Current Drug Targets - Volume 22, Issue 4, 2021

The increasing armamentarium of drugs for inflammatory bowel disease (IBD) requires a direct comparison of different therapeutic options in order to guide physicians in the choice of the most appropriate treatment for their patients. Head-to-head trials, considered the gold standard in comparative research in IBD, allow to compare different therapies in the same population and setting, but also to evaluate different treatment strategies. Although head-to-head trials including biologics and immunosuppressive therapy in IBD have been performed decades ago, the interest in these direct comparisons is growing since the publication of the first randomized controlled trial directly comparing biologic agents with different molecular targets. This review provides an overview of the past and current IBD head-to-head trials, considering their respective strengths and limitations in a real-life setting.

Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas diseases are among the most severe NTDs, and are caused by the Leishmania sp and Trypanosoma cruzi, respectively. Glucantime, pentamidine, and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, are known to improve biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluorosynthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand-searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth mentioning that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro-, and chloro-groups in the compound backbone. All in all, nitro and halogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as the baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts in in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

Atherothrombosis results from direct interaction between atherosclerotic plaque and arterial thrombosis and is the most common type of cardiovascular disease. As a long term progressive disease, atherosclerosis frequently results in an acute atherothrombotic event through plaque rupture and platelet-rich thrombus formation. The pathophysiology of atherothrombosis involves cholesterol accumulation endothelial dysfunction, dyslipidemia, immuno-inflammatory, and apoptotic aspects. Platelet activation and aggregation is the major cause for stroke because of its roles, including thrombus, contributing to atherosclerotic plaque, and sealing off the bleeding vessel. Platelet aggregates are associated with arterial blood pressure and cardiovascular ischemic events. Under normal physiological conditions, when a blood vessel is damaged, the task of platelets within the circulation is to arrest the blood loss. Antiplatelet inhibits platelet function, thereby decreasing thrombus formation with complementary modes of action to prevent atherothrombosis. In the present scientific scenario, researchers throughout the world are focusing on the development of novel drug delivery systems to enhance patient’s compliance. Immediate responding pharmaceutical formulations become an emerging trend in the pharmaceutical industries with better patient compliance. The proposed review provides details related to the molecular pathogenesis of atherothrombosis and recent novel formulation approaches to treat atherothrombosis with particular emphasis on commercial formulation and upcoming technologies.

Breast Cancer Resistance Protein (BCRP) is an efflux transporter responsible for causing multidrug resistance (MDR). It is known to expel many potent antineoplastic drugs, owing to its efflux function. Efflux of chemotherapeutics because of BCRP develops resistance to many drugs, leading to failure in cancer treatment. BCRP plays an important role in physiology by protecting the organism from xenobiotics and other toxins. It is a half-transporter affiliated to the ATP- binding cassette (ABC) superfamily of transporters, encoded by the gene ABCG2 and functions in response to adenosine triphosphate (ATP). Regulation of BCRP expression is critically controlled at molecular levels, which help in maintaining the balance of xenobiotics and nutrients inside the body. Expression of BCRP can be found in brain, liver, lung cancers and acute myeloid leukemia (AML). Moreover, it is also expressed at high levels in stem cells and many cell lines. This frequent expression of BCRP has an impact on the treatment procedures and, if not scrutinized, may lead to the failure of many cancer therapies.

The Glioblastoma Multiforme (GBM; grade IV astrocytoma) exhorts tumors of star-shaped glial cells in the brain. It is a fast-growing tumor that spreads to nearby brain regions specifically to cerebral hemispheres in frontal and temporal lobes. The etiology of GBM is unknown, but major risk factors are genetic disorders like neurofibromatosis and schwannomatosis, which develop the tumor in the nervous system. The management of GBM with chemo-radiotherapy leads to resistance, and current drug regimen like Temozolomide (TMZ) is less efficacious. The reasons behind the failure of drugs are due to DNA alkylation in the cell cycle by enzyme DNA guanidase and mitochondrial dysfunction. Naturally occurring bioactive compounds from plants referred as phytochemicals, serve as vital sources for anti-cancer drugs. Some prototypical examples include taxol analogs, vinca alkaloids (vincristine, vinblastine), podophyllotoxin analogs, camptothecin, curcumin, aloe-emodin, quercetin, berberine etc. These phytochemicals often regulate diverse molecular pathways, which are implicated in the growth and progression of cancers. However, the challenges posed by the presence of BBB/BBTB to restrict the passage of these phytochemicals, culminates in their low bioavailability and relative toxicity. In this review, we integrated nanotech as a novel drug delivery system to deliver phytochemicals from traditional medicine to the specific site within the brain for the management of GBM.

Cancer is the most ruinous disease globally. Natural products have impressive characteristics, such as exceptional chemical versatility, chemical and biological properties of macromolecular specificity and less toxicity which make them good leads in finding novel drugs. The phytochemicals not only help to prevent but also treat chronic cancerous conditions. The present review attempts to put forth some selected anticancer phytochemicals that had reported omics characteristic and specifically suppressed cancer with in vitro and in vivo activity. Certain issues pertaining to anticancer phytochemicals like delivery to target site in the body and achieving controlled release in order to prevent overdoses have been a major concern for medical researchers worldwide. The most conventional chemotherapy protocols for the treatment of cancer lead to adverse effects that limit biological efficacy and compromise patient outcomes. In order to defeat incompetency of current and upcoming natural anticancer agents and to attain targeted drug delivery with good efficacy and fewer side effects, there is a special focus on novel nanostructured particles and nano approaches consisting of carrier system. Recent studies have led to the discovery of mesoporous and nanoporous drug delivery mechanisms, such as inorganic or organic-based nanosponges. The metal based inorganic systems have exhibited toxicity and non-biodegradable character in vivo. As a result of problems related to inorganic systems, major shift of research from inorganic to organic nanosystems has occurred. About decades ago, researchers developed organic nanosponges to control the limitation of drug delivery and cancer therapies. This review article discusses the development and application of nanosponges encapsulated phytochemicals for cancer therapy.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation, swelling, and joint destruction primarily affecting the peripheral joints. In recent years, RA has become an alarming concern affecting more than 1.5% of the population worldwide. The majority of the drugs in clinical trials for rheumatoid arthritis are immunomodulatory. The development of novel drugs for RA is impending and scientists are exploring new strategies through various innovative approaches for RA drug development. Treat-to-target and window of opportunity hypothesis are the new approaches that are used to treat, improve outcomes, and prevent long-term use of ineffective therapy, respectively. Novel therapeutic agents (e.g. GM-CSF inhibitors, Matrix metalloproteinase inhibitors) and delivery systems (e.g., Liposomes, Superparamagnetic iron oxide nano particles (SPIONs)) are under investigation for more target based therapy with reduced side effects and toxicity. The new drug discovery and repositioning of previously FDA-approved drugs are also being considered for chronic inflammatory disorder. The review encompasses a vast array of information, including genetics, etiology, clinical symptoms, current treatment, and newer therapeutics approaches, focused on the development of RA interventions. The introduction of the bioinformatics-based approach in RA has also been significantly discussed in the review. This review provides a general understanding of the challenges and uncertainties in the treatment of RA and summarizes the evolving scenario as well as innovative approaches taken into consideration for drug development in rheumatoid arthritis.