Current Clinical Pharmacology - Volume 13, Issue 2, 2018

Background: Most patients with advanced non-small cell lung cancer (NSCLC) have a poor prognosis and receive limited benefit from conventional treatments, especially in later lines of therapy. In recent years, several novel therapies have been approved for second- and third-line treatment of advanced NSCLC beyond old chemotherapy agents (docetaxel and pemetrexed) and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI, erlotinib). In particular, the new antiangiogenetics (nindetanib and ramucirumab) in combination with docetaxel and immunotherapy (nivolumab, pembrolizumab and atezolizumab) have been recently approved and represent new treatment options. Methods: The Italian Association of Thoracic Oncology (AIOT) organized five meetings in different Italian regions representing North, Middle and South of the country in order to discuss the issue. Results: In light of these new approvals, it is valuable to understand the uptake of these new therapies in routine clinical practice and their impact on patient care. With these treatment options to define an appropriate algorythm is object of debate. Conclusion: The present paper discusses the old and new treatment opportunities, proposing a shared algorithm for second-line setting in advanced NSCLC.

Background: Over the last three decades, monoclonal antibodies (MAbs) have made a striking transformation from scientific tools to powerful human therapeutics. Muromonab CD3 a murine MAb was the first FDA approved therapeutic MAb for the prevention of kidney transplant rejection. Since its approval in 1986, there has been a decline in further application and approvals until the late 1990s when the first chimeric Mab, Rituximab was approved for the treatment of lowgrade B cell lymphoma in 1997. With the approval by licensing authorities of chimeric, followed by humanized and then fully human monoclonal antibodies, the rate of approval and monoclonal antibodies available in the market for the treatment of various diseases has increased dramatically. As of March 2017, FDA has approved approximately 60 therapeutic MAbs which are currently under evaluation in various phases of clinical trials. Objective: MAbs are approved for the treatment of diseases belonging to various systems like cardiovascular, respiratory, hematology, kidney, immunology and oncology. MAbs are approved for the treatment of orphan diseases or indications such as paroxysmal nocturnal hemoglobinuria as well as cancers and multiple sclerosis where hundreds of patients are treated and even diseases such as breast cancer, asthma and rheumatoid arthritis where millions are being treated. This review focuses briefly on types, molecular targets, mechanism of actions and therapeutic indications of FDA approved MAb products that are currently available in the market. Conclusion: With the advent of fully human MAbs, the efficacy and safety have improved in the treatment of various cardiovascular, cancer, respiratory, hematology, autoimmune diseases and infections. The introduction of biosimilars will increase the affordability and utilization of MAbs in the treatment of various diseases.

Oxidative stress is a major mechanism underlying the development of various neurodegenerative diseases (Alzheimer, Parkinson, Huntington and amyotrophic lateral sclerosis). Excessive formation of reactive oxygen species (ROS) and nitrogen (RNSs) can overburden the ability of the enzymatic antioxidant defense mechanisms (superoxide dismutase, catalase and glutathione reductase) and non-enzymatic (uric acid, ascorbic acid, α-tocopherol and reduced glutathione), causing the development of oxidative stress, and consequently, impairing the neuronal system cells by means of oxidative damage to a variety of important biological molecules such as lipids, DNA and proteins. Considering the importance of oxidative stress in neurodegenerative diseases, the present review aims to address the main parameters evaluated in in vitro studies on oxidative stress in different models of neurodegenerative diseases.The literary review was conducted through Pubmed, Science Direct, LILACS, Scielo and Google using following keywords: oxidative stress, neurodegenerative diseases and parameters of oxidative stress. We selected articles published between 2002 and 2017.The in vitro evaluation of the oxidative stress related parameters has provided a preliminary view about the pathogenesis of many neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's and Amyotrophic lateral sclerosis). In this way, it has demonstrated the mechanism of action of ROS/RNSs in these diseases by direct or indirect detection through several experimental procedures in vitro.

Background: This review elucidates ongoing research, which show improved delivery of anticancer drugs alone and/ or enclosed in carriers collectively called nanomedicines to cross the BBB/ BTB to kill tumor cells and impact patient survival. We highlighted various advances in understanding the mechanism of BTB function that has an impact on anticancer therapeutics delivery. We discussed latest breakthroughs in developing pharmaceutical strategies, including nanomedicines and delivering them across BTB for brain tumor management and treatment. Methods: We performed an extensive literature search and highlighted important studies on the regulation of BTB permeability with respect to nanotech-based nanomedicines for targeted treatment of brain tumors. We have reviewed research articles that describe the development of specialized molecules and nanospheres, which carry payload of anticancer agents to brain tumor cells across the BBB/ BTB and avoid drug efflux systems. We highlighted research on the identification and development of targeted anti-cancer drug delivery to brain tumors. In addition, we discussed multimeric molecular therapeutics and nanomedicines that were encapsulated in nanospheres for treatment and monitoring of brain tumors. Results: In this context, we quoted our research on large conductance calcium-activated potassium channels (BKCa) and ATP-dependent potassium channels (KATP) as portals of enhanced antineoplastic drugs delivery. We showed that several innovative drug delivery agents such as liposomes, polymeric nanoparticles, dendrimers and many such tools can be utilized to improve anticancer drugs and nanomedicines across the BTB to reach brain tumor cells. Conclusion: This review might interest both academic and drug company scientists involved in drug delivery to brain tumors. We further seek to present evidence that BTB modulators can be clinically developed as combination drug or/ and as stand-alone anticancer drugs. Eventually, it is expected that unrelenting effort from the scientific community in developing novel drug delivery methods should increase the survival rate of brain tumor patients, which is dismally low presently.

Background: The current study investigates the cytotoxicity mechanism of common drugs with piperazine ring such as cetirizine, olanzapine and buspirone on human lymphocytes. Methods: The viability of lymphocytes, reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) collapse, lysosomal integrity, content of glutathione and lipid peroxidation was determined. Results: Buspirone and cetirizine showed more toxicity than olanzapine on human lymphocytes with an IC50 value of 200 μg/ml, after 6 h of incubation. Significant ROS formation, MMP collapse, lipid peroxidation, lysosomal damage and elevation of glutathione disulfide (GSSG) were observed in treated lymphocytes concentrations (4, 20, 40 μg/ml) of buspirone and cetirizine. Conclusion: Our results show the exposure of human lymphocytes with buspirone and cetirizine, which usually happens during the poisoning, triggers oxidative stress and organelle damages. Our study suggests that using antioxidants, mitochondrial and lysosomal protective agents can protect blood lymphocytes, from probable side effects of these highly consumed medications.

Objective: The aim of present research work was to develop a herbal fast disintegrating tablet containing Fagonia schweinfurthii Hadidi dried extract and determining its antihistaminic activity using guinea pig ileum. Method: The tablets were formulated by wet granulation technique using three different superdisintegrants (croscarmillose, crospovidone and sodium starch glycolate) at three different levels. The tablets were evaluated for various physical properties like hardness, friability weight variation etc. and various mechanical properties like disintegration time, wetting time to select the best superdisintegrant. The selected superdisintegrant was further used as intra as well as extra granulating agent to develop fast disintegrating tablets of Fagonia schweinfurthii Hadidi dried extract. The optimized formulation was subjected to stability study as per the ICH guidelines. Finally, Ex-vivo antihistaminic study was conducted on guinea pig ileum for optimized formulation and compared with marketed tablet containing cetrizine HCl as API (Stanhist-10, Ranbaxy, Pvt. Ltd). Results: Physical properties of all tablet batches were found to be acceptable and comply with various official specifications. The disintegration time and wetting time of optimized formulation (F'3) were found to be 1.15±0.08 and 0.56±0.04 min respectively. Results of Ex-vivo study showed a comparable histamine inhibition between optimized tablet (15%) and marketed tablet formulation (18.8%) in a dose of 5 μg/ml. Conclusion: On the basis of in-vitro and Ex-vivo studies, it was concluded that prepared herbal fast disintegrating tablets were stable and had potent antihistaminic activity.

Background: Postpartum haemorrhage (PPH) is an important cause of early maternal death which needs to be controlled. Objective: This study was designed to compare the effect of intravenous tranexamic acid (TXA) and prostaglandin analogue on reducing PPH resulted from uterine atony in women undergoing C section or vaginal delivery. Method: A randomized, triple-blind, placebo-controlled study was conducted on 248 pregnant women with PPH due to uterine atony who were randomly assigned into two groups of TXA as the intervention group (n=124) and prostaglandin analogue as the control group (n=124). The intervention group received 4 g TXA for an hour and then 1 g over 6 hours infusion intravenously and the control group received prostaglandin analogue. Results: Postoperative bleeding did not significantly differ between the two groups (68.2±6.1 ml and 69.1±175.73 ml, respectively, P =0.6). Moreover, hemoglobin declines were 1±0.4 g/dl and 1.2±0.5 g/dL in TXA and prostaglandin group respectively, indicating that the difference was not statistically significant (P =0.7). Conclusion: The results of the present study showed that administrating intravenous TXA had comparable effects with prostaglandin analogue on reducing PPH in women with uterine atony and in those undergoing C section or vaginal delivery. Therefore, TXA can be used instead of prostaglandin in managing such patients.