Hardik Gandhi

Cardio protective effect of Coriandrum sativum L. on isoproterenol induced myocardial necrosis in rats.

The preventive effect of Coriandrum sativum L. (CS) on cardiac damage was evaluated by Isoproterenol (IP) induced cardiotoxicity model in male Wistar rats. Rats were pretreated with methanolic extract of CS seeds at a dose of 100, 200 or 300 mg/kg orally for 30 days and they were subsequently administered (s.c.) with IP (85 mg/kg body weight) for the last two days. IP treated rats showed increased LPO, decreased levels of endogenous antioxidants and ATPases in the cardiac tissue together with increased plasma lipids and markers of cardiac damage. TTC staining showed increased infarct areas while HXE staining showed myofibrillar hypertrophy and disruption. CS (200 and 300 mg/kg body weight) pretreatment significantly prevented or resisted all these changes. Our results show that methanolic extract of CS is able to prevent myocardial infarction by inhibiting myofibrillar damage. It is also concluded that, the rich polyphenolic content of CS extract is responsible for preventing oxidative damage by effectively scavenging the IP generated ROS.

Adipocytokines: The pied pipers

Even though there have been major advances in therapy, atherosclerosis and coronary artery disease retain their lead as one of the major causes of morbidity and mortality in the first decade of 21st century. To add to the woes, we have diabetes, obesity and insulin resistance as the other causes. The adipose tissue secretes several bioactive mediators that influence inflammation, insulin resistance, diabetes, atherosclerosis and several other pathologic states besides the regulation of body weight. These mediators are mostly proteins and are termed “adipocytokines”. Adiponectin, resistin, visfatin, retinol binding protein-4 (RBP-4) and leptin are a few such proteins. Adiponectin is a multimeric protein, acting via its identified receptors, AdipoR1 and AdipoR2. It is a potential biomarker for metabolic syndrome and has several antiinflammatory actions. Adiponectin increases insulin sensitivity and ameliorates obesity. Resistin, another protein secreted by the adipose tissue, derived its name due to its involvement in the development of insulin resistance. It plays a role in the pathophysiology of several conditions because of its robust proinflammatory activity mediated through the activation of extracellular signal regulated kinases 1 and 2 (ERK 1/2). In 2007, resistin was reported to have protective effect in ischemia-reperfusion injury and myocyte-apoptosis in the setting of myocardial infarction (MI). RBP-4 is involved in the developmental pathology of type 2 diabetes mellitus and obesity. Visfatin has been described as an inflammatory cytokine. Increased expression of visfatin mRNA has been observed in inflammatory conditions like atherosclerosis and inflammatory bowel disease. Leptin mainly regulates the food intake and energy homeostasis. Leptin resistance has been associated with development of obesity and insulin resistance. Few drugs (thiazolidinediones, rimonabant, statins, etc.) and some lifestyle modifications have been found to improve the levels of adipocytokines. Their role in therapy has a lot in store to be explored upon.

Effect of vitamin E alone and in combination with lycopene on biochemical and histopathological alterations in isoproterenol-induced myocardial infarction in rats.

Background: The present study has been designed to evaluate the combined cardioprotective effect of vitamin E and lycopene on biochemical and histopathological alteration in isoproterenol-induced myocardial infarction in rats. Materials and Methods: Adult male albino rats of Wistar strain were treated with isoproterenol (200 mg/kg, s.c.) for 2 days at an interval of 24 h to develop myocardial infarction. Vitamin E (100 mg/kg/day, p.o.) and lycopene (10 mg/kg/day, p.o.) were administered alone and in combination for 30 days. Change in body weight and organ weight were monitored. Levels of serum marker enzymes (AST, ALT, LDH and CK-MB), lipid peroxidation, endogenous antioxidants (GSH, GPX, GST, SOD and CAT), membrane bound enzymes (Na+/K+ ATPases, Mg2+ ATPases and Ca2+ ATPases) were evaluated. LDH isoenzyme separation was carried out using gel electrophoresis. Histopathology of heart tissue was performed. Results: Induction of rats with isoproterenol resulted in a significant elevation in organ weight, lipid peroxidation, serum marker enzymes (AST, ALT, CK-MB and LDH), and Ca 2+ ATPases, whereas it caused a significant (P < 0.001) decrease in body weight, activities of endogenous antioxidants (GSH, GPx, GST, SOD and CAT), Na+/K+ and Mg2+ ATPases. ISO treated rats showed high intensity band of LDH1-LDH2 isoenzymes. Treatment with the combination of Vitamin E and lycopene for 30 days significantly attenuated these changes as compared to the individual treatment and ISO treated groups. Histopathological observations were also in correlation with the biochemical parameters. Conclusion: These findings indicate the synergistic cardioprotective effects of vitamin E and lycopene during ISO-induced myocardial infarction in rats.

ACAT Inhibitors: The Search for Novel Cholesterol Lowering Agents

Increased level of serum cholesterol (hyperlipidemia) is the most significant risk factor for the development of atherosclerosis. Cholesterol levels are affected by factors such as rate of endogenous cholesterol synthesis, biliary cholesterol excretion and dietary cholesterol absorption. Acyl CoA: Cholesterol O-acyl transferases (ACAT) are a small family of enzymes that catalyze cholesterol esterification and cholesterol absorption in intestinal mucosal cells and maintain the cholesterol homeostasis in the blood. Inhibition of the ACAT enzymes is one of the attractive targets to treat hyperlipidemia. Literature survey shows that structurally diverse compounds possess ACAT inhibitory properties. In this review, a comprehensive presentation of the literature on diverse ACAT inhibitors has been given.

Doxorubicin mediated cardiotoxicity in rats: protective role of felodipine on cardiac indices.

Anthracyclines find vital uses in the treatment of solid tumors and other kind of malignancies. A typical side effect observed with few agents of this class is dose-dependent cardiotoxicity. Doxorubicin is one such agent which backs the generation of free radicals through metabolism of its quinone structure. This effect combined with induction of apoptotic and necrotic pathways leads to the development of irreversible cardiotoxicity. Reports showing the cardioprotective effects of felodipine have been published in the past. We chose to evaluate protective effect of felodipine in acute cardiotoxicity in rats induced by single dose of doxorubicin. Felodipine was assessed against doxorubicin-induced cardiotoxicity and we found that felodipine not only improves cardiac marker enzymes (P<0.001 for LDH; P<0.01 for CK-MB) but also prevents damage to myocardial tissue (20.61% necrosed area in doxorubicin intoxication; 11.52% necrosed area in felodipine treated group). Activation of apoptotic pathways is decelerated which is indicated by a significant reduction in myocardial caspase-3 activity (P<0.05) following felodipine pretreatment. Felodipine pretreatment was able to maintain normal cardiac morphology and histoarchitecture. Gravimetric analysis revealed beneficial effects following felodipine pretreatment. Abnormalities seen in the ECG after doxorubicin treatment were normalized to a significant extent (ST interval normalization was significant at P<0.01) in felodipine treated rats. In itself, felodipine was not found to have any detrimental effects on the myocardium or hemodynamic parameters of rats. Findings of the study suggest that pretreatment with felodipine prevents doxorubicin induced cardiotoxicity.

Revelation on the potency of α1 -blockers – parallel blockade of angiotensin II receptor: A new finding

Context: The problem of hypertension has gained enormous proportions in the past decade. Multifactorial etiology and complex pathophysiology of the disease has rendered the treatment of the disease a hard task. Sympathetic nervous system and the renin–angiotensin–aldosterone system are primary contributors of blood pressure homeostasis. Objective: Structural similarities were identified among AT1 and α1-antagonists, initiating a speculation that α1-antagonists could possibly block the AT1 receptor and vice-versa. Methods: To corroborate this speculation, we screened prototypical α1-antagonists such as prazosin, doxazosin, and terazosin for antagonism of angiotensin II on rat aortic strips. We also examined the AT1 antagonists losartan, valsartan, and olmesartan for their possible antagonistic effect, on contractions of rat aortic strips induced by phenylephrine. Results: To our astonishment, we found that prazosin and its analogs which have been reported to have α1-antagonistic activity only, were able to shift concentration response curves of angiotensin II. Conclusion: Our findings suggest that the potent antihypertensive effect of prazosin-type α1-antagonists is not purely due to α1-receptor blocking activity of these compounds but also due to blockade of AT1 receptors. This finding may lead to the development of more potent dual inhibitors which would prove to be of immense value in the control of the scourge of hypertension.

Comparative evaluation of HMG CoA reductase inhibitors in experimentally-induced myocardial necrosis: Biochemical, morphological and histological studies

The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins.

Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism

Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.

Design, green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents (.).

Abstract The aim of this research work was to investigate a series of novel 5,6-diaryl-1,2,4-triazines (3a–3q) containing 3-morpholinoethylamine side chain, and to address their antiplatelet activity by in vitro, ex vivo and in vivo methods. All compounds were synthesized by environment benign route and their structures were unambiguously confirmed by spectral data. Compounds (3l) and (3m) were confirmed by their single crystal X-ray structures. Out of all the synthesized compounds, 10 were found to be more potent in vitro than aspirin; six of them were found to be prominent in ex vivo assays and one compound (3d) was found to have the most promising antithrombotic profile in vivo. Moreover, compound (3d) demonstrated less ulcerogenicity in rats as compared to aspirin. The selectivity of the most promising compound (3d) for COX-1 and COX-2 enzymes was determined with the help of molecular docking studies and the results were correlated with the biological activity.

Ipilimumab: Melanoma and beyond

Sir, Recently, USFDA has approved ipilimumab, a fully human monoclonal antibody, under the trade name Yervoy for the treatment of metastatic melanoma. Metastatic melanoma is one of the most common type of cancers, standing fifth while considering the frequency of occurrence of cancers. It is a type of skin cancer that demographically affects individuals in the fourth or fifth decade of their life. Incidence of the disease increases with age, and older men have the highest propensity of suffering from this disease. Primary risk factor for the occurrence of metastatic melanoma is prolonged exposure to UV in the range of 280 to 320 nm. Pathophysiology involves abnormal growth and proliferation of melanocytes in areas exposed to UV radiation. Full thickness ablative procedures are the primary modalities of treatment in such conditions, followed by radiation therapy. However, for patients in an advanced stage of the disease, surgical excision is not curative and they require adjunctive chemotherapy and immunotherapy.[1] IL-2 has been approved by the USFDA for immunotherapy in patients with metastatic melanoma. IL-2 stimulates cytotoxic T-lymphocytes which ultimately cause tumor cell lysis. A response rate of about 16% is achieved with this modality of treatment. Another drug approved for the treatment of this condition is dacarbazine, achieving an overall response rate of up to 25%. However, both the alternatives have their own shortcomings (chronic side effects, need to monitor laboratory functions, relapsing disease).[1] To prevail over this condition, Bristol-Myers Squibb (BMS) has come up with ipilimumab which is a fully human monoclonal antibody (IgG1 isotype).