Current Issue : April - June Volume : 2013 Issue Number : 2 Articles : 10 Articles
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease that affects the skeletal muscle nerve cell. In which neurons in the brain and spinal cord that control voluntary movement (LMN and UMN) gradually deteriorate. Impending symptoms like twitching, cramping or stiffness of muscles, muscle weakness, difficulty in chewing or swallowing etc. Approximately 5,600 people are diagnosed with ALS in the US every year. There are 20% more men cases than women with ALS. Principally two recognised forms of ALS are: (A) sporadic (B) familial. The sporadic form accounts for 90% and residual 10% for familial form. It can be diagnosed by electrical and biochemical methods like electromyography, nerve conduction velocity of L/UMN, MRI scan, proteomics and metabolomics which involve potential biomarkers SOD1 gene, ALS2 gene, ALS6 gene. Presently reluzole is the only FDA approved drug for treatment which acts by preventing damage to motor neurons by obstructing glutamate release. Certain drugs under trials are TCH386, topiramate, IGF-1, BDNF-IT, pentoxyfilline etc. Herbal drugs retaining tonic properties help to treat symptoms of ALS like cannabis, licorice, yisui tang etc. Models used to study ALS are neurotoxin, viral, autoimmune, naturally occurring motor neuron disease models and transgenic animal models like SOD1 gene overexpression and human neuro-filament heavy gene expression. Novel targeting therapies aims for glutamate targets, RNA targets, protein misfolding and stem cells therapy. In the present article, an attempt has been made to emphasize on ALS, its animal models and novel targeting site for future drug development....
A layer that lines all the internal surfaces of the blood vessels is termed as endothelium. It separates circulating blood from the tissues. It helps in maintenance of vasomotor balance and vascular tissue homeostasis. It regulates the smooth muscle cells relaxation and contraction property by secretion of a large number of anti-atherosclerotic substances, the most important of them is nitric oxide (NO). Endothelium regulates homeostasis by controlling the production of prothrombotic, antithrombotic, fibrynolitics and antifibrynolitics components. Imbalance between vasodilation and vasocontraction leads to endothelial dysfunction. Endothelial dysfunction is considered as a key early event in majority of cardiovascular diseases. Oxidant stress plays an important role in altering the function of endothelial cells. Oxidant stress is excessive production of reactive oxygen species (ROS) which leads to oxidation of biological macromolecules like DNA, RNA, protein, carbohydrates and lipids. Endothelial dysfunction is involved in pathogenesis of many cardiovascular diseases i.e. diabetes, hypertension, atherosclerosis, hypercholesterolemia and heart attack. Endothelial Dysfunction therapies are effective in cardiovascular diseases....
Although anti-obesity drugs today seem to be one promising solution to curb the most universal problem of obesity, our optimism has been dashed with their unintended consequences that are overlooked or due to inadequate study on the unwanted effects produced on human body. The present study evaluated the effects of four weeks exposure prior to mating and two weeks during mating to schedule sacrifice of Phentermine HCl through oral gavage at dose levels 7.5, 15 and 30 mg/kg on reproductive tissues and fertility of male Wistar rats. Treatment showed clinical signs and mortality at the high dose. Reduced body weight was evident with decrease in feed intake throughout the study period at 30 mg/kg. Weights of testes, epididymides, brain and accessory sex organs were found to be normal. Gross and microscopic evaluation of reproductive tissues did not produce any adverse changes up to 30 mg/kg. Sperm evaluations revealed changes in sperm count at low and mid dose and adverse effects in sperm morphology at 30 mg/kg without any adverse effects on sperm motility. In conclusion, Phentermine HCl showed parenteral toxicity in behavioral changes, reduction in body weight or decreased weight gain and food consumption, mortality. Based on above reproductive assessments Phentermine HCl did not impair the fertility of male Wistar rats....
It is found out that in models of rats’ chronic stress an oral administration of Mexidol (100 mg/kg) during 10 days decreases a degree of DNA oxidative modification markers (8-OHG), proteins APH and KPH, hyperproduction of NO, and activity of NO-synthase. Also it changes an expression of early gene c-Fos and increases a concentration of Bcl-2 in neurons of paraventricular nuclei of the hypothalamus....
The NADPH oxidase (NOX) family of superoxide (O2•−) and hydrogen peroxide (H2O2) producing proteins has been important source of reactive oxygen species (ROS). ROS produced by Nox proteins Nox1-5 and Duox1/2 are now recognized to play essential role in the physiology of the brain, immune system, vasculature, digestive tract as well as in hormone synthesis. Reactive oxygen species (ROS) contribute to several aspects of vascular diseases including ischemia reperfusion injury, scavenging of nitric oxide, or stimulation of inflammation and hypertrophy. NADPH oxidases are differentially expressed in the cardiovascular system, induced or activated by cardiovascular risk factors and importantly contribute to the oxidative burden of vascular diseases. Surprisingly, large clinical trials have shown that ROS scavenging by antioxidant vitamins is ineffective or harmful. Therefore, prevention of ROS formation, by targeting specific sources of superoxide anion and other ROS, might prove beneficial. In this review article we have discussed structure, activation, localization and function of NADPH oxidases (NOX) family and its central role in oxidative stress and cardiovascular diseases.....
Cancer is one of the leading causes of death all over the world. Now days, most emphasized work is to develop a medicine that can cure cancer from its root. Many eminent scientists are burning the midnight oil to find the target for which a lead can be generated and later on developed into a safe and efficacious medicine. In their endeavor, p53 has come up as a prime target for drug development. Currently, around 11 million people are living with tumour having mutation of TP53 and another 11 million have tumour with partially abrogated p53 pathway. p53 is a transcription factor that has essential role in guarding cell in response to various stress signals through induction of cell cycle arrest, apoptosis etc. p53 is under precise control of many regulator proteins like MDM2, CBP/p300, p14ARF, c-Abl and many more. From the downstream and regulatory pathways of p53, many targets for the drug development are derived and has been set forth for the clinical study in which both macro and micro molecules are involved. In addition to that, gene therapy has also shown its efficacy. p53 recombinant adenovirus-based gene therapy has been approved in China(Gendicine®), but remains in extended preregistration trials in US(Advexin®). At present, most of this knowledge is confined to the bench, but as more discoveries of the underlying mechanisms come into light, p53 will become increasingly important at the bedside and which may pave the path of the drugs targeting p53 to the market....
Tumor Necrosis Factor [TNF] is main cytokine that is involved many pathological condition like inflammation, alzheimer's disease, cancer, major depression and inflammatory bowel disease (IBD), rheumatoid arthritis, asthma, diabetes, diabetes nephropathy, cardiovascular disease, CHF, endothelial dysfunction, neuropathic pain, hepatitis, renal disease, tuberculosis. TNF found in two systemic form known as Tumor Necrosis Factor Alpha [TNF-α] or Tumor Necrosis Factor-Beta [TNF-β]TNF is first produced as a transmembrane protein (tmTNF), which then is cleaved by a metalloproteinase to a soluble form (sTNF). Transmembrane TNF-α is a precursor form of soluble TNF-α that is expressed on TNF-α-producing cells as a homotrimer. The remaining transmembrane TNF-α after cleavage with TACE is further processed by SPPL2b and the intracellular domain is translocated into the nucleus and is supposed to mediate cytokine production. Tm TNF [transmembrane TNF-α] & sTNF [soluble TNF-α]. TNF mediates its pleiotropic activities via two cell surface receptors, p55TNFR (p60, TNFRI, CD120a, utr antigen) and p75TNFR (p80, p70, TNFRII, CD120b, htr antigen)....
Pharmacogenetics is a rapidly growing field of interest encompassing genetic variation in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, as well as genes related to the action of drugs. The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. Pharmacogenetics refers to genetic differences in metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects, while pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. The present review summarizes about importance of pharmacogenetics to variability in drug response and role of pharmacogenetics in drug development and predicting drug-drug interactions. However, by extrapolation from the past 25 years of experience in the field of pharmacogenetics/genomics will lead to new important insights and discoveries that will ultimately lead to the development of new and better drugs and to the rational use of drugs that are already on the market....
HMG-CoA reductase inhibitors were developed for the treatment of lipid disorders and have been proved to reduce cardiovascular morbidity and mortality when used for primary or secondary prevention. The most important positive pleiotropic effects of statins are anti inflammatory, antiproliferative, and antithrombotic ones, improving endothelial dysfunction and immunomodulatory. However, by inhibiting HMG-CoA reductase, statins can also inhibit the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. Therefore, it is possible that statins might exert cholesterol-independent or ‘pleiotropic’ effects through direct inhibition of these small GTP binding proteins statins have several anti-inflammatory and immunomodulatory effects through which they may modify the inflammatory mechanisms involved in the generation and rupture of atherosclerotic plaques. These effects may also be useful for controlling rheumatoid inflammation. Thus statins may be an important adjunctive therapy in RA, aiming to both reduce joint inflammation and improve cardiovascular outcome....
Pain is an important yet the most troublesome physiological response able to be categorized in many types and operated by certain mechanisms. Countering pain becomes the first goal in any illness or state of injury. Opioids are the most potent analgesics under use but with serious drawbacks including physical dependence making their use to be restricted to an extent. Inhibition of nitric oxide synthesis produces analgesia evident by the experiments on L-NG-nitro arginine methyl ester, L-NAME, 1-(2-trifluoromethylphenyl) imidazole (TRIM), 7-Nitroindazole and most importantly neurotoxins from Ophiophagus Hannah(king cobra). The neurotoxins from various cobra venoms, epibatidine (an alkaloid from skin of Ecuadorian frog) and its synthetic and safer congener ABT-594 have been proved to possess prominent analgesic effect interestingly by neuronal acetyl choline receptors modulation. They are devoid of side effects and toxicities of opioids including physical dependence because of their opioid independent mechanism. Cobrotoxin is the one such product developed from cobra venom neurotoxins igniting a hope of emergence of more candidates of this category having a fair advantage over opioids with equal efficacy in future. A vast range of neurotoxins present in nature are yet to be explored for their therapeutic applicability as analgesics which may be acting either through nitric oxide synthesis inhibition or neuronal acetyl choline receptors modulation. Extensive research in this field is expected to build a new series of effective and safe analgesics....
Loading....