Amyotrophic lateral sclerosis (ALS) is an untreatable and fatal neurodegenerative disease that is identified by the loss of motor neurons in the spinal cord, brain stem, and motor cortex which theatrically reduces life expectancy. Although the primary cause of ALS remains unclear, its heterogeneity put forward for consideration of association with various factors, including endogenous and/or environmental ones, which may be involved in progressive motor neuron stress that causes activation of different cell death pathways. It is hypothesized that this disease is triggered by factors related to genetic, environmental, and age-dependent risk. In spite of large neurobiological, molecular and genetic research, at the beginning of the 21^st century, ALS still remains one of the most devastating neurodegenerative diseases because of the lack of effective therapeutic targets. It is a challenge for the clinical and scientific community. A better understanding of the etiology of ALS is necessary to develop specific targets of this progressive neurodegenerative disease. This review states about the current knowledge of targets in ALS research. This review provides an overview of the contribution of different targets like mitochondrial dysfunction, glutamate transport and excitotoxicity, protein accumulation, Oxidative stress, neuromuscular junction, microglia, and other molecular targets in the pathogenesis of ALS.

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AIM: The aim of the study was to compare the dose-adjusted plasma levels of carbamazepine (CBZ) among expressers and nonexpressers of cytochrome P450 3A5 (CYP3A5)* 3 genotypes. SUBJECTS AND METHODS: The study was carried out in 100 epileptic patients who were on CBZ monotherapy. Steady-state plasma CBZ levels were measured using reverse-phase high-performance liquid chromatography method, and genotyping of CYP3A5 was done using real-time polymerase chain reaction method. RESULTS: Patients inheriting CYP3A5*3/*3 variant (nonexpressers) had an increased plasma concentration of CBZ (4.86 μg/ml) when compared to patients inheriting either CYP3A5*1/*1 or CYP3A5*1/*3 (expressers) (4.3 μg/ml, P = 0.004). Nonexpressers had significantly increased plasma concentrations of CBZ when adjusted for dose and weight when compared to expressers (P < 0.002 and P < 0.001, respectively). The frequency of adverse reactions in expressers and nonexpressers was 12% and 9%, respectively. CONCLUSION: There is a significant influence of CYP3A5*3 genetic polymorphism (6986A>G) on dose-adjusted plasma levels of CBZ in epileptic patients in the South Indian population.

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There are very few reports which suggest an association between antipsychotic clozapine low dose and seizure. We report a case in which intial titration of low dose clozapine developed seizure. A 42-year-old female who did not have any history of seizure and had normal blood parameters and normal computed tomography brain at the baseline developed seizure while on clozapine 300 mg/day. Reduction of the dose of clozapine to 250 mg/day led to the return to baseline, with having another episode of seizure on again increasing the dose of clozapine, requiring tablet haloperidol 10 mg/day as an add-on therapy for normalization of behavioral problems. Later, clozapine was maintained on 250 mg/day, with no recurrence of seizure episodes. To conclude, this case report suggests that clozapine can rarely lead to seizure during the initial phase of titration of treatment.

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Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in the elderly. These drugs are mostly inaccessible due to their high cost. Bevacizumab is a VEGF inhibitor, approved for cancer treatment. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of eye diseases. In this article, we have analyzed similarities and differences between bevacizumab and ranibizumab, and potential long-term safety concerns with off-label use of bevacizumab. We also analyzed legal, regulatory, and ethical background of off-label use and provided recommendations to resolve this issue. Based on the extensive clinical data, actions taken, and recommendations provided by agencies such as the National Institute for Health and Care Excellence, International Council of Ophthalmology, United Kingdom and Thailand regulatory agency, intravitreal bevacizumab has adequate evidence for controlled licensing. Claiming better safety for ranibizumab at the expense of nonaffordability cannot be considered a positive risk-benefit scenario. Intravitreal bevacizumab is being used and will continue to be used off-label, if not regulatory controlled. Licensing will ensure the availability of intravitreal bevacizumab to the patients with eye diseases, without any legal or ethical concerns for the clinicians, and will also assist in generating long-term safety data. Safest delivery formulation and dosage form should be considered for approval. Both the regulatory agency and technical experts should join and take critical decision, which will be a big step forward to making a cost-effective drug available to the public.

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We present a case report of a heart failure patient after heart transplantation due to end-stage ischemic cardiomyopathy with significant clinical and echocardiographic improvement 3 months after the introduction of sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor. This new class of drugs is proved to be beneficial in heart failure patients, especially with reduced ejection fraction (HFrEF), but they have not yet been used in heart failure patients after heart transplantation. We believe that the increase of left ventricular systolic function, improvement of global longitudinal strain, and reduction of pulmonary hypertension with consequent clinical recovery in our patient may have been caused by sacubitril/valsartan.

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BACKGROUND: Incidences of resistance to current drugs by Plasmodium is increasing, hence, it is necessary to investigate and explore new drug targets to combat malarial disease. OBJECTIVE: Analysis of the transcriptome sequence information to characterize hub genes and their nonsynonymous single nucleotide polymorphisms (nsSNPs) to derive therapeutic objectives for Plasmodium falciparum. MATERIALS AND METHODS: Differentially expressed genes between Ring and other stages of P. falciparum were identified using Cufflinks tool. Using DAVID and KAAS programs, the gene ontology and pathway analysis were performed. The networks of protein-protein interaction (PPI) were developed by Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape, and the node degree in the network was calculated by using Network Analyzer, and MCODE plugins of Cytoscape. SIFT, PROVEAN, and PredictSNP programs were used to study the genetic variations, which affect protein functions. RESULTS: A list of 4196 nonredundant genes was used for functional annotation cluster analysis, and 8 significant hub genes have been picked from the PPI network using MCODE plugins of Cytoscape. Various nsSNPs were identified in these 8 hub genes and were investigated both for its native and mutant stage for solvent accessibility and alteration in secondary structure protein residues. CONCLUSION: Hub genes identified in this study serve as potential targets to develop therapy to suppress the pathogenic action of P. falciprum through experimental techniques.

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OBJECTIVE: The objective of the study is to evaluate the perception of postgraduate pharmacology students toward computer-simulated method (CSM) in comparison to the prevalent isolated live tissue-based bioassay method. MATERIALS AND METHODS: A questionnaire-based survey was conducted in 30 postgraduate pharmacology students who had used the animal simulation software and had completed at least five isolated tissue experiments. Students' opinions on the usage, logistics, advantages, disadvantages, and usefulness of CSM compared to live animal experiments (LAE) were analyzed. RESULTS: Four tissues were used for LAE, whereas with CSM, students could perform experiments using 11 different tissues. Of the total nine bioassay methods, students had performed six assay methods using both LAE and CSM. Majority of the students (23/30) agreed that CSM reduces anxiety, technical errors and is less time consuming when used before LAE. Most of the students agreed that CSM can be used for difficult, lengthy experiments (19/30), and for UG/PG teaching (19/30). However, opinions regarding replacing LAE with CSM in PG teaching were divided (agree: 7, neutral: 12, and disagree: 12). CONCLUSION: CSM should be integrated alongside LAE to complement, reinforce, and enhance learning from other techniques.

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Mannitol has been the cornerstone of osmotherapy in the treatment of raised intracranial pressure for the past several decades. We discuss here a case of subcutaneous mannitol extravasation, leading to bullous eruptions and swelling in the forearm of a postoperative patient of arteriovenous malformation. We emphasize the importance of careful selection of peripheral intravenous catheter site, especially when infusing hypertonic solutions with propensity for subcutaneous leaks and tissue damage.

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