We selected 305 articles on EO-Ro in the most diverse subjects and six articles with of R. officinalis associated with hypertension. 59 patents were analyzed. The results demonstrate how extensive the studies are on the biological activities with the extract and EO-Ro. These have shown effects antibacterial, antifungal, anti-inflammatory, antitumor and other. The properties exhibited by EO-Ro reinforce the use of this plant as a phytotherapeutic agent.

Expert opinion: Although there are several pharmacological properties, studies on the prevention or treatment of cardiovascular diseases with EO-Ro are scarce, especially to evaluate the antihypertensive activity of EO-Ro. It has also become clear that EO-Ro can be exploited in different commercial products as supplement, cosmetics and new formulations     

Patent focus on antiparasitic agents: May - October 1999

Patent applications germane to parasite chemotherapy are reviewed for the period May to October, 1999. The scope of the review, covering antiprotozoal and antihelmintic agents has been extended to include the atypical unicellular fungus Pneumocystis carinii, the causative agent of the AIDS-associated disease Pneumocystis carinii pneumonia (PCP). This organism although phylogenically related to fungi is ‘protozoan-like’ in its response to drugs and often appears in patents classified as a parasite. Reviews are presented from 16 patents. Somewhat surprisingly no applications of interest emerged concering helminth chemotherapy. Specifically the review reports on compounds of relevance to the chemotherapy of malaria, leishmaniasis and PCP, and is organised according to disease indication. A brief introduction to each disease precedes the patent analysis.     

Perceived Importance of Factors in Cannabis Purchase Decisions: A Best-worst Scaling Experiment

BackgroundConsumers’ access to cannabis has been considerably expanded in US states where recreational cannabis was legalized and commercialized. However, little is known about the important factors influencing consumers’ purchase decisions in cannabis retail dispensaries. This study examined cannabis users’ perceptions of the relative importance of policy-relevant factors when they made cannabis purchase decisions.MethodsAn online survey was administered to 817 adult cannabis users in seven states in the US (California, Colorado, Maine, Massachusetts, Nevada, Oregon, and Washington) that had approved cannabis commercialization by the time of interview in January 2018. Twenty policy-relevant cannabis attributes were evaluated, including those pertaining to product characteristics, quality, package characteristics, price and free sample, store characteristics, and restrictions on use. A best-worst scaling experiment was employed, which asked respondents to select the most and the least important attributes in a choice scenario. Each respondent answered 10 choice scenarios, each including a random combination of four attributes out of the 20. The relative importance of each attribute was evaluated using hierarchical Bayesian estimation of mixed logit models.ResultsOverall, ‘quality’, ‘strain type’, ‘price’, ‘THC’ (tetrahydrocannabinol) and ‘pesticide’ were the top five important attributes affecting cannabis users’ willingness to buy cannabis in a dispensary. These five attributes jointly accounted for approximately half of the total importance. In subsample analysis, both recreational and dual-purpose users attached higher importance to ‘quality’, ‘THC’, and ‘price’, whereas medical users tended to think ‘CBD’ (cannabidiol) and ‘pesticide’ were more important. All cannabis users perceived ‘package’ to be the least important attribute. Gender had no major differences in perceptions.ConclusionsCannabis users in general perceived product characteristics, quality, and price to be important factors in their willingness to buy cannabis in dispensaries. There were heterogeneities in the perceptions by cannabis use purposes. The findings might deserve consideration in cannabis policy design.     

Current drugs in early development for hereditary angioedema: potential for effective treatment

Background: The role of growth hormone (GH) in augmenting fracture healing has been postulated for over half a century. GH has been shown to play a role in bone metabolism and this can be mediated directly or indirectly through IGF-I. Objectives: The use of GH was evaluated as a possible therapeutic agent in augmenting fracture healing. Method: A literature search was undertaken on GH and its effect on bone fracture healing primarily using MEDLINE/OVID (1950 to January 2009). Key words and phrases including ‘growth hormone’, ‘insulin like growth factor’, ‘insulin like growth factor binding protein’, ‘insulin like growth factor receptor’, ‘fracture repair’, ‘bone healing’, ‘bone fracture’, ‘bone metabolism’, ‘osteoblast’ and ‘osteoclast’ were used in different combinations. Manual searches of the bibliography of key papers were also undertaken. Results: Current evidence suggests a positive role of GH on fracture healing as demonstrated by in vitro studies on osteoblasts, osteoclasts and the crosstalk between the two. Animal studies have demonstrated a number of factors influencing the effect of GH in vivo such as dose, timing and method of administration. Application of this knowledge in humans is limited but clearly demonstrates a positive effect on fracture healing. Concern has been raised in the past regarding the safety profile of the pharmacological use of GH when used in critically ill patients. Conclusion: The optimal dose and method of administration is still to be determined, and the safety profile of this novel use of GH needs to be investigated prior to establishing its widespread use as a fracture-healing agent.     

The effect of visual interventions on illness beliefs and medication adherence for chronic conditions: A scoping review of the literature and mapping to behaviour change techniques (BCTs)

BackgroundMaintaining health with chronic conditions often involves taking multiple medications; however, approximately 50% of patients with chronic conditions are non-adherent to medication. Patients’ illness beliefs inform health behaviour, including medication-taking. Research has shown that visuals accompanying health information increased patient comprehension and the accuracy of illness perceptions. To date, the influence of visuals on illness beliefs and medication adherence has not been comprehensively reviewed.ObjectivesThe review aimed to collate available literature on visualisation interventions for illness beliefs and medication adherence in chronic conditions and identify key intervention characteristics.MethodsA scoping review was conducted according to recommended guidelines and the PRISMA-ScR statement. Searches used keywords relating to ‘illness’, ‘visual’, ‘adherence’, ‘illness perception’, ‘intervention’, and ‘medication’. Six databases were searched from inception to 2019; reference-list searching provided additional articles. Articles were included if the study population had a chronic health condition, the intervention included a visual element, had a measure of illness beliefs or medication adherence. Data regarding intervention characteristics and outcomes were extracted. Behaviour change techniques (BCTs) were identified to provide further insight into intervention characteristics.ResultsInitially, 18,012 articles were identified. Screening led to 293 full-text articles, ultimately resulting in 45 studies for final analysis. Forty-four were quantitative studies, 1 was qualitative. Studies were grouped into those using visuals to conceptualise a condition, medication reminders and educational interventions. Almost two-thirds of visual interventions were effective post-intervention, 3 sustained post-1-year, although many studies only assessed impact immediately post-intervention. BCTs from ‘Natural consequences’, ‘Social support’ and ‘Feedback and monitoring’ categories were prevalent in effective interventions for both outcomes, particularly the ‘Salience of consequences’ BCT.ConclusionsThis comprehensive scoping review found that visual interventions can positively influence illness beliefs and medication adherence. These findings highlight the need to further evaluate the impact and sustainability of visual interventions.     

Famciclovir: a focus on efficacy and safety

Importance of the field: Famciclovir is the prodrug of penciclovir, a guanosine analogue that inhibits viruses of the α sub-family of the Herpesviridae, as well as hepatitis B virus. It is indicated for management of mucocutaneous herpes simplex virus disease and acute herpes zoster, and has been investigated for management of hepatitis B virus infection.

Areas covered in this review: Data for this review were identified by searches of papers published in English on Medline and Scopus, spanning the years 1975 through 1 February 2010 with the key words: ‘famciclovir’, ‘famvir’, ‘penciclovir’, ‘herpes’, ‘oral’, ‘genital’, ‘varicella’, ‘zoster’ and ‘virus’ in association with ‘safety’, ‘toxicity’, ‘tolerability’, ‘efficacy’ and ‘indications’. Relevant references were also obtained from articles acquired through the search strategy.

What the reader will gain: Readers are also provided with up-to-date information on the use of famciclovir for infections due to herpes simplex, varicella zoster and hepatitis B viruses. Clinical data pertaining to the safety and tolerability of famciclovir are also reviewed.

Take home message: Famciclovir is a safe, convenient, and well-tolerated drug when used for its approved indications. The most common side effects indicated in the majority of studies were headache and nausea. Data for its use in childhood and pregnancy are limited.     

Acylhydrazone derivatives: a patent review

Introduction: The N-acylhydrazone (NAH) moiety has been characterized as a privileged structure, capable of providing ligands points for more than one type of bioreceptor. Modifications of the subunits bonded to its acyl and imine functions resulted in several derivatives, which modulate a great diversity of molecular targets. In this context, this patent review reflects the use of the NAH moiety in different compounds.

Areas covered: In this review, the authors perform an analysis of the therapeutic profile of NAH compounds together with their perspective of its usability. The Espacenet and Delphion databases were used as main sources of search, and ‘N-acylhydrazone,’, ‘Acylhydrazone’ and ‘hydrazone’ were used as keywords. From a total of 117 patents retrieved, 22 presented pharmacological activities described in the document, thus being chosen for this review.

Expert opinion: In the last century, only six patents disclosing NAH derivatives for therapeutic purposes were published, and only in 2010, this subunit started receiving some real attention regarding its therapeutic potential. In this review, the Brazilian and Chinese Universities were identified as the major patent applicants, especially for drug candidates for the treatment of chronic pain, inflammatory disorders and cancer. The NAH subunit is very versatile both from synthetic and medicinal chemistry point of view. This feature is a direct result from the conformational diversity that this framework presents, achievable by subtle and simple chemical changes. Therefore, our opinion is that this moiety suits a lot more drug discovery projects than it seems to at first glance. In conclusion, we strongly support and encourage a raise in the use of this unique subunit.     

Toxicity of sorafenib: clinical and molecular aspects

Importance of the field: Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-β. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Sorafenib has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer. Despite its inherent selectivity, sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists.

Areas covered in this review: Relevant literature was identified using a Pubmed search of articles published up to June 2009. Search terms included ‘sorafenib’ and ‘toxicity’. Original articles were reviewed and relevant citations from these articles were also considered.

What the reader will gain: The clinical aspect of sorafenib-induced adverse events and the molecular basis behind this toxicity are discussed. Finally, recommendations for the management of these adverse events are proposed.

Take home message: Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist.     

Alternative Animal and Non-Animal Models for Drug Discovery and Development: Bonus or Burden?

Mammalian models have served as a basis for R&D over the past decades. Nevertheless, these models are expensive, laborious, may yield results that cannot always be translated into the human in vivo situation and, more recently, have reverberated great social and ethical dilemmas. Hence, the prospect of changes in the global scientific scenario and the Three Rs principle (Reduction, Replacement and Refinement) have encouraged the development of alternative methods to the use of mammals. Despite the efforts, suitable alternative tests are not available in all areas of biomedical research, as regulatory acceptance requires time, prior validation and robust financial and scientific investment. In this perspective, we aim to shed light on the concepts, challenges and perspectives for implementation of innovative alternative animal and non-animal methods in scientific research. The applicability and meaningfulness of invertebrate animal models, in silico analysis and reverse pharmacology are discussed, among other aspects of relevance in today’s scenario. Overall, the use of alternative models, including Artemia salina (brine shrimp), Caenorhabditis elegans (roundworm), Danio rerio (zebra fish), Drosophila melanogaster (fruit fly), Galleria mellonella (greater waxmoth) and in silico modelling, increased 909% from 1990 to 2015, as compared to 154% of conventional mammals in the same period. Thus, technological and scientific advancements in the fields of toxicology and drug development seem to have diminished the need for mammalian models. Today, however, mammals still remain critically indispensable to provide – in most cases –reliable data subsidizing and validating translation into the clinical setting.     

Fifty-Eight Years and Counting: High-Impact Publishing in Computational Pharmaceutical Sciences and Mechanism-Based Modeling

With this issue of the Journal of Pharmaceutical Sciences, we celebrate the nearly 6 decades of contributions to mechanistic-based modeling and computational pharmaceutical sciences. Along with its predecessor, The Journal of the American Pharmaceutical Association: Scientific Edition first published in 1911, JPharmSci has been a leader in the advancement of pharmaceutical sciences beginning with its inaugural edition in 1961. As one of the first scientific journals focusing on pharmaceutical sciences, JPharmSci has established a reputation for publishing high-quality research articles using computational methods and mechanism-based modeling. The journal’s publication record is remarkable. With over 15,000 articles, 3000 notes, and more than 650 reviews from industry, academia, and regulatory agencies around the world, JPharmSci has truly been the leader in advancing pharmaceutical sciences.     

Oxidative stress as a mechanism underlying sulfasalazine-induced toxicity

Introduction: Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease (CD) and rheumatoid arthritis (RA). A high incidence of side effects limits therapy with this drug. Getting a wider knowledge of drug pharmacology, indications and side effects is essential to ensure the best possible clinical care, minimizing toxicity and inappropriate use.

Areas covered: This paper gives an overview of recent research about SASP and its main adverse effects, highlighting the mechanisms underlying them. To give an overview and comment on the data available so far on this topic, relevant literature was identified using a PubMed search of articles published up to December 2009. Search terms included: ‘sulfasalazine’, ‘oxidative stress, ‘renal effects’, ‘hepatotoxicity’ and ‘male fertility’. Original papers were reviewed and relevant citations from these articles were also considered.

Expert opinion: Although SASP and 5-aminosalicylic acid also scavenge ROS, which may account for some of their anti-inflammatory properties, the reaction with ROS may also generate toxic free radicals; hence, the ability of other antioxidants to suppress the toxicity of SASP in vivo. Further investigations, particularly about SASP mechanism, are still needed.     

Research and innovation in the development of everolimus for oncology

Introduction: The critical role of increased activity of mammalian target of rapamycin (mTOR) in the pathophysiology of multiple diseases is well established. Inhibition of the mTOR pathway may block disease progression and improve patient outcomes. Everolimus, an mTOR inhibitor, began in clinical development as part of a regimen (Certican, Zortress) for prevention of organ transplant rejection and is now an approved oncology agent.

Areas covered: The objective of this review is to discuss the history of key findings and innovative cancer research undertaken to successfully develop everolimus as an oncology therapy (Afinitor) now approved for patients with advanced renal cell carcinoma (RCC) and for subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis. In addition, data for the use of everolimus in the treatment of other cancers and rare diseases are also discussed. A PubMed search of English articles without time restrictions was conducted using the search terms ‘everolimus or rapamycin’ and ‘cancer’. Bibliographies of retrieved articles were manually searched for additional relevant articles. Major cancer congresses were also searched.

Expert opinion: The clinical efficacy of everolimus alone and in combination with other agents has been observed in recently completed Phase II–III studies in a wide spectrum of tumors, including RCC, neuroendocrine tumors, tuberous sclerosis complex, SEGAs and angiomyolipomas, lymphoma and gastric, breast and hepatocellular cancers. These findings emphasize the importance of mTOR in diverse cancers and rare diseases and underscore the potential role for everolimus as an effective agent in multiple indications.     

Analyzing research trends on drug safety using topic modeling

Introduction: Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts.

Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years.

Expert Opinion/Commentary: We found that ‘benefit-risk assessment and communication’, ‘diabetes’ and ‘biologic therapy for autoimmune diseases’ are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time.     

Therapeutic use of colchicine and its derivatives: a patent review

Introduction: Colchicine, the major alkaloid extracted from the meadow saffron (Colchicum autumnale) is one of the most prominent natural products belonging to the class of organic compounds known as tropones. Colchicine’s medicinal properties have been long-known, but it has been attracting renewed attention due to its action as an antimitotic agent.

Areas covered: This review presents an update and analysis of the patents claiming therapeutic activity of colchicine and its derivatives published in the last five years (2010–2015). Other patents claiming the application of colchicine in the areas of biotechnology, veterinary, and agriculture are therefore excluded from this review.

Expert opinion: Rapid increase in the number of publications and patent filings in recent years for the significant therapeutic potential of colchicine, for several conditions beyond gout, clearly indicates the growing interest of research on this molecule. Although the molecular structure of colchicine fulfils the four Lipinski’s requisites for high oral bioavailability, the toxic side effects resulting from its fast metabolism need to be assessed. Further efforts are therefore required to explore the appropriate dosage and possible administration techniques of colchicine for practical use.