Levosimendan: mechanistic insight and its diverse future aspects in cardiac care.

Inotropic agents are generally recommended to use in patients with acute decompensated heart failure (HF) with reduced ejection fraction (HFrEF) concurrent to end-organ dysfunction. However, due to certain pharmacological limitations like developing life threatening arrhythmia and tolerance, cannot be employed as much as needed. Meanwhile, Calcium ion (Ca2+) sensitisers exhibits their inotropic action by increasing the sensitivity of the cardiomyocyte to intracellular Ca2+ ion and have been reported as emerging therapeutic alternative in HF cases. Levosimendan (LEVO) is an inodilator and with its unique pharmacology justifying its use in a wide range of cardiac alterations in HF particularly in undergoing cardiac surgery. It is also reported to be better than classical inotropes in maintaining cardiac mechanical efficacy and reducing congestion in acute HF with hypotension. This review paper was designed to compile various evidence about basic pharmacology and potential clinical aspects of LEVO in cardiac surgery and other HF associated alterations. This will benefit directly to the researcher in initiating research and to fill the gaps in the area of thrust.

Analgesic and Anticancer Activity of Benzoxazole Clubbed 2-Pyrrolidinones as Novel Inhibitors of Monoacylglycerol Lipase.

Ten benzoxazole clubbed 2-pyrrolidinones (11-20) as human monoacylglycerol lipase inhibitors were designed on the criteria fulfilling the structural requirements and on the basis of previously reported inhibitors. The designed, synthesized, and characterized compounds (11-20) were screened against monoacylglycerol lipase (MAGL) in order to find potential inhibitors. Compounds 19 (4-NO2 derivative) and 20 (4-SO2NH2 derivative), with an IC50 value of 8.4 and 7.6 nM, were found most active, respectively. Both of them showed micromolar potency (IC50 value above 50 µM) against a close analogue, fatty acid amide hydrolase (FAAH), therefore considered as selective inhibitors of MAGL. Molecular docking studies of compounds 19 and 20 revealed that carbonyl of 2-pyrrolidinone moiety sited at the oxyanion hole of catalytic site of the enzyme stabilized with three hydrogen bonds (~2 Å) with Ala51, Met123, and Ser122, the amino acid residues responsible for the catalytic function of the enzyme. Remarkably, the physiochemical and pharmacokinetic properties of compounds 19 and 20, computed by QikProp, were found to be in the qualifying range as per the proposed guideline for good orally bioactive CNS drugs. In formalin-induced nociception test, compound 20 reduced the pain response in acute and late stages in a dose-dependent manner. They significantly demonstrated the reduction in pain response, having better potency than the positive control gabapentin (GBP), at 30 mg/kg dose. Compounds 19 and 20 were submitted to NCI, USA, for anticancer activity screening. Compounds 19 (NSC: 778839) and 20 (NSC: 778842) were found to have good anticancer activity on SNB-75 cell line of CNS cancer, exhibiting 35.49 and 31.88% growth inhibition (% GI), respectively.

Pyrrolidin-2-one linked benzofused heterocycles as novel small molecule monoacylglycerol lipase inhibitors and antinociceptive agents.

Eighteen pyrrolidin-2-one linked benzothiazole, and benzimidazole derivatives (10-27) were designed and synthesized. The structure of the compounds was confirmed by elemental and spectral (IR, 1 H-NMR and MS) data analysis. All the compounds were screened by human monoacylglycerol lipase (hMAGL) inhibition assay. Three benzimidazole compounds, 22 (4-Cl phenyl), 23 (3-Cl,4-F phenyl) and 25 (4-methoxy phenyl) were found to be the most potent, having an IC50 value of 8.6, 8.0 and 9.4 nm, respectively. Among them, the halogen-substituted phenyl derivatives, compound 22 (4-Cl phenyl) and compound 23 (3-Cl,4-F phenyl), showed micromolar potency against fatty acid amide hydrolase (FAAH), having an IC50 value of 35 and 24 µm, respectively. Benzimidazole derivative having 4-methoxyphenyl substitution (compound 25) was found to be a selective MAGL inhibitor (IC50  = 9.4 nm), with an IC50 value above 50 µm against FAAH. In the formalin-induced nociception test, compound 25 showed a dose-dependent reduction of pain response in both acute and late phases. At 30 mg/kg dose, it significantly reduced the pain response and showed greater potency than the reference drug gabapentin (GBP).

Edaravone and benidipine protect myocardial damage by regulating mitochondrial stress, apoptosis signalling and cardiac biomarkers against doxorubicin-induced cardiotoxicity.

Background: Doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity. Edaravone is a potent-free radical scavenging agent used in cerebral ischaemia. Benidipine is a triple calcium channel blocker.Objective: We investigated the potential cardioprotective effects of edaravone and benidipine alone and their combination against DOX-induced cardiotoxicity. Cardiotoxicity was induced by administering six equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.Result: DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity. Cardiotoxity effect of DOX illustrated by significantly increased the cardiac biomarkers such as Cardiac troponin-I, Brain natriuretic peptide, Creatine kinase-MB in serum. Significant increased activation of TNF-α, Caspase-3 activity and myocardial infarct size in DOX-treated group. Histopathological evaluation also confirmed the DOX-induced cardiotoxicity. Pretreated with edaravone and benidipine was significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers. Furthermore, pretreated group showed decreased activation of TNF-α, Caspase-3 activity along with reduction in the myocardial infarct size. Histopathological evaluation also strengthened the above results.Conclusion: Taken together these results suggest that the pretreated with edaravone and benidipine have potential protective effect against DOX-induced cardiotoxicity.

Sacubitril and valsartan protect from experimental myocardial infarction by ameliorating oxidative damage in Wistar rats.

BACKGROUND: Sacubitril (SAC), a neprilysin inhibitor prevent degradation of neprilysin and activate cGMP signaling pathways leading to rise in blood volume concurrent to blood pressure by means of vasoactive peptides, adrenomedullin, and bradykinin. OBJECTIVE: The aim of this study was to evaluate the anti-ischemic effects of SAC through inhibiting neprilysin in isoproterenol (ISO) induced myocardial infarction (MI) in Wistar albino rats. ISO (85 mg/kg) was injected subcutaneously at the end of 14 days pre-treatment with SAC and valsartan (VAL). RESULT: Biochemical investigation revealed that SAC along with VAL significantly prevented the antioxidant enzymes (SOD, Catalase, GR, GPx, GST, and GSH) degradation and malondialdehyde (MDA) induced by ISO intoxication in Wistar rats. Along with this, cardiac biomarkers (LDH, CK-MB, ALT, AST, and ALP) were also significantly ameliorated by SACand VAL in ISO-treated rats. Concurrently, decreased infarction area (IA)and marked reduction in myofibril damage by SACand VAL further supported its protective benefits in MI. CONCLUSION: Taken together, the results suggest that inhibition of enzyme neprilysin alleviated the ISO induces myocardial damage mediated by its strong antioxidant potential.

Pitavastatin ameliorates myocardial damage by preventing inflammation and collagen deposition via reduced free radical generation in isoproterenol-induced cardiomyopathy.

Pitavastatin inhibits 3 hydroxy 3 methyl glutaryl coenzyme A (HMGCoA) reductase enzyme, preventing cholesterol synthesis along with elevating high density apolipoprotein A1 (Apo-A1). The present study was designed to evaluate cardioprotective potential of pitavastatin at 1 mg/kg/day and 3 mg/kg/day dose for 14 days in low dose isoproterenol (ISO) (5 mg/kg/day for 7 consecutive days) induced myocardial damage. ISO administration induced significant reduction in endogenous antioxidant enzymes like reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and raised thiobarbituric acid reactive substances (TBARS) indicating activated lipid peroxidation. Along with this, a significant increase in level of cardiac injury biomarkers vie, creatine kinase (CK-MB), lactate dehydrogenase (LDH), aspartate amino transferase (AST), tumor necrosis factor (TNF-α) and transforming growth factor (TGF-ß) as well as brain natriuretic peptide (BNP). Histological examination also revealed marked myocardial tissue damage in ISO treated rats. However, pretreatment with pitavastatin (3 mg/kg/day) significantly maintained nearly normal levels of cardiac biomarkers and oxidant antioxidant status as well as lipid peroxidation in ISO induced MI rats. Cardiac histological assessment and infarct size assessment also showed marked reduction in myocardial architecture alteration including infarct size as well as collagen deposition by pitavastatin that strongly supported biochemical findings. These observations strongly corroborate that pitavastatin prevents myocardial damages via up regulation of endogenous oxidants along with its hypocholesterolemic activity.

EGFR tyrosine kinase inhibition decreases cardiac remodeling and SERCA2a/NCX1 depletion in streptozotocin induced cardiomyopathy in C57/BL6 mice.

AIM: Epidermal growth factor receptor (EGFR) related reactive oxygen species (ROS) generation results in myocardial damage. We aimed to investigate the role of gefitinib (EGFR-tyrosine kinase inhibitor) in diabetic cardiomyopathy (DbCM). METHOD: DbCM was induced by injecting streptozotocin (55 mg/kg for 5 consecutive days) to C57/BL6 mice intraperitoneally. Diabetic C57/BL6 mice (fasting blood glucose level ≥ 250 mg/dl) were allocated into four study groups and treated with two doses of gefitinib (30 mg/kg and 350 mg/kg per day) as well as ramipril (3 mg/kg/day) for four weeks. KEY FINDINGS: We observed a significant correlation between persistent hyperglycaemia with cardiac remodeling and alterations in myocardial architecture. Gefitinib significantly prevented lipid peroxidation (MDA), damage of antioxidant enzymes like superoxide dismutase (SOD), Catalase, glutathione (GSH) and thioredoxin reductase (TrxR). Gefitinib also prevented hypertrophy of myocardium evidenced by reduced heart weight to body weight ratio and TGF­ß related collagen deposition. Gefitinib maintained cardiac biomarkers like lactate dehydrogenase (LDH), Creatine Kinase­MB, brain natriuretic peptide (BNP) and cardiac Troponin­I (cTroponinI) indicating reduced myocardial damage. Decreased sarcoplasmic endoplasmic reticulum Ca2 + ATPase2a (SERCA2a) and sodium­calcium exchanger-1 (NCX1) protein depletion after gefitinib administration indicated improved Ca2+ homeostasis during myocardial contractility. Histopathology and transmission electron microscopy clearly showed almost normal myofibrils and mitochondrial arrangements in gefitinib treated mice. SIGNIFICANCE: Our findings suggest that gefitinib protects myocardial damage in DbCM via balancing oxidant-antioxidant system, decreased collagen deposition as well as improved CKMB, BNP, cTroponinI and SERCA2a/NCX-1. Thereby, it indicated that gefitinib may be a potential therapeutic drug for treating DbCM.

Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors.

A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC50 = 2.2 µM) and EGFR binding (IC50 = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G2/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = -34.581 Kcal/mol.

Design, synthesis and molecular docking of thiazolidinedione based benzene sulphonamide derivatives containing pyrazole core as potential anti-diabetic agents.

We herein report the design, synthesis and molecular docking studies of 2,4-thiazolidinedione derivatives containing benzene sulphonyl group which are docked against the Peroxisome Proliferator Activated Receptor (PPARγ) target. Compound 7p was most effective in lowering the blood glucose level as compared to standard drugs pioglitazone and rosiglitazone. Compound 7p exhibited potent PPAR-γ transactivation of 61.2% with 1.9 folds increase in gene expression. In molecular docking studies 7p showed excellent interactions with amino acids TYR 473, SER 289, HIE 449, TYR 327, ARG 288, MET 329 and LEU 228. Compound 7p did not cause any damage to the liver without any noteworthy weight gain and may be considered as promising candidates for the development of new antidiabetic agents.

Renin Inhibition by Aliskiren Protects Rats Against Isoproterenol Induced Myocardial Infarction.

OBJECTIVE: Cardioprotective potential of aliskiren against isoproterenol-induced myocardial infarction was evaluated in this study. METHODS: Wistar albino rats (n=36) were randomly divided into six groups. Normal control rats received 1 ml saline, orally for 14 days and 0.1 ml saline, subcutaneously on 13th and 14th treatment day while the toxic group animals were administered with saline orally for 14 days and isoproterenol (85 mg/kg, subcutaneously) on 13th and 14th day. In different pre-treatment groups, aliskiren (30, 50 & 100 mg/kg, orally) was administered for 14 days along with isoproterenol (85 mg/kg, subcutaneously) on the last two days. Per se group animals were given aliskiren (100 mg/kg orally) for 14 days. Twenty-four hours after the last drug treatment, cardiac marker enzymes (creatine kinase-MB and lactate dehydrogenase), apoptotic marker enzyme (caspase-3) and antioxidative enzymes (malondialdehyde, reduced glutathione, superoxide dismutase and catalase) were estimated, along with histopathological analysis of myocardium. RESULTS: Isoproterenol treatment caused a significant increase in cardiac markers, malondialdehyde, and caspase-3 levels with a considerable decrease in reduced glutathione, superoxide dismutase and catalase enzyme levels. Aliskiren at 50 and 100 mg/kg doses significantly alleviated the increase of caspase-3 and cardiac marker enzymes as well as the changes in antioxidant enzymes, which was confirmed by histopathological analysis. Aliskiren (100 mg/kg) produced more pronounced protective effects than its other two doses. Moreover, the changes in per se group were insignificant as compared to normal control group. CONCLUSION: The present study thus provides an evidence for the protective effects of aliskiren in isoproterenol-induced myocardial infarction.

Tacrolimus-loaded nanostructured lipid carriers for oral delivery-in vivo bioavailability enhancement.

The aim of the present study was to assess the Tacrolimus (TL) loaded nanostructured lipid carrier for enhancement in solubilisation potential, pharmacokinetic parameters and lymphatic distribution profile. The solubilisation potential of TL-NLC was determined via application of dynamic lipolysis models, which simulate the GIT environment and the intestinal conditions. The in vitro lipolysis studies revealed significantly high solubilisation (***p<0.001) of TL-NLCs in aqueous phase (69.3%) in contrast to TL suspension (1.6%) and the results were very well corroborated with in vivo AUC values of the corresponding formulations (R2>0.99). The in vivo, lymphatic and organ distribution studies were performed in albino wistar rats. There was marked increase of 7.2 folds in relative bioavailability of TL-NLC in comparison to TL suspension. Furthermore, study findings demonstrated that the lymphatic distribution of TL-NLC was enhanced by 19.25 folds in comparison to TL suspension. The results of dynamic lipolysis, bioavailability, lymphatic and other organ distribution studies confirmed that incorporation of TL in hybrid of lipids with different fatty acid chain length could substantially improve its in vivo prospect.

Levosimendan reduces myocardial damage and improves cardiodynamics in streptozotocin induced diabetic cardiomyopathy via SERCA2a/NCX1 pathway.

AIMS: Diabetic cardiomyopathy (DCM) is one of the most common causes of mortality. Its pathophysiology is not fully understood and involve number of factors including, cardiovascular and metabolic disorders. The present study was designed to study the pathogenesis of DCM and to explore the effects of levosimendan along with either ramipril or insulin in the long term management of DCM. MATERIALS AND METHODS: Streptozotocin (STZ) was used to develop DCM in Wistar rats at the dose of 25mg/kg body weight for three consecutive days. Rats were randomly divided into 9 groups and treatments were started after 2weeks of STZ administration. KEY FINDINGS: Persistent hyperglycemia was observed in STZ treated rats, leading to significant contractile dysfunction as evidenced by decreased left ventricular pressure (LVP), +LV (dp/dt), -LV (dp/dt) as well as elevated Tau and LVEDP. Marked myocardial damage such as fibrosis, increased wall tension, depletion of contractile proteins were observed as evidenced by increased levels of TGF-ß, BNP, cTroponin-I, as well as decreased expression of SERCA2a and NCX1 proteins in diabetic rats. The levosimendan alone and also in combination with either ramipril or insulin significantly normalized the myocardial dysfunctions developed during the course of persistent hyperglycemia. SIGNIFICANCE: The study suggests that levosimendan treatment improves cardiac dysfunction significantly. Its combined use with ramipril proves better than with insulin in correcting myocardial performance as well as reduction in myocardial damage.

Edaravone, a potent free radical scavenger and a calcium channel blocker attenuate isoproterenol induced myocardial infarction by suppressing oxidative stress, apoptotic signaling and ultrastructural damage.

OBJECTIVES: In the present study, we investigated whether combination therapy of low-dose benidipine with the potent free radical scavenger edaravone has a cardioprotective effect against isoproterenol (ISO)-induced myocardial infarction (MI) in Wistar rats. METHODS: Rats were pretreated with concurrent doses of benidipine and edaravone (1 µg/kg/day + 1 mg/kg/day and 3 µg/kg/day + 3 mg/kg/day) by intravenous (i.v.) and intraperitoneal (i.p.) routes respectively for 28 days, followed by MI induction using ISO (85 mg/kg) by subcutaneous route for two days at 24 h intervals. After the treatment period, blood was withdrawn and the heart was preserved for biochemical estimations. RESULTS: The activities of the cardiac biomarkers (lactate dehydrogenase and creatine kinase-MB), and the level of malondialdehyde (MDA) significantly increased, while antioxidant markers (reduced glutathione, catalase, superoxidase dismutase, glutathione peroxidase, glutathione reductase) were significantly decreased in the ISO intoxicated group compared with the control group. Moreover, the level of C-reactive protein (CRP) and Caspase-3 activity significantly increased in ISO-intoxicated group. An ultrastructure study was also carried out. Pretreatment with a combination of benidipine and edaravone significantly attenuated the activities of the cardiac biomarkers and the level of MDA, and significantly increased the antioxidant markers compared with the ISO-intoxicated group. Furthermore, pretreatment with the combination of benidipine and edaravone significantly decreased the level of CRP and Caspase-3 activity as compared to the ISO-treated group. The ultrastructure study of myocardium revealed that pretreated groups preserved the mitochondrial shape, the membrane and its internal structures. CONCLUSION: Taken together these results suggest that the combination of benidipine and edaravone showed significant protective effect in ISO-induced MI.

Biodegradable intranasal nanoparticulate drug delivery system of risedronate sodium for osteoporosis.

CONTEXT: Osteoporosis (OP) is the most common metabolic bone disease predominantly found in elderly people. It is associated with reduced bone mineral density, results in a higher probability of fractures, especially of the hip, vertebrae, and distal radius. Worldwide prevalence of OP is considered a serious public health concern. OBJECTIVE: The purpose of the present work was to develop and evaluate polymeric nanoparticles (NPs) of risedronate sodium (RIS) for the treatment of OP using intranasal (IN) route in order to reduce peripheral toxic effects. MATERIALS AND METHODS: Polymeric NPs of RIS were prepared by nanoprecipitation methods. Formulations were developed and evaluated in context to in vitro drug release, ex vivo permeation, in vivo study, and biochemical studies. RESULTS AND DISCUSSIONS: The particles size, entrapment efficiency (EE) (%), and loading capacity (LC) (%) of optimized formulations were found to be 127.84 ± 6.33 nm, 52.65 ± 5.21, and 10.57 ± 1.48, respectively. Release kinetics showed diffusion-controlled, Fickian release pattern. Ex vivo permeation study showed RIS from PLGA-NPs permeated significantly (p < 0.05) through nasal mucosa. In vivo study showed a marked difference in micro-structure (trabeculae) in bone internal environment. Biochemical estimation of treated group and RIS PLGA indicated a significant recovery (p < 0.01) as compared with the toxic group. CONCLUSION: Polymeric NPs of RIS were prepared successfully using biodegradable polymer (PLGA). Intranasal delivery showed a good result in in vivo study. Thus PLGA-NPs have great potential for delivering the RIS for the treatment and prevention of OP after clinical evaluation in near future.

Brain delivery of buspirone hydrochloride chitosan nanoparticles for the treatment of general anxiety disorder.

The present work discusses the preparation, characterization and in vivo evaluation of thiolated chitosan nanoparticles (TCS-NPs) of buspirone hydrochloride (BUH) for brain delivery through intranasal route. TCS NPs were prepared by ionic gelation method and characterized for various parameters. The NPs formed were having particle size of 226.7±2.52nm with PDI 0.483±0.031. Drug entrapment efficiency (EE) and loading capacity (LC) were found to be 81.13±2.8 and 49.67±5.5%. The cumulative percentage drug permeation through nasal mucosa was 76.21%. Bioadhesion study carried out on porcine mucin and showed a bioadhesion efficiency of 90.218±0.134%. Nose-to-brain delivery of placebo NPs was investigated by confocal laser scanning microscopy (CLSM) technique using rhodamine-123 as a marker. The brain concentration achieved after intranasal administration of TCS-NPs was 797.46±35.76ng/ml with tmax 120min which was significantly higher than achieved after intravenous administration on BUH solution 384.15±13.42ng/ml and tmax of 120min and intranasal administration of BUH solution 417.77±19.24ng/ml and tmax 60min.

Edaravone protects rats against oxidative stress and apoptosis in experimentally induced myocardial infarction: Biochemical and ultrastructural evidence.

OBJECTIVES: The present study was designed to evaluate the cardioprotective potential of edaravone on oxidative stress, anti-apoptotic, anti-inflammatory and ultrastructure findings in isoproterenol (ISO) induced myocardial infarction (MI) in rats. METHODS: Rats were pretreated with edaravone (1, 3, 10 mg/kg body weight-1 day-1) intraperitoneally. MI was induced by subcutaneous administration of ISO (85 mg/kg body weight-1) at two doses with 24h interval. RESULTS: ISO treated rats showed significant increase in the levels of thiobarbituric acid reactive substances (TBARS) and decreased levels of reduced glutathione, glutathione perdoxidase, glutathione reductase and glutathione-S- transferase in the cardiac tissues. Moreover, significant increase in the levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), C--reactive protein and caspase-3 activity was observed in ISO treated group. Pretreatment of ISO intoxicated rats with edaravone showed significant decrease in the level of TBARS, increased activities of antioxidant enzymes and significantly decreased levels of LDH and CK-MB. Moreover, results also showed decreased C-reactive protein level, caspase-3 activity and maintained ultrastructure of the myocardial cells. DISCUSSION: Our study suggests that edaravone possess strong cardioprotective potential. Edaravone may have exhibited cardioprotective effects by restoring antioxidant defense mechanism, maintaining integrity of myocardial cell membrane, reducing apoptosis and inflammation against ISO induced MI and associated oxidative stress.

Benidipine prevents oxidative stress, inflammatory changes and apoptosis related myofibril damage in isoproterenol-induced myocardial infarction in rats.

OBJECTIVE: The effects of benidipine on oxidative stress and myocardial apoptosis were assessed in isoproterenol (ISO)-induced myocardial infarction (MI) in wistar rats. MATERIALS AND METHOD: Animals were pretreated with benidipine (1, 3, 10 µg/kg/day Body weight) intravenously for a period of 28 days. After pretreatment, ISO (85 mg/kg Body weight, subcutaneous) was injected in rats at an interval of 24 h to induce MI. Myocardial oxidative stress, cardiac biomarkers, apoptosis, inflammatory mediators, and ultrastructural architecture of the cardiac tissue were assessed in ISO-induced MI in rats. RESULT: Significant variation in the level of TBA, antioxidant enzymes (GSH, CAT, SOD, GPx, GRx, GST) in myocardium, cardiac biomarkers (CK-MB, LDH) in serum, Caspase-3, C-reactive protein (CRP), and alteration in ultrastructural architecture of cardiac tissue confirmed the cardiotoxicity induced by ISO. Pretreatment with benidipine preserved the lipid peroxide and antioxidant enzymes, and furthermore showed maintained levels of myocardial biomarker, CRP and caspase-3. Ultrastructure architecture of cardiac tissue was also found to be well preserved. CONCLUSION: The present study suggested cardioprotective effect of benidipine which may possibly be due to its antioxidant activity and antiapoptotic nature.

Role of Multiparameter Analysis of AgNORs in FNA Smears of Thyroid Swellings in Differentiating Benign and Malignant Lesions.

Background. The aim of this study is to assess the role of multiparameter analysis of silver (Ag)-stained nucleolar organizer regions (AgNORs) technique on aspiration smears of thyroid swellings to distinguish between benign and malignant lesions. Materials and Methods. Aspiration smears from 166 cases of thyroid swellings were examined. Diagnosis was confirmed by histology in 61 cases. AgNOR staining was done on FNA smears according to silver-staining protocol proposed by the International Committee for AgNOR quantification. Multiparameter analysis of AgNORs such as mAgNOR, pAgNOR, and AgNOR size grade was done on 50-100 cells under oil immersion lens. Results. AgNOR parameter of benign and malignant thyroid lesions was compared and was found to be statistically significant. Out of 157 satisfactory AgNOR stained cases, 148 (94.3%) were benign lesions and 9 (5.7%) cases were malignant lesions. In AgNOR analysis, sensitivity was found to be 83.33%, specificity 100%, PPV 100%, NPV 98.21%, and accuracy was 98.36%. Conclusions. AgNOR analysis in the FNA smears is a simple, sensitive, and cost-effective method for differentiating benign from malignant thyroid swellings.