Current Clinical Pharmacology - Volume 11, Issue 2, 2016

Head and neck cancers (thyroid and head and neck squamous cell carcinoma (HNSCC)) are relatively common malignancies and although often curable at initial diagnosis, treatment of advanced disease is palliative in intent. There is a scarcity of treatment options, many of which are traditionally associated with significant toxicities and poor survival. Translational studies have identified numerous dysregulated pathways amongst head and neck cancers, including VEGFR and EGFR, highlighting the potential role for targeted therapies. This review details the role of VEGFR in both head and neck cancers and discusses recent trials utilizing axitinib, a multi-tyrosine kinase inhibitor with targets including VEGFR-1, -2, and -3. The article discusses the toxicity data as well as ongoing clinical trials.

Non–small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.

Dolutegravir (DTG), a novel integrase strand transfer inhibitor (INSTI), is one of the newest addition to the arsenal of anti-human immunodeficiency virus (HIV) therapeutics. Dolutegravir is the first member of the class of second generation integrase strand transfer inhibitors aimed primarily to address the current unmet need for novel unboosted integrase inhibitors with convenient once-daily dosing and a superior resistance profile. During its clinical development, DTG has demonstrated noninferior or superior efficacy in both treatment-naive as well as treatmentexperienced individuals including those who have previously failed first generation INSTIs. Other potential advantages include a favorable safety profile, low propensity for drug-drug interactions, and prolonged serum half-life permitting once-daily administration in treatment-naive or treatment-experienced INSTI naive HIV patients. Twice-daily administration is recommended in individuals with established or suspected resistance to first-generation INSTIs. This review outlines the need for new HIV therapeutics and summarizes the efficacy, safety, and pharmacokinetic profile of dolutegravir.

Background: In 2011 a list of 20 drugs linked to drug-induced Tako-Tsubo cardiomyopathy (TCM) was published. Thus, the objectives were both to identify cases of drug-induced TCM, and update the 2011 list of drugs as possible triggers of this cardiomyopathy. Method: As the 2011 report of drug-induced TCM, case reports of drug-induced TCM were identified by a comprehensive search in Medline/PubMed database. From December 2010 to March 2015 search terms were Takotsubo cardiomyopathy, Takotsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with “iatrogenic”, “drug-induced”, OR “induced by”. Publications limited to English, Spanish, and French, in humans, and with full texts were retrieved. Articles that recognized any drug as a possible trigger of TCM were selected. Results: Overall, 405 different references were retrieved and 67 were selected (62 case reports and 5 case series) involving 78 patient cases with TCM possibly associated to drugs were reviewed. At total of 44 drugs were recognized as possible drug-induced TCM, mainly with sympathetic effect, and 37 (84.1%) were different to those 20 identified in the 2011 review; therefore, a list of 57 drugs associated to TCM was obtained. Conclusion: There are new case reports that linked drug-use with the development of TCM. The list of 57 drugs obtained is principally integrated by drugs that generate sympathetic overstimulation. Consequently, the recommendation “drug-induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified” is endorsed.

Cannabis sativa is also popularly known as marijuana. It has been cultivated and used by man for recreational and medicinal purposes since many centuries. Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries. The research of drugs acting on endocannabinoid system has seen many ups and downs in the recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions. Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system. Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008. Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists. One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that act selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted. Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids. In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.

Advanced glycation end products (AGE) such as N--carboxy-ethyl-lysine (CEL), N--carboxy-methyl-lysine (CML), imidazolone, methyl-glyoxal-lysine dimer (MOLD), glyoxal-lysine dimer (GOLD), pyrraline and pentosidine have been imparted in the development and worsening of complications of diabetes. They are also involved in atherosclerosis, normal aging process, arthritis, cancer and progression of age-related neurodegenerative diseases like Alzheimer's disease. Endogenously, they are formed by nonenzymatic glycation by aldoses/ketoses to form intermediate precursor that were slowly converted into AGE. A positive correlation was observed with the level of AGEs formation and progression of the diseases. Exogenously, they formed in foods when they were cooked at very high temperature. AGEs can interact with the cell surface receptors of AGE (RAGE) to release cytokines, free radicals as well as directly modify the extracellular matrix and action of hormones. Hence, the mechanism of AGE association with pathogenesis of diseases can be ascribed mainly to the generated cytokines and free radicals. Second type of receptors such as AGE receptor-1, 2 and 3 were more specific and involved in their detoxification and clearance. Therapeutic agents were used to inhibit AGEs formation, traps the reactive carbonyl intermediate precursors, interfering with Amadori's products, cross-link breaker and low molecular weight inhibitors of RAGE had been described as well. Despite the several therapeutic agents described so far, none of them have proven to be recommended for clinical use. Furthermore, no methods or standard units were accepted universally to measure AGEs are existing. This review discusses AGEs formation, association with diseases and therapeutic agents to alleviate them.

Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products, and their integration with self-care, music and mHealth, expands precision/personalized medicine strategies for chronic diseases via pharmacological-behavioral combination therapies.

Psoriasis is a common skin disorder characterized by hyper proliferation of keratinocytes. Although the exact pathophysiology of psoriasis is not entirely understood, immune system and its interaction with nervous system have been postulated and investigated as the underlying mechanism. The interaction between these two systems through cholinergic anti-inflammatory pathway and also endocannabinoid system, may suggest cannabinoids as potential addition to antipsoriatic armamentarium.