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Sample records for ranolazine rasagiline mesilate

  1. Rasagiline

    National Research Council Canada - National Science Library

    Dina A Palmese; Aneta Grauer

    2004-01-01

      At this time, rasagiline's future role in the treatment of PD is unclear. Rasagiline has demonstrated moderate results over placebo in clinical trials evaluating its use as monotherapy in early PD therapy...

  2. Ranolazine Therapy in Cardiac Arrhythmias.

    Science.gov (United States)

    Pulford, Brian R; Kluger, Jeffrey

    2016-09-01

    Ranolazine is an antianginal medication originally granted approval by the U.S. Food and Drug Administration for therapeutic use in 2006. Since its introduction into the U.S. market, there have been multiple trials and clinical case reports that demonstrate ranolazine may be effective in the prevention and treatment of both atrial and ventricular arrhythmias, including postoperative atrial fibrillation following coronary artery bypass graft (CABG) surgery. More recently, the combination of dronedarone with ranolazine has demonstrated in initial studies to have a synergistic effect in the reduction of burden of atrial fibrillation. This article will review the basic pharmacology of ranolazine, the studies demonstrating use of ranolazine in atrial and ventricular arrhythmias, the limitations to the use of ranolazine as antiarrhythmic therapy, and explore the synergistic effect with other agents in the suppression of arrhythmias. © 2016 Wiley Periodicals, Inc.

  3. Rasagiline

    Science.gov (United States)

    ... the nervous system causing a fixed face without expression, tremor at rest, slowing of movements, walking with ... It is important for you to keep a written list of all of the prescription and nonprescription ( ...

  4. Ranolazine for the treatment of atrial fibrillation.

    Science.gov (United States)

    Rosa, Gian Marco; Dorighi, Ulrico; Ferrero, Simone; Brunacci, Michele; Bertero, Giovanni; Brunelli, Claudio

    2015-06-01

    Atrial fibrillation (AF) is a frequent occurrence with advancing age and is associated with increased morbidity and mortality. Unfortunately, the currently available AF therapies have a great deal of side effects. In this review, the authors discuss the evidence upon which the use of Ranolazine as an anti-arrhythmic drug is based. Specifically, the authors review the Phase I-III trials that studied ranolazine as potential treatment for AF. They also discuss the efficacy, safety, tolerability and side effects and compare the MERLIN TIMI 36, HARMONY and ROLE trials. Although ranolazine is considered an anti-angina drug, it may also be, according to the available data, used in patients with AF. Ranolazine has anti-AF efficacy, both alone or in combination with other drugs such as amiodarone and dronedarone. Indeed, its efficacy has been demonstrated in various settings such as the termination of paroxysmal AF, the facilitation of AF electrical cardioversion, and postoperative AF prevention. Although there is a great deal of evidence from pioneering experimental studies, the clinical evidence of the AF-suppressing effect of ranolazine is derived from studies with small sample size or from secondary analyses. A better understanding of the role of ranolazine as an anti-AF drug will be obtained through larger, prospective, placebo-controlled clinical trials in different populations.

  5. Rasagiline : niet voor elke nieuwe parkinsonpatiënt

    NARCIS (Netherlands)

    Laar, T. van; Boon, A.J.; Bloem, B.R.

    2010-01-01

    Rasagiline is a MAO-B inhibitor that is currently registered for the symptomatic treatment of Parkinson disease. The ADAGIO trial studied the potential disease-modifying properties of rasagiline in 1100 patients with Parkinson disease, using an innovative 'delayed start' design. Patients were

  6. Adjunctive therapy in Parkinson's disease: the role of rasagiline

    Directory of Open Access Journals (Sweden)

    Gaines KD

    2012-07-01

    Full Text Available Kathryn D Gaines,1 Vanessa K Hinson21Department of Neurology, Aurora Advanced Healthcare, Milwaukee, WI, 2Department of Neurosciences, Movement Disorders Program, Medical University of South Carolina, Charleston, SC, USAAbstract: Parkinson's disease is the second most common neurodegenerative disorder, currently affecting 1.5 million people in the US. In this review, we describe the diagnostic and pathological features of Parkinson's disease, as well as its clinical course. We then review pharmacologic treatments for the disease, with a particular focus on therapies adjunctive to levodopa and specifically the role of rasagiline. We review the four pivotal rasagiline trials, and discuss rasagiline and its use as adjunctive therapy for Parkinson's disease. Finally, we discuss potential side effects, drug interactions, and other practical aspects concerning the use of rasagiline in Parkinson's disease.Keywords: Parkinson's disease, treatment, rasagiline, clinical trials

  7. Solid Material Characterization of Freeze-Dried Gabexate Mesilate Containing D-Mannitol by Terahertz Spectroscopy

    Science.gov (United States)

    Otsuka, Makoto; Fukura, Naomi; Abe, Hiroyuki

    2013-02-01

    The purpose of the present study is to characterize polymorphic forms and intermolecular interactions of freeze-dried pharmaceuticals containing additives by terahertz (THz) spectroscopy as a, process analytical technology tool in the pharmaceutical industry. Freeze-dried gabexate mesilate/D-mannitol products containing 17-75 mol% gabexate mesilate were obtained using a conventional freeze-dryer. Freeze-dried products and physical mixtures of gabexate mesilate and mannitol with various drug contents were characterized by X-ray powder diffraction (XRD) analysis, differential scanning calorimetry (DSC) and THz. The XRD and DSC results indicated that freeze-dried mannitol was obtained as a mixture of β and δ forms of mannitol from a plain solution, but the freeze-dried product of the gabexate mesilate/mannitol mixture consisted of crystalline gabexate mesilate and the pure δ form of mannitol. Similar to the results of XRD and DSC, THz before the freeze-drying of gabexate mesilate was almost the same as that after. In contrast, the THz of mannitol before freeze-drying had specific peaks due to the β form, but that after had peaks due to δ and β forms. To clarify the polymorphic forms of the freeze-dried products, the THz were analyzed by least squares regression. The calibration models used to predict the amounts of gabexate mesilate and mannitol had sufficient accuracy and linearity, respectively. Two decomposed THz in FGMs had specific peaks due to the δ form of mannitol or gabexate mesilate.

  8. Linezolid and Rasagiline - A culprit for serotonin syndrome

    National Research Council Canada - National Science Library

    Hisham, Mohamed; Sivakumar, Mundalipalayam N; Nandakumar, V; Lakshmikanthcharan, S

    2016-01-01

    A 65-year-old female patient was admitted to the hospital for cellulitis. She had a history of diabetes mellitus and parkinsonism on levodopa/carbidopa, rasagiline, ropinirole, trihexyphenidyl, amantadine, metformin, and glipizide...

  9. Rasagiline in treatment of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Lakshmi Nayak

    2008-03-01

    Full Text Available Lakshmi Nayak1, Claire Henchcliffe21Department of Neurology; 2Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, USAAbstract: Rasagiline (N-propargyl-1 (R-aminoindan is a novel propargylamine, irreversible, selective monoamine oxidase inhibitor for treatment of Parkinson’s disease (PD, a progressive condition associated with degeneration of dopaminergic neurons in the substantia nigra. Rasagiline inhibits striatal dopamine metabolism, thereby providing relief from motor symptoms of PD. It may be dosed once daily and, unlike selegiline, it is metabolized to non-amphetamine compounds. In a large clinical trial, rasagiline has proved effective, safe, and well tolerated in early PD as monotherapy. In two phase III clinical trials in advanced PD with motor fluctuations, rasagiline as an adjunct to levodopa significantly decreases “off” time. In animal models of PD, data supports a neuroprotective effect of rasagiline, and its active metabolite aminoindan. Analysis of delayed-start clinical trial suggests the potential for disease modification, and further trials are examining this effect.Keywords: rasagiline, monoamine oxidase inhibitor, propargylamine, Parkinson’s disease

  10. Ranolazine recruits muscle microvasculature and enhances insulin action in rats.

    Science.gov (United States)

    Fu, Zhuo; Zhao, Lina; Chai, Weidong; Dong, Zhenhua; Cao, Wenhong; Liu, Zhenqi

    2013-10-15

    Ranolazine, an anti-anginal compound, has been shown to significantly improve glycaemic control in large-scale clinical trials, and short-term ranolazine treatment is associated with an improvement in myocardial blood flow. As microvascular perfusion plays critical roles in insulin delivery and action, we aimed to determine if ranolazine could improve muscle microvascular blood flow, thereby increasing muscle insulin delivery and glucose use. Overnight-fasted, anaesthetized Sprague-Dawley rats were used to determine the effects of ranolazine on microvascular recruitment using contrast-enhanced ultrasound, insulin action with euglycaemic hyperinsulinaemic clamp, and muscle insulin uptake using (125)I-insulin. Ranolazine's effects on endothelial nitric oxide synthase (eNOS) phosphorylation, cAMP generation and endothelial insulin uptake were determined in cultured endothelial cells. Ranolazine-induced myographical changes in tension were determined in isolated distal saphenous artery. Ranolazine at therapeutically effective dose significantly recruited muscle microvasculature by increasing muscle microvascular blood volume (∼2-fold, P < 0.05) and increased insulin-mediated whole body glucose disposal (∼30%, P = 0.02). These were associated with an increased insulin delivery into the muscle (P < 0.04). In cultured endothelial cells, ranolazine increased eNOS phosphorylation and cAMP production without affecting endothelial insulin uptake. In ex vivo studies, ranolazine exerted a potent vasodilatatory effect on phenylephrine pre-constricted arterial rings, which was partially abolished by endothelium denudement. In conclusion, ranolazine treatment vasodilatates pre-capillary arterioles and increases microvascular perfusion, which are partially mediated by endothelium, leading to expanded microvascular endothelial surface area available for nutrient and hormone exchanges and resulting in increased muscle delivery and action of insulin. Whether these actions

  11. Emerging clinical role of ranolazine in the management of angina

    Directory of Open Access Journals (Sweden)

    David S Vadnais

    2010-10-01

    Full Text Available David S Vadnais, Nanette K WengerDivision of Cardiology, Emory University School of Medicine, Atlanta, Georgia, USAAbstract: Chronic stable angina is an exceedingly prevalent condition with tremendous clinical, social, and financial implications. Traditional medical therapy for angina consists of beta-blockers, calcium channel blockers, and nitrates. These agents decrease myocardial oxygen demand and ischemia by reducing heart rate, lowering blood pressure, and/or optimizing ventricular loading characteristics. Unique in its mechanism of action, ranolazine is the first new antianginal agent approved for use in the US for chronic angina in over 25 years. By inhibiting the late inward sodium current (INa, ranolazine prevents pathologic intracellular calcium accumulation that leads to ischemia, myocardial dysfunction, and electrical instability. Ranolazine has been proven in multiple clinical trials to reduce the symptoms of angina safely and effectively and to improve exercise tolerance in patients with symptomatic coronary heart disease. These benefits occur without reduction in heart rate and blood pressure or increased mortality. Although ranolazine prolongs the QTc, experimental data indicate that ranolazine may actually be antiarrhythmic. In a large acute coronary syndrome clinical trial, ranolazine reduced the incidence of supraventricular tachycardia, ventricular tachycardia, new-onset atrial fibrillation, and bradycardic events. Additional benefits of ranolazine under investigation include reductions in glycosylated hemoglobin levels and improved left ventricular function. Ranolazine is a proven antianginal medication in patients with symptomatic coronary heart disease, and should be considered as an initial antianginal agent for those with hypotension or bradycardia.Keywords: chronic angina, myocardial ischemia, ranolazine, pharmacotherapy, antianginal, sodium current

  12. Cognitive Effects of Rasagiline in Mild-to-Moderate Stage Parkinson's Disease Without Dementia.

    Science.gov (United States)

    Frakey, Laura L; Friedman, Joseph H

    2017-01-01

    The authors studied the effects of rasagiline on cognition in a sample of 50 nondemented patients with mild to moderate Parkinson's disease (PD) using a double-blind, placebo controlled design. Cognition and motor symptoms were assessed at baseline and after 6 months of receiving either rasagiline or placebo. Participants receiving rasagiline showed improvement in their motor symptoms of PD compared to participants receiving placebo. No significant changes in performance on neuropsychological measures of cognition were observed between the groups. Rasagiline is an effective treatment for the motor symptoms of PD. Rasagiline did not appear to affect cognition during this 6-month study.

  13. Rasagiline for the treatment of Parkinson's disease: an update.

    Science.gov (United States)

    Stocchi, Fabrizio; Fossati, Chiara; Torti, Margherita

    2015-01-01

    Rasagiline is a potent, selective, irreversible Monoamine Oxidase-B (MAO-B) inhibitor, developed to prolong the action of dopamine in the brain. It has been demonstrated that rasagiline can improve motor and some non-motor symptoms (NMS) in both early and advanced Parkinson's disease (PD) patients, and it also exhibits neuroprotective and antiapoptotic properties. The objective of this review, performed by a Medline search on the most recent papers investigating the therapeutic effects of rasagiline, is to describe the role of rasagiline in the schedule of treatment of early and advanced PD patients. It will then focus on its role in treating NMS, fatigue, early morning off and cognitive decline, which heavily affect quality of life for PD patients. Rasagiline is an efficacious, well-tolerated, easy to use drug. The drug has been extensively studied and has proven its efficacy in monotherapy and in combination with any other antiparkinsonian therapy. It proved to be efficacious in reducing 'off' time and in improving early morning 'off' but also some NMS, thus enhancing the therapeutic approach to PD.

  14. Update on ranolazine in the management of angina

    Science.gov (United States)

    Codolosa, J Nicolás; Acharjee, Subroto; Figueredo, Vincent M

    2014-01-01

    Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome)-TIMI (Thrombolysis In Myocardial Infarction) 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life. PMID:25028555

  15. Update on ranolazine in the management of angina

    Directory of Open Access Journals (Sweden)

    Codolosa JN

    2014-06-01

    Full Text Available J Nicolás Codolosa,1 Subroto Acharjee,1 Vincent M Figueredo1,2 1Einstein Center for Heart and Vascular Health, Einstein Medical Center, 2Jefferson Medical College, Philadelphia, PA, USA Abstract: Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA remains prevalent, and the goal of treatment is control of symptoms and reduction in cardiovascular events. Ranolazine is a selective inhibitor of the late sodium current in myocytes with anti-ischemic and metabolic properties. It was approved by the US Food and Drug Administration in 2006 for use in patients with CSA. Multiple, randomized, placebo-controlled trials have shown that ranolazine improves functional capacity and decreases anginal episodes in CSA patients, despite a lack of a significant hemodynamic effect. Ranolazine did not improve cardiovascular mortality or affect incidence of myocardial infarction in the MERLIN (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-TIMI (Thrombolysis In Myocardial Infarction 36 trial, but significantly decreased the incidence of recurrent angina. More recently, ranolazine has been shown to have beneficial and potent antiarrhythmic effects, both on supraventricular and ventricular tachyarrhythmias, largely due to its inhibition of the late sodium current. Randomized controlled trials testing these effects are underway. Lastly, ranolazine appears to be cost-effective due to its ability to decrease angina-related hospitalizations and improve quality of life. Keywords: ranolazine, chronic stable angina, coronary artery disease

  16. Ranolazine attenuation of CFA-induced mechanical hyperalgesia.

    Science.gov (United States)

    Casey, Gregory P; Roberts, Jomar S; Paul, Dennis; Diamond, Ivan; Gould, Harry J

    2010-01-01

    To determine whether ranolazine, a new anti-angina medication, could be an effective analgesic agent in complete Freund's adjuvant-induced inflammatory pain. Plantar injection of complete Freund's adjuvant (CFA) produces an extended period of hyperalgesia that is associated with a dramatic up-regulation of Na(v) 1.7 sodium channels in populations of large and small dorsal root ganglion neurons related to the injection site. Ranolazine appears to produce its anti-angina effect through blocking the late sodium current associated with the voltage-gated sodium channel, Na(v) 1.5. Because ranolazine also inhibits Na(v) 1.7, and 1.8, we sought to determine whether it could be an effective analgesic agent in CFA-induced inflammatory pain. Baseline determinations of withdrawal from thermal and mechanical stimulation were made in Sprague-Dawley rats ( approximately 300-350 x g). Following determination of baseline, one hindpaw in each group was injected with 0.1 mL of CFA. The contralateral paw received saline. Thermal and mechanical stimulation was repeated on the third day post-injection. Vehicle (0.9% isotonic saline; pH 3.0) or ranolazine was then administered in randomized and blinded doses either by intraperitoneal (ip) injection (0, 10, 20, and 50 mg/kg) or by oral gavage (po; 0, 20, 50, 100, and 200 mg/kg). Animals were again tested 30 minutes (ip) and 1 hour (po) after drug administration. Ranolazine produced dose-dependant analgesia on mechanical allodynia induced by CFA injection, but had no effect on thermal hyperalgesia. Ranolazine's potential as a new option for managing both angina and chronic inflammatory pain warrants further study.

  17. Novel Use of Ranolazine as an Antiarrhythmic Agent in Atrial Fibrillation.

    Science.gov (United States)

    White, C Michael; Nguyen, Elaine

    2017-03-01

    To review the limitations of current antiarrhythmic drugs in atrial fibrillation (AF) and discuss the rationale and clinical trials supporting the use of ranolazine in AF. MEDLINE was searched from 1980 to September 2016 using the terms ranolazine, atrial fibrillation, coronary artery bypass grafting, and valve surgery. English-language studies and reviews assessing antiarrhythmic drugs, including ranolazine, were incorporated. The use of ranolazine monotherapy has been evaluated in 2 clinical trials. In the RAFFAELLO trial, higher doses of ranolazine showed a trend toward lower AF recurrence versus placebo ( P = 0.053), but further evidence is needed to support its use as a sole therapeutic agent. Ranolazine has shown utility in a limited number of studies as an adjunctive agent, which is critical for those in whom standard therapy is inadequate or the adverse event profile precludes optimized standard therapy. In the HARMONY trial, ranolazine 750 mg and dronedarone 225 mg twice daily reduced the AF burden by 59.1% from baseline ( P = 0.008 vs placebo). In a trial by Koskinas and colleagues, patients receiving ranolazine 1500 mg once and intravenous amiodarone had a higher conversion rate than those receiving amiodarone alone ( P = 0.024). There are also promising studies for the prevention and treatment of post-cardiothoracic surgery AF, which require further investigation. Ranolazine's pharmacological properties and available evidence suggest potential for its use in AF.

  18. The role of rasagiline in the treatment of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Julie Leegwater-Kim

    2010-05-01

    Full Text Available Julie Leegwater-Kim1, Elena Bortan21Tufts University School of Medicine and Department of Neurology, Lahey Clinic, Burlington, MA, USA; 2Department of Neurology, Lahey Clinic, Burlington, MA, USAAbstract: Parkinson’s disease (PD is the second most common neurodegenerative disorder, affecting 1% to 2% of people older than 60 years. Treatment of PD consists of symptomatic therapies while neuroprotective strategies have remained elusive. Rasagiline is a novel, potent, and irreversible monoamine oxidase type B (MAO-B inhibitor which has been approved for treatment of PD. Rasagiline inhibits MAO-B more potently than selegiline and has the advantage of once-daily dosing. In several large, randomized, placebo-controlled trials, rasagiline has demonstrated efficacy as monotherapy in early PD and as adjunctive therapy in advanced PD. In addition, rasagiline has been shown to have neuroprotective effects in in vitro and in vivo studies. The recently completed delayed-start ADAGIO (Attenuation of Disease Progression with Azilect Given Once-daily trial suggests a potential disease-modifying effect for rasagiline 1 mg/day, though the clinical import of this finding has yet to be established.Keywords: rasagiline, monoamine oxidase inhibitor, Parkinson’s disease

  19. Rasagiline ameliorates olfactory deficits in an alpha-synuclein mouse model of Parkinson's disease.

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    Géraldine H Petit

    Full Text Available Impaired olfaction is an early pre-motor symptom of Parkinson's disease. The neuropathology underlying olfactory dysfunction in Parkinson's disease is unknown, however α-synuclein accumulation/aggregation and altered neurogenesis might play a role. We characterized olfactory deficits in a transgenic mouse model of Parkinson's disease expressing human wild-type α-synuclein under the control of the mouse α-synuclein promoter. Preliminary clinical observations suggest that rasagiline, a monoamine oxidase-B inhibitor, improves olfaction in Parkinson's disease. We therefore examined whether rasagiline ameliorates olfactory deficits in this Parkinson's disease model and investigated the role of olfactory bulb neurogenesis. α-Synuclein mice were progressively impaired in their ability to detect odors, to discriminate between odors, and exhibited alterations in short-term olfactory memory. Rasagiline treatment rescued odor detection and odor discrimination abilities. However, rasagiline did not affect short-term olfactory memory. Finally, olfactory changes were not coupled to alterations in olfactory bulb neurogenesis. We conclude that rasagiline reverses select olfactory deficits in a transgenic mouse model of Parkinson's disease. The findings correlate with preliminary clinical observations suggesting that rasagiline ameliorates olfactory deficits in Parkinson's disease.

  20. Evaluation of different substrates for inkjet printing of rasagiline mesylate

    DEFF Research Database (Denmark)

    Genina, Natalja; Janßen, Eva Maria; Breitenbach, Armin

    2013-01-01

    The main goal of the present study was to evaluate applicability of the different model substrates, namely orodispersible films (ODFs), porous copy paper sheets, and water impermeable transparency films (TFs) in preparation of the inkjet-printed drug-delivery systems. Rasagiline mesylate (RM......) was used as a low-dose active pharmaceutical ingredient (API). Flexible doses of the drug in a single unit were obtained by printing several subsequent layers on top of the already printed ones, using an off-the-shelf consumer thermal inkjet (TIJ) printer. The produced drug-delivery systems were subjected...... to microscopic and chemical analysis together with solid-state characterization and content uniformity studies. The results revealed that RM recrystallized on the surface of ODFs and TFs, and the printed crystals were arranged in lines. No drug crystals were detected after printing on the surface of the copy...

  1. Rasagiline: a review of its use in the treatment of idiopathic Parkinson's disease.

    Science.gov (United States)

    Hoy, Sheridan M; Keating, Gillian M

    2012-03-26

    Rasagiline (Azilect®), a selective, irreversible, monoamine oxidase-B inhibitor, is available in the EU, the US and in several other countries worldwide, including Canada and Israel. It is indicated for the treatment of idiopathic Parkinson's disease as monotherapy or as adjunctive therapy to levodopa in patients [corrected]with end-of-dose fluctuations in the EU and for the treatment of adult patients with the signs and symptoms of idiopathic Parkinson's disease in the US. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of rasagiline as monotherapy or as adjunctive therapy to levodopa in patients with Parkinson's disease. Oral rasagiline as monotherapy or as adjunctive therapy to levodopa was effective in the symptomatic treatment of adult patients with Parkinson's disease participating in double-blind, placebo-controlled, multinational studies. In patients with early Parkinson's disease, monotherapy with rasagiline 1 mg/day (recommended dosage) significantly slowed the rate of worsening (i.e. an increase in the Unified Parkinson's Disease Rating Scale [UPDRS] score) in the ADAGIO and TEMPO studies, with the results from the ADAGIO study for rasagiline 1 mg/day suggesting a slowing of clinical progression. However, at the higher dosage of 2 mg/day, rasagiline met the primary endpoint in the TEMPO study and the first, but not the second, of three hierarchical primary endpoints in the ADAGIO study. Compared with delayed-start rasagiline monotherapy, early initiation was associated with a slower long-term progression of the clinical signs and symptoms of Parkinson's disease in the TEMPO study. As adjunctive therapy to levodopa in the LARGO and PRESTO studies, rasagiline 0.5 and/or 1 mg/day significantly reduced the total daily 'off' time (primary efficacy endpoint) and significantly improved the Clinical Global Impression score, the UPDRS activities of daily living subscale score during 'off' time and the UPDRS

  2. Rasagiline for sleep disorders in patients with Parkinson's disease: a prospective observational study.

    Science.gov (United States)

    Schettino, Carla; Dato, Clemente; Capaldo, Guglielmo; Sampaolo, Simone; Di Iorio, Giuseppe; Melone, Mariarosa Ab

    2016-01-01

    Rasagiline is a selective, irreversible monoamine oxidase B inhibitor that ameliorates the symptoms of Parkinson's disease (PD) by inhibiting striatal dopamine metabolism. There is also evidence that monoamine oxidase B inhibitors increase melatonin levels in the pineal gland and may have a beneficial effect on sleep disorders, which are a common feature in patients with PD. This single-center, prospective, observational, 12-week study compared the effect of combination therapy with levodopa 200-300 mg/d + rasagiline 1 mg/d (n=19) with levodopa 200-300 mg/d alone (n=19) in the treatment of sleep disorders in patients with idiopathic PD. After 12 weeks' treatment, mean sleep latency was significantly (Psleep latency from baseline was significantly (P=0.001) greater in patients receiving levodopa + rasagiline than in patients receiving levodopa alone. Similarly, at the end of the study, the mean total sleep time was significantly (P=0.002) longer and the improvement from baseline in mean total sleep time was significantly (P=0.026) greater in patients receiving levodopa + rasagiline than levodopa alone. There were no significant differences between treatment groups for the mean number of awakenings reported at week 12 nor the change from baseline to week 12 in mean number of awakenings. Adding rasagiline to levodopa improved sleep outcomes and may be an appropriate option for patients with PD experiencing sleep disorders.

  3. Efficacy of ranolazine in preventing atrial fibrillation following cardiac surgery: Results from a meta-analysis

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    Chintan Trivedi, MD, MPH

    2017-06-01

    Conclusions: Ranolazine may prove beneficial in POAF prevention following cardiac surgeries. Although the pooled treatment effect is quite impressive with a reduction of more than 50% of risk of developing POAF, small number of studies and variation in ranolazine dose regimen in each study make our results inconclusive, but worthy of further investigation. That is why this result has to be interpreted as only hypothesis generating, rather than conclusion drawing.

  4. Drug Interaction between Sirolimus and Ranolazine in a Kidney Transplant Patient

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    Joanna C. Masters

    2014-01-01

    Full Text Available Purpose. The case of a kidney transplant recipient who experienced a probable drug interaction between sirolimus and ranolazine is reported. Summary. The narrow therapeutic window of immunosuppressive therapy in transplant recipients requires close monitoring for potential drug-drug interactions. The patient, a 57-year-old Caucasian male kidney transplant recipient, was stable for years on sirolimus as his primary immunosuppressive agent and had a history of chronic angina, for which he was prescribed ranolazine. Upon addition and dose escalation of ranolazine, whole blood sirolimus levels more than tripled, rising to immeasurably high concentrations. After holding sirolimus on multiple occasions and reducing dosage more than 50%, blood levels returned to therapeutic range, while continuing ranolazine. Conclusion. Since ranolazine is a documented P-GP and CYP3A inhibitor, and sirolimus a known substrate for both pathways, it is proposed that ranolazine inhibition of P-GP and CYP3A4 contributed to the significant elevation in sirolimus exposure. No alternative causes for the rise in sirolimus exposure were found, and assessment with the Drug Interaction Probability Scale finds this interaction to be probable. Clinicians should be aware of the potential for this interaction to cause elevated sirolimus exposure and subsequent increase in clinical effect or toxicity, in this case overimmunosuppression.

  5. From a Parkinson's disease expert: Rasagiline and the Future of Therapy

    Directory of Open Access Journals (Sweden)

    Lakhan Shaheen E

    2007-07-01

    Full Text Available Abstract John Finberg is a professor of pharmacology at the Faculty of Medicine, Technion – Israel Institute of Technology, home of Israel's two Nobel laureates. He and his colleague Prof. Moussa Youdim were instrumental in the early clinical development of the anti-Parkinson drug rasagiline, which gained UK- and EU-marketing authorization in 2005 and US FDA approval in 2006. In our interview, Finberg reflects on his clinical research to develop rasagiline as a commercial drug and its proposed pharmacological mechanisms of action. Moreover, he elucidates the current state of anti-Parkinson drug discovery and offers direction for future research.

  6. Stability of gabexate mesilate products: Influence of the addition of mannitol.

    Science.gov (United States)

    Sakurai, Miyuki; Abe, Hiroyuki; Okamura, Noboru; Inoue, Yohei; Akiyoshi, Takeshi; Matsuyama, Kenji; Uchida, Takahiro; Otsuka, Makoto

    2010-01-01

    Gabexate mesilate is a non-peptide protease inhibitor, developed in Japan, which is used in the treatment of acute pancreatitis and disseminated intravascular coagulation. This compound is readily hydrolyzed as it has ester bonds in its structure. It is now out of patent in Japan and there are many generic versions on the market. The crystal structure and the hydrolysate content of the branded product and nine generic versions were evaluated by X-ray diffractometry, thermal analysis and HPLC. The results showed that generic products containing mannitol as an additive had a higher content of hydrolysate as an impurity than the branded product or generic products formulated without mannitol, suggesting that the crystal structure might be altered and stability impaired in mannitol-containing drug products.

  7. Reversed-Phase UHPLC Enantiomeric Separation of Rasagiline Salts Using a Chiralpak® AGP Column

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    Nagarajan Balaji

    2017-07-01

    Full Text Available We report the first rapid ultra-high performance liquid chromatographic (UHPLC enantiomeric reversed-phase separation of rasagiline mesylate and its tartrate salts using a Chiralpak® AGP column (50 mm × 2.1 mm, 5 μm as a stationary phase. This method was developed as an alternative to the usage of previously reported normal-phase chiral LC columns for isomer separation. Our method is based on an isocratic approach using a mixture of ammonium acetate and isopropyl alcohol (90:10, v/v as the mobile phase (0.6 mL/min flow rate. The detection limit (at a detection wavelength of 210 nm and quantification limit for the rasagiline enantiomers were 0.06 and 0.2 μg/mL, respectively. This method is compatible with the UHPLC-MS technique. The successful separation of rasagiline and its enantiomer was confirmed by determining the corresponding specific optical rotation values. Our method will be applicable for detecting rasagiline enantiomers during the control of manufacturing processes, and for use in rapid analysis for quality control in pharmaceutical industry to obtain optically pure pharmaceutical substances. This method was validated in terms of its precision, limit of detection, limit of quantification, linearity, accuracy, robustness, ruggedness, specificity, forced degradation, and solution stability, according to International Council on Harmonization Validation Guidelines Q2 (R1.

  8. Role of rasagiline in treating Parkinson’s disease: effect on disease progression

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    Irene A Malaty

    2009-05-01

    Full Text Available Irene A Malaty, Hubert H FernandezUniversity of Florida Movement Disorders Center, Gainesville, FL, USAAbstract: Rasagiline is a second generation, selective, irreversible monoamine oxidase type B (MAO-B inhibitor. It has demonstrated efficacy in monotherapy for early Parkinson’s disease (PD patients in one large randomized, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson’s Disease Outpatients, and has shown ability to reduce off time in more advanced PD patients with motor fluctuations in two large placebo-controlled trials (Parkinson’s Rasagiline: Efficacy and Safety in the Treatment of “Off”, and Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily. Preclinical data abound to suggest potential for neuroprotection by this compound against a variety of neurotoxic insults in cell cultures and in animals. The lack of amphetamine metabolites provides an advantage over the first generation MAO-B inhibitor selegiline. One large trial has investigated the potential for disease modification in PD patients (Attenuation of Disease progression with Azilect Given Once-daily and preliminary results maintain some possible advantage to earlier initiation of the 1 mg/day dose. The clinical significance of the difference detected remains a consideration.Keywords: rasagiline, Parkinson’s disease, neuroprotection, selegiline

  9. Ranolazine in Symptomatic Diabetic Patients Without Obstructive Coronary Artery Disease: Impact on Microvascular and Diastolic Function.

    Science.gov (United States)

    Shah, Nishant R; Cheezum, Michael K; Veeranna, Vikas; Horgan, Stephen J; Taqueti, Viviany R; Murthy, Venkatesh L; Foster, Courtney; Hainer, Jon; Daniels, Karla M; Rivero, Jose; Shah, Amil M; Stone, Peter H; Morrow, David A; Steigner, Michael L; Dorbala, Sharmila; Blankstein, Ron; Di Carli, Marcelo F

    2017-05-04

    Treatments for patients with myocardial ischemia in the absence of angiographic obstructive coronary artery disease are limited. In these patients, particularly those with diabetes mellitus, diffuse coronary atherosclerosis and microvascular dysfunction is a common phenotype and may be accompanied by diastolic dysfunction. Our primary aim was to determine whether ranolazine would quantitatively improve exercise-stimulated myocardial blood flow and cardiac function in symptomatic diabetic patients without obstructive coronary artery disease. We conducted a double-blinded crossover trial with 1:1 random allocation to the order of ranolazine and placebo. At baseline and after each 4-week treatment arm, left ventricular myocardial blood flow and coronary flow reserve (CFR; primary end point) were measured at rest and after supine bicycle exercise using 13N-ammonia myocardial perfusion positron emission tomography. Resting echocardiography was also performed. Multilevel mixed-effects linear regression was used to determine treatment effects. Thirty-five patients met criteria for inclusion. Ranolazine did not significantly alter rest or postexercise left ventricular myocardial blood flow or CFR. However, patients with lower baseline CFR were more likely to experience improvement in CFR with ranolazine (r=-0.401, P=0.02) than with placebo (r=-0.188, P=0.28). In addition, ranolazine was associated with an improvement in E/septal e' (P=0.001) and E/lateral e' (P=0.01). In symptomatic diabetic patients without obstructive coronary artery disease, ranolazine did not change exercise-stimulated myocardial blood flow or CFR but did modestly improve diastolic function. Patients with more severe baseline impairment in CFR may derive more benefit from ranolazine. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01754259. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

  10. Effects of Ranolazine on Angina and Quality of Life After Percutaneous Coronary Intervention With Incomplete Revascularization: Results From the Ranolazine for Incomplete Vessel Revascularization (RIVER-PCI) Trial.

    Science.gov (United States)

    Alexander, Karen P; Weisz, Giora; Prather, Kristi; James, Stefan; Mark, Daniel B; Anstrom, Kevin J; Davidson-Ray, Linda; Witkowski, Adam; Mulkay, Angel J; Osmukhina, Anna; Farzaneh-Far, Ramin; Ben-Yehuda, Ori; Stone, Gregg W; Ohman, E Magnus

    2016-01-05

    Angina often persists or returns in populations following percutaneous coronary intervention (PCI). We hypothesized that ranolazine would be effective in reducing angina and improving quality of life (QOL) in incomplete revascularization (ICR) post-PCI patients. In RIVER-PCI, 2604 patients with a history of chronic angina who had ICR post-PCI were randomized 1:1 to oral ranolazine versus placebo; QOL analyses included 2389 randomized subjects. Angina and QOL questionnaires were collected at baseline and months 1, 6, and 12. Ranolazine patients were more likely than placebo to discontinue study drug by month 6 (20.4% versus 14.1%, Pdiabetics (mean difference 3.3; 95% CI 0.6, 6.1; P=0.02) and those with more angina (baseline SAQ angina frequency ≤60; mean difference 3.4; 95% CI 0.6, 6.2; P=0.02), but was not maintained at month 12. Despite ICR following PCI, there was no incremental benefit in angina or QOL measures by adding ranolazine in this angiographically-identified population. These measures markedly improved within 1 month of PCI and persisted up to 1 year in both treatment arms. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01442038. © 2015 American Heart Association, Inc.

  11. The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline

    National Research Council Canada - National Science Library

    Bar-Am, Orit; Weinreb, Orly; Amit, Tamar; Youdim, Moussa B H

    2010-01-01

    The anti-parkinsonian drug, rasagiline [N-propargyl-1-(R)-aminoindan; Azilect(R)], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B...

  12. Antiarrhythmic Effects of Combining Dofetilide and Ranolazine in a Model of Acutely Induced Atrial Fibrillation in Horses

    DEFF Research Database (Denmark)

    Carstensen, Helena; Kjær, Line; Haugaard, Maria Mathilde

    2017-01-01

    reducing the likelihood of adverse side effects. The purpose of this study was to investigate whether the effective doses of dofetilide and ranolazine can be reduced if the drugs are combined. METHODS: Dofetilide, ranolazine, and a combination of these were administered in 4 incremental dosing regimens...

  13. Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy.

    Science.gov (United States)

    Coppini, Raffaele; Mazzoni, Luca; Ferrantini, Cecilia; Gentile, Francesca; Pioner, Josè Manuel; Laurino, Annunziatina; Santini, Lorenzo; Bargelli, Valentina; Rotellini, Matteo; Bartolucci, Gianluca; Crocini, Claudia; Sacconi, Leonardo; Tesi, Chiara; Belardinelli, Luiz; Tardiff, Jil; Mugelli, Alessandro; Olivotto, Iacopo; Cerbai, Elisabetta; Poggesi, Corrado

    2017-03-01

    Current therapies are ineffective in preventing the development of cardiac phenotype in young carriers of mutations associated with hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na + current blocker, reduced the electromechanical dysfunction of human HCM myocardium in vitro. To test whether long-term treatment prevents cardiomyopathy in vivo, transgenic mice harboring the R92Q troponin-T mutation and wild-type littermates received an oral lifelong treatment with ranolazine and were compared with age-matched vehicle-treated animals. In 12-months-old male R92Q mice, ranolazine at therapeutic plasma concentrations prevented the development of HCM-related cardiac phenotype, including thickening of the interventricular septum, left ventricular volume reduction, left ventricular hypercontractility, diastolic dysfunction, left-atrial enlargement and left ventricular fibrosis, as evaluated in vivo using echocardiography and magnetic resonance. Left ventricular cardiomyocytes from vehicle-treated R92Q mice showed marked excitation-contraction coupling abnormalities, including increased diastolic [Ca 2+ ] and Ca 2+ waves, whereas cells from treated mutants were undistinguishable from those from wild-type mice. Intact trabeculae from vehicle-treated mutants displayed inotropic insufficiency, increased diastolic tension, and premature contractions; ranolazine treatment counteracted the development of myocardial mechanical abnormalities. In mutant myocytes, ranolazine inhibited the enhanced late Na + current and reduced intracellular [Na + ] and diastolic [Ca 2+ ], ultimately preventing the pathological increase of calmodulin kinase activity in treated mice. Owing to the sustained reduction of intracellular Ca 2+ and calmodulin kinase activity, ranolazine prevented the development of morphological and functional cardiac phenotype in mice carrying a clinically relevant HCM-related mutation. Pharmacological inhibitors of late Na + current are promising candidates for an

  14. Rasagiline for sleep disorders in patients with Parkinson’s disease: a prospective observational study

    Directory of Open Access Journals (Sweden)

    Schettino C

    2016-09-01

    Full Text Available Carla Schettino,1,2,* Clemente Dato,1,2,* Guglielmo Capaldo,1,2 Simone Sampaolo,1,2 Giuseppe Di Iorio,1,2 Mariarosa AB Melone1,2 1Department of Medical, Surgical, Neurological, Metabolic Sciences, and Aging, 2Division of Neurology and InterUniversity Center for Research in Neurosciences, Second University of Naples, Naples, Italy *These authors contributed equally to this work Introduction: Rasagiline is a selective, irreversible monoamine oxidase B inhibitor that ameliorates the symptoms of Parkinson’s disease (PD by inhibiting striatal dopamine metabolism. There is also evidence that monoamine oxidase B inhibitors increase melatonin levels in the pineal gland and may have a beneficial effect on sleep disorders, which are a common feature in patients with PD.Methods: This single-center, prospective, observational, 12-week study compared the effect of combination therapy with levodopa 200–300 mg/d + rasagiline 1 mg/d (n=19 with levodopa 200–300 mg/d alone (n=19 in the treatment of sleep disorders in patients with idiopathic PD.Results: After 12 weeks’ treatment, mean sleep latency was significantly (P<0.001 lower and the improvement in sleep latency from baseline was significantly (P=0.001 greater in patients receiving levodopa + rasagiline than in patients receiving levodopa alone. Similarly, at the end of the study, the mean total sleep time was significantly (P=0.002 longer and the improvement from baseline in mean total sleep time was significantly (P=0.026 greater in patients receiving levodopa + rasagiline than levodopa alone. There were no significant differences between treatment groups for the mean number of awakenings reported at week 12 nor the change from baseline to week 12 in mean number of awakenings.Conclusion: Adding rasagiline to levodopa improved sleep outcomes and may be an appropriate option for patients with PD experiencing sleep disorders. Keywords: Parkinson’s disease, rasagiline, sleep disorders, Parkinson

  15. Bio-analytical method development and validation of Rasagiline by high performance liquid chromatography tandem mass spectrometry detection and its application to pharmacokinetic study

    Directory of Open Access Journals (Sweden)

    Ravi Kumar Konda

    2012-10-01

    Full Text Available The most suitable bio-analytical method based on liquid–liquid extraction has been developed and validated for quantification of Rasagiline in human plasma. Rasagiline-13C3 mesylate was used as an internal standard for Rasagiline. Zorbax Eclipse Plus C18 (2.1 mm×50 mm, 3.5 μm column provided chromatographic separation of analyte followed by detection with mass spectrometry. The method involved simple isocratic chromatographic condition and mass spectrometric detection in the positive ionization mode using an API-4000 system. The total run time was 3.0 min. The proposed method has been validated with the linear range of 5–12000 pg/mL for Rasagiline. The intra-run and inter-run precision values were within 1.3%–2.9% and 1.6%–2.2% respectively for Rasagiline. The overall recovery for Rasagiline and Rasagiline-13C3 mesylate analog was 96.9% and 96.7% respectively. This validated method was successfully applied to the bioequivalence and pharmacokinetic study of human volunteers under fasting condition. Keywords: High performance liquid chromatography, Mass spectrometry, Rasagiline, Liquid–liquid extraction

  16. No synergism between bis(propyl-cognitin and rasagiline on protecting dopaminergic neurons in Parkinson's disease mice

    Directory of Open Access Journals (Sweden)

    Cheng-you Zheng

    2016-01-01

    Full Text Available Rasagiline, a monoamine oxidase-B inhibitor, and bis(propyl-cognitin (B3C, a novel dimer are reported to be neuroprotective. Herein, the synergistical neuroprotection produced by rasagiline and B3C was investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced mice of Parkinsonism. By using neurobehavioural tests, high-performance liquid chromatography and western blot assay, we showed that B3C at 0.3 mg/kg, rasagiline at 0.02 mg/kg, as well as co-treatment with B3C and rasagiline prevented MPTP-induced behavioural abnormities, increased the concentrations of dopamine and its metabolites in the striatum, and up-regulated the expression of tyrosine hydroxylase in the substantia nigra. However, the neuroprotective effects of co-treatment were not significantly improved when compared with those of B3C or rasagiline alone. Collectively, we have demonstrated that B3C at 0.3 mg/kg and rasagline at 0.02 mg/kg could not produce synergistic neuroprotective effects

  17. Rasagiline adjunct therapy in patients with Parkinson's disease: post hoc analyses of the PRESTO and LARGO trials.

    Science.gov (United States)

    Elmer, Lawrence W

    2013-11-01

    Rasagiline was safe and effective when used as adjunct therapy with levodopa in patients with moderate-to-advanced Parkinson's disease (PD) in the phase III PRESTO and LARGO studies. To assess clinical effects of rasagiline 1 mg/day on cardinal PD symptoms and motor fluctuations in defined patient subgroups using pooled data from PRESTO and LARGO. Both double-blind, randomized, and placebo-controlled studies included PD patients with motor fluctuations despite optimized therapy with levodopa, with or without concomitant dopamine agonists (DA) or catechol-O-methyltransferase inhibitor (COMT-I) treatment. These post hoc analyses measured effects of rasagiline 1 mg vs placebo on individual cardinal PD symptoms during ON time and mean change from baseline in daily OFF time in subgroups of patients who at baseline were receiving only levodopa, were considered "mild fluctuators" (daily OFF time ≤ 4 h), and who were or were not receiving concomitant DA or COMT-I therapy. Compared with placebo, rasagiline significantly improved all cardinal PD symptoms and significantly reduced adjusted mean daily OFF time when used as first adjunct therapy in levodopa-treated patients and in patients with mild motor fluctuations. Significant improvement in motor fluctuations was reported with rasagiline regardless of concomitant DA or COMT-I use. Overall incidence of dopaminergic adverse events did not increase with concomitant DA or COMT-I use. Rasagiline was an effective first adjunct therapy in levodopa-treated patients; benefited patients with signs of early "wearing off"; improved all cardinal PD symptoms; and further improved symptoms in patients already receiving other adjunctive dopaminergic treatment. Copyright © 2013 Elsevier Ltd. All rights reserved.

  18. Ranolazine decreases diastolic calcium accumulation caused by ATX-II or ischemia in rat hearts.

    Science.gov (United States)

    Fraser, Heather; Belardinelli, Luiz; Wang, Lianguo; Light, Peter E; McVeigh, Jeffrey J; Clanachan, Alexander S

    2006-12-01

    Cardiac pathologies are associated with increased late INa that contributes to the dysregulation of ion homeostasis and causes electrical and contractile dysfunction. This study was designed to test the hypothesis that an increased late sodium channel current (INa) leads to Ca2+ overload and left ventricular (LV) dysfunction, and thereby inhibition of late INa (e.g., by ranolazine) improves Ca2+ homeostasis and reduces LV dysfunction. Intracellular Ca2+ ([Ca2+]i) and LV function were measured simultaneously in rat isolated perfused hearts. Augmentation of late INa with sea anemone toxin-II (ATX-II, 12 nM) increased diastolic [Ca2+]i (d[Ca2+]i), and impaired LV mechanical function, but had no effect on [Ca2+]i transient amplitude. Although ranolazine (4 and 9 microM), an inhibitor of late INa, had no direct effects on d[Ca2+]i or LV function, it significantly reduced the deleterious effects of ATX-II. Global ischemia increased d[Ca2+]i and inhibited Ca2+ transient amplitude. During reperfusion, Ca2+ transient amplitude recovered fully, but d[Ca2+]i remained elevated and LV function was depressed, indicative of Ca2+ overload. Ranolazine (9 microM) reduced d[Ca2+]i accumulation during ischemia as well as reperfusion and improved recovery of LV function. These results show that augmentation of late INa with ATX-II or by ischemia is associated with diastolic Ca2+ overload and LV dysfunction. The beneficial effects of ranolazine in reducing Ca2+ overload and LV mechanical dysfunction during ischemia/reperfusion is consistent with the inhibition of late INa mechanism of action.

  19. A novel thermosensitive in-situ gel of gabexate mesilate for treatment of traumatic pancreatitis: An experimental study.

    Science.gov (United States)

    Gao, Han-jing; Song, Qing; Lv, Fa-qin; Wang, Shan; Wang, Yi-ru; Luo, Yu-kun; Mei, Xing-guo; Tang, Jie

    2015-10-01

    Gabexate mesilate (GM) is a trypsin inhibitor, and mainly used for treatment of various acute pancreatitis, including traumatic pancreatitis (TP), edematous pancreatitis, and acute necrotizing pancreatitis. However, due to the characteristics of pharmacokinetics, the clinical application of GM still needs frequently intravenous administration to keep the blood drug concentration, which is difficult to manage. Specially, when the blood supply of pancreas is directly damaged, intravenous administration is difficult to exert the optimum therapy effect. To address it, a novel thermosensitive in-situ gel of gabexate mesilate (GMTI) was developed, and the optimum formulation of GMTI containing 20.6% (w/w) P-407 and 5.79% (w/w) P188 with different concentrations of GM was used as a gelling solvent. The effective drug concentration on trypsin inhibition was examined after treatment with different concentrations of GMTI in vitro, and GM served as a positive control. The security of GMTI was evaluated by hematoxylin-eosin (HE) staining, and its curative effect on grade II pancreas injury was also evaluated by testing amylase (AMS), C-reactive protein (CRP) and trypsinogen activation peptide (TAP), and pathological analysis of the pancreas. The trypsin activity was slightly inhibited at 1.0 and 5.0 mg/mL in GM group and GMTI group, respectively (Ptreatment as compared with TP group (Ptreatment as compared with TP group (Ptreatment, pancreas cells were gradually restored to tight distribution, with slightly stained nuclei. This preliminary study indicated that GMTI could effectively inhibit pancreatic enzymes, and alleviate the severity of trauma-induced pancreatitis, and had a potential drug developing and clinic application value.

  20. Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization.

    Science.gov (United States)

    Ravi, P R; Aditya, N; Patil, S; Cherian, L

    2015-01-01

    Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson's disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934 P and chitosan). The formulations were evaluated for sol-gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28-33 °C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p < 0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.

  1. Cost-utility of ranolazine for the symptomatic treatment of patients with chronic angina pectoris in Spain.

    Science.gov (United States)

    Hidalgo-Vega, Alvaro; Ramos-Goñi, Juan Manuel; Villoro, Renata

    2014-12-01

    Ranolazine is an antianginal agent that was approved in the EU in 2008 as an add-on therapy for symptomatic chronic angina pectoris treatment in patients who are inadequately controlled by, or are intolerant to, first-line antianginal therapies. These patients' quality of life is significantly affected by more frequent angina events, which increase the risk of revascularization. To assess the cost-utility of ranolazine versus placebo as an add-on therapy for the symptomatic treatment of patients with chronic angina pectoris in Spain. A decision tree model with 1-year time horizon was designed. Transition probabilities and utility values for different angina frequencies were obtained from the literature. Costs were obtained from Spanish official DRGs for patients with chronic angina pectoris. We calculated the incremental cost-utility ratio of using ranolazine compared with a placebo. Sensitivity analyses, by means of Monte Carlo simulations, were performed. Acceptability curves and expected value of perfect information were calculated. The incremental cost-utility ratio was €8,455 per quality-adjusted life-year (QALY) per patient in Spain. Sensitivity analyses showed that if the decision makers' willingness to pay is €15,000 per QALY, the treatment with ranolazine will be cost effective at a 95 % level of confidence. The incremental cost-utility ratio is particularly sensitive to changes in utility values of those non-hospitalized patients with mild or moderate angina frequency. Ranolazine is a highly efficient add-on therapy for the symptomatic treatment of chronic angina pectoris in patients who are inadequately controlled by, or intolerant to, first-line antianginal therapies in Spain.

  2. Myocardial tissue deformation is reduced in subjects with coronary microvascular dysfunction but not rescued by treatment with ranolazine.

    Science.gov (United States)

    Nelson, Michael D; Sharif, Behzad; Shaw, Jaime L; Cook-Wiens, Galen; Wei, Janet; Shufelt, Chrisandra; Mehta, Puja K; Thomson, Louise E J; Berman, Daniel S; Thompson, Richard B; Handberg, Eileen M; Pepine, Carl J; Li, Debiao; Bairey Merz, C Noel

    2017-05-01

    Patients with coronary microvascular dysfunction (CMD) often have diastolic dysfunction, representing an important therapeutic target. Ranolazine-a late sodium current inhibitor-improves diastolic function in animal models and subjects with obstructive coronary artery disease (CAD). We hypothesized that ranolazine would beneficially alter diastolic function in CMD. To test this hypothesis, we performed retrospective tissue tracking analysis to evaluate systolic/diastolic strain, using cardiac magnetic resonance imaging cine images acquired in a recently completed, randomized, double-blind, placebo-controlled, crossover trial of short-term ranolazine in subjects with CMD and from 43 healthy reference controls. Diastolic strain rate was impaired in CMD vs controls (circumferential diastolic strain rate: 99.9% ± 2.5%/s vs 120.1% ± 4.0%/s, P = 0.0003; radial diastolic strain rate: -199.5% ± 5.5%/s vs -243.1% ± 9.6%/s, P = 0.0008, case vs control). Moreover, peak systolic circumferential strain (CS) and radial strain (RS) were also impaired in cases vs controls (CS: -18.8% ± 0.3% vs -20.7% ± 0.3%; RS: 35.8% ± 0.7% vs 41.4% ± 0.9%; respectively; both P CMD cases after 2 weeks of ranolazine vs placebo. The case-control comparison both confirms and extends our prior observations of diastolic dysfunction in CMD. That CMD cases were also found to have subclinical systolic dysfunction is a novel finding, highlighting the utility of this retrospective approach. In contrast to previous studies in obstructive CAD, ranolazine did not improve diastolic function in CMD. © 2016 Wiley Periodicals, Inc.

  3. The Use Of Oral Ranolazine To Convert New Or Paroxysmal Atrial Fibrillation: A Review Of Experience With Implications For Possible "Pill In The Pocket" Approach To Atrial Fibrillation

    Directory of Open Access Journals (Sweden)

    David K Murdock

    2009-09-01

    Full Text Available Background: Atrial fibrillation (AF is the most common arrhythmia requiring treatment. High dose oral anti-arrhythmics may cardiovert some paroxysmal AF. This "pill in pocket" approach has allowed patients to treat themselves on an as needed basis. Pro-arrhythmic concerns have limited the usefulness of this approach to patients without structural heart disease. Ranolazine is an anti-anginal agent, which inhibits abnormal late Na+ channel currents in cardiomyocytes and decreases sodium-calcium overload. Ranolazine is a potent inhibitor of after-depolarizations, which have been implicated in the initiation and propagation of AF. Because ranolazine has no known pro-arrhythmic effects, it could be useful as a safe "pill in the pocket" agent if it were effective in converting AF. We describe our experience using oral ranolazine to convert new or paroxysmal AF. Method: 2000 mg of ranolazine were administered to 18 patients with new (11 patients or paroxysmal (7 patients AF of at least 3, but not greater than 48 hours duration. Most patients (14 were in the hospital at the time ranolazine was administered. Age, sex, echocardiographic data, associated health conditions and structural heart disease were recorded. Successful conversion was defined as restoring sinus rhythm within 6 hours of ranolazine administration. Results: All but 1 patient had some form of structural heart disease and all but 2 patients had left atrial enlargement. Thirteen of 18 patients converted to sinus rhythm. No pro-arrhythmic effects, hemodynamic instability, adverse rate effects, or perceived intolerance (other than constipation were noted. The 72% conversion rate was comparable to other reported "pill in the pocket" protocols. Conclusion: High dose oral ranolazine shows utility as a possible safe agent to convert new or paroxysmal AF. Lack of blinded controls and small numbers limits the power of this observation.

  4. The serine protease inhibitor camostat mesilate attenuates the progression of chronic kidney disease through its antioxidant effects.

    Science.gov (United States)

    Ueda, Miki; Uchimura, Kohei; Narita, Yuki; Miyasato, Yoshikazu; Mizumoto, Teruhiko; Morinaga, Jun; Hayata, Manabu; Kakizoe, Yutaka; Adachi, Masataka; Miyoshi, Taku; Shiraishi, Naoki; Kadowaki, Daisuke; Sakai, Yoshiki; Mukoyama, Masashi; Kitamura, Kenichiro

    2015-01-01

    We have so far demonstrated the renoprotective effect of camostat mesilate (CM) in 5/6 nephrectomized rats at least partly through its antioxidant effect. However, precise mechanisms were not fully clarified. Therefore, we now examined the renoprotective and antioxidant mechanisms of CM by using the adenine-induced chronic kidney disease (CKD) rat model. In protocol 1, we analyzed the effect of CM on CKD. Rats were fed on a 0.75% adenine diet for 3 weeks to induce CKD followed by the experimental period with vehicle, CM, or hydralazine (HYD) treatment for 5 weeks. In protocol 2, we examined the safety of CM and HYD on the normal rats. In addition, we explored free radical scavenging activities of CM and its metabolites in vitro using electron paramagnetic resonance (EPR) spectroscopy. CM, but not HYD, significantly reduced the serum creatinine levels, although both treatments showed similar reduction in the blood pressure. CM decreased mRNA expression and protein levels of fibrotic markers, the severity of renal fibrosis, the accumulation of oxidative stress, and the expression of NADPH oxidase components in the kidney. In the protocol 2, there were no statistically significant differences in general parameters except for the systolic blood pressure in HYD group. EPR study revealed that CM and its metabolites have potent hydroxyl radical scavenging activities in vitro. Our findings indicate that CM significantly ameliorates the progression of CKD partly through its antioxidant effect independently from its blood pressure-lowering effect. Our results suggest the possibility that CM could be a new therapeutic agent that could arrest the progression of CKD.

  5. Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson’s Disease with Neuroprotective Potential

    Directory of Open Access Journals (Sweden)

    John P.M. Finberg

    2010-07-01

    Full Text Available Rasagiline (Azilect is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl. Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of β-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT. Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time.

  6. Cost effectiveness of rasagiline and pramipexole as treatment strategies in early Parkinson's disease in the UK setting: an economic Markov model evaluation.

    Science.gov (United States)

    Haycox, Alan; Armand, Christophe; Murteira, Susana; Cochran, John; François, Clément

    2009-01-01

    Levodopa is the most effective treatment for the symptoms of Parkinson's disease (PD). However, after an initial period of benefit, several limitations become apparent, including motor complications such as dyskinesia. Dyskinesia can severely affect patients' quality of life and increases healthcare resource use. Thus, delaying the need for levodopa, and therefore the onset of levodopa-induced dyskinesia, is important. The aim of this study was to compare the cost effectiveness, from a UK healthcare payer perspective, of two antiparkinsonian treatment strategies in early PD: first-line monotherapy with rasagiline, a novel monoamine oxidase B inhibitor; and the non-ergoline dopamine receptor agonist pramipexole. An economic Markov model was developed as a pragmatic tool to derive comparative information on the effectiveness, utility and costs of these two strategies over a 5-year period. Model input data were obtained from the TEMPO study for rasagiline and from a study by the Parkinson Study Group for pramipexole. Effectiveness outcomes were time to levodopa and time to levodopa-induced dyskinesia. Cost and quality-adjusted life-year (QALY) data were derived from published sources. Rasagiline was the dominant strategy. Compared with pramipexole, use of the rasagiline strategy was estimated to reduce costs by 18% per patient over 5 years and was associated with an additional 10% delay in dyskinesia onset (0.41 years; 95% CI 0.27, 0.55). This strategy was also found to prolong the time to levodopa initiation by 25% through a gain of 0.83 levodopa-free years (95% CI 0.56, 1.1). In addition, use of the rasagiline strategy was found to generate a 5% gain in QALYs over 5 years compared with the pramipexole strategy (3.7 +/- 0.02 vs 3.51 +/- 0.03). Sensitivity analyses confirmed that the model was robust. Rasagiline represents a cost-effective alternative to pramipexole in the treatment of early PD in the UK.

  7. Ranolazine inhibition of hERG potassium channels: drug-pore interactions and reduced potency against inactivation mutants.

    Science.gov (United States)

    Du, Chunyun; Zhang, Yihong; El Harchi, Aziza; Dempsey, Christopher E; Hancox, Jules C

    2014-09-01

    The antianginal drug ranolazine, which combines inhibitory actions on rapid and sustained sodium currents with inhibition of the hERG/IKr potassium channel, shows promise as an antiarrhythmic agent. This study investigated the structural basis of hERG block by ranolazine, with lidocaine used as a low potency, structurally similar comparator. Recordings of hERG current (IhERG) were made from cell lines expressing wild-type (WT) or mutant hERG channels. Docking simulations were performed using homology models built on MthK and KvAP templates. In conventional voltage clamp, ranolazine inhibited IhERG with an IC50 of 8.03μM; peak IhERG during ventricular action potential clamp was inhibited ~62% at 10μM. The IC50 values for ranolazine inhibition of the S620T inactivation deficient and N588K attenuated inactivation mutants were respectively ~73-fold and ~15-fold that for WT IhERG. Mutations near the bottom of the selectivity filter (V625A, S624A, T623A) exhibited IC50s between ~8 and 19-fold that for WT IhERG, whilst the Y652A and F656A S6 mutations had IC50s ~22-fold and 53-fold WT controls. Low potency lidocaine was comparatively insensitive to both pore helix and S6 mutations, but was sensitive to direction of K(+) flux and particularly to loss of inactivation, with an IC50 for S620T-hERG ~49-fold that for WT IhERG. Docking simulations indicated that the larger size of ranolazine gives it potential for a greater range of interactions with hERG pore side chains compared to lidocaine, in particular enabling interaction of its two aromatic groups with side chains of both Y652 and F656. The N588K mutation is responsible for the SQT1 variant of short QT syndrome and our data suggest that ranolazine is unlikely to be effective against IKr/hERG in SQT1 patients. Copyright © 2014. Published by Elsevier Ltd.

  8. Ranolazine Added to Amiodarone Facilitates Earlier Conversion of Atrial Fibrillation Compared to Amiodarone-Only Therapy.

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    Tsanaxidis, Nikos; Aidonidis, Isaac; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Giamouzis, Grigorios; Triposkiadis, Filippos; Skoularigis, Ioannis

    2017-04-01

    Amiodarone (AMIO) is for many years effectively used to control ventricular rate during atrial fibrillation (AF) and to convert it into sinus rhythm. However, due to its delayed onset of action, ranolazine (RAN), a new antianginal agent with atrial-selective electrophysiologic properties, has recently been attempted as add-on therapy with AMIO to facilitate AF conversion. To establish the role of this combination therapy, we enrolled 173 consecutive patients (68 ± 10 years, 54% male) with recent-onset (conversion (8.6 ± 2.8 hours vs 19.4 ± 4.4 hours, P conversion rate at 24 hours (98% vs 58%, P conversion rate of AF after AMIO plus RAN in patients with preserved ejection fraction and left atrial size, implicating a synergistic effect of the two agents. © 2017 Wiley Periodicals, Inc.

  9. Development and Validation of Spectrophotometric Methods for the Determination of Rasagiline in Pharmaceutical Preparations

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    Serife Evrim Kepekci Tekkeli

    2013-01-01

    Full Text Available This study presents three simple, rapid, and accurate spectrophotometric methods for the determination of Rasagiline (RSG in pharmaceutical preparations. The determination procedures depend on the reaction of RSG with chloranilic acid for method A, tetrachloro-1,4-benzoquinone for method B, and 7,7,8,8-tetracyanoquinodimethane for method C. The colored products were quantitated spectrophotometrically at 524, 535, and 843 nm for methods A, B, and C, respectively. Different variables affecting the reaction were optimized. Linearity ranges of the methods with good correlation coefficients (0.9988–0.9996 were observed as 25–300 µg mL−1, 25–350 µg mL−1, and 50–500 µg mL−1 for methods A, B, and C, respectively. The formation of products takes place through different mechanisms. The sites of interaction were confirmed by elemental analysis using IR and 1H-NMR spectroscopy. The validation of the methods was carried out in terms of specificity, linearity, accuracy, precision, robustness, limit of detection, and limit of quantitation. No interference was observed from concomitants usually present in dosage forms. The methods were applied successfully to the determination of RSG in pharmaceutical preparations.

  10. Development and Validation of a Stability-Indicating HPTLC Method for Analysis of Rasagiline Mesylate in the Bulk Drug and Tablet Dosage Form

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    Singaram Kathirvel

    2012-01-01

    Full Text Available A simple and sensitive thin-layer chromatographic method has been established for analysis of rasagiline mesylate in pharmaceutical dosage form. Chromatography on silica gel 60 F254 plates with 6 : 1 : 2(v/v/v butanol-methanol water as mobile phase furnished compact spots at Rf  0.76±0.01. Densitometric analysis was performed at 254 nm. To show the specificity of the method, rasagiline mesylate was subjected to acid, base, neutral hydrolysis, oxidation, photolysis, and thermal decomposition, and the peaks of degradation products were well resolved from that of the pure drug. Linear regression analysis revealed a good linear relationship between peak area and amount of rasagiline mesylate in the range of 100–350 ng/band. The minimum amount of rasagiline mesylate that could be authentically detected and quantified was 11.12 and 37.21 ng/band, respectively. The method was validated, in accordance with ICH guidelines for precision, accuracy, and robustness. Since the method could effectively separate the drug from its degradation products, it can be regarded as stability indicating.

  11. Synthesis of a Parkinson's Disease Treatment Drug, the "R,R"-Tartrate Salt "of R"-Rasagiline: A Three Week Introductory Organic Chemistry Lab Sequence

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    Aguilar, Noberto; Garcia, Billy; Cunningham, Mark; David, Samuel

    2016-01-01

    A synthesis of the "R,R"-tartrate salt of the popular anti-Parkinson's drug "R"-rasagiline (Azilect) was adapted to introduce the organic laboratory student to a medically relevant synthesis. It makes use of concepts found in the undergraduate organic chemistry curriculum, appropriately fits into three approximately 4 h lab…

  12. Ranolazine improves autonomic balance in heart failure when added to guideline-driven therapy

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    Gary L. Murray

    2014-12-01

    Full Text Available Background The effect of ranolazine (RAN on cardiac autonomic balance in congestive heart failure (CHF was studied. Methods Fifty-four CHF patients were randomized to (1 open-label RAN (RANCHF added to usual therapy vs. (2 usual therapy (NORANCHF. Parasympathetic and sympathetic (P&S measurements were taken at baseline and at 12 months. Results A total of 16/27 (59% patients in both groups had initially abnormal P&S measures, including high sympathovagal balance (SB, cardiovascular autonomic neuropathy (CAN or both. High SB normalized in 10/12 (83% RANCHF patients vs. 2/11 (18% NORANCHF patients. SB became high in 5/11 (45% NORANCHF vs. 1/11 (9% RANCHF patients. CAN improved in 4/6 (67% RANCHF patients vs. 5/7 (45% NORANCHF patients. CAN developed in 1/11 (9% RANCHF vs. 4/11 (36% NORANCHF patients. Since improved P&S in RANCHF patients seemed independent of improved brain natriuretic peptide and impedance cardiography (BioZ measurements, 5 day RAN was given to 30 subjects without CHF but with high SB or CAN. P&S improved in 90% of these subjects. Conclusions RAN improves unfavorable P&S activity in CHF possibly by a direct effect upon autonomic sodium channels.

  13. Effects of ranolazine on wild-type and mutant hNav1.7 channels and on DRG neuron excitability

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    Estacion Mark

    2010-06-01

    Full Text Available Abstract Background A direct role of sodium channels in pain has recently been confirmed by establishing a monogenic link between SCN9A, the gene which encodes sodium channel Nav1.7, and pain disorders in humans, with gain-of-function mutations causing severe pain syndromes, and loss-of-function mutations causing congenital indifference to pain. Expression of sodium channel Nav1.8 in DRG neurons has also been shown to be essential for the manifestation of mutant Nav1.7-induced neuronal hyperexcitability. These findings have confirmed key roles of Nav1.7 and Nav1.8 in pain and identify these channels as novel targets for pain therapeutic development. Ranolazine preferentially blocks cardiac late sodium currents at concentrations that do not significantly reduce peak sodium current. Ranolazine also blocks wild-type Nav1.7 and Nav1.8 channels in a use-dependent manner. However, ranolazine's effects on gain-of-function mutations of Nav1.7 and on DRG neuron excitability have not been investigated. We used voltage- and current-clamp recordings to evaluate the hypothesis that ranolazine may be effective in regulating Nav1.7-induced DRG neuron hyperexcitability. Results We show that ranolazine produces comparable block of peak and ramp currents of wild-type Nav1.7 and mutant Nav1.7 channels linked to Inherited Erythromelalgia and Paroxysmal Extreme Pain Disorder. We also show that ranolazine, at a clinically-relevant concentration, blocks high-frequency firing of DRG neurons expressing wild-type but not mutant channels. Conclusions Our data suggest that ranalozine can attenuate hyperexcitability of DRG neurons over-expressing wild-type Nav1.7 channels, as occurs in acquired neuropathic and inflammatory pain, and thus merits further study as an alternative to existing non-selective sodium channel blockers.

  14. Ranolazine versus placebo in patients with ischemic cardiomyopathy and persistent chest pain or dyspnea despite optimal medical and revascularization therapy: randomized, double-blind crossover pilot study

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    Shammas NW

    2015-03-01

    Full Text Available Nicolas W Shammas,1 Gail A Shammas,1 Kathleen Keyes,2 Shawna Duske,1 Ryan Kelly,1 Michael Jerin3 1Midwest Cardiovascular Research Foundation, 2Cardiovascular Medicine, Private Corporation, 3St Ambrose University, Davenport, IA, USA Background: Patients with ischemic cardiomyopathy (ICM may continue to experience persistent chest pain and/or dyspnea despite pharmacologic therapy and revascularization. We hypothesized that ranolazine would reduce anginal symptoms or dyspnea in optimally treated ICM patients.Methods: In this randomized, double-blind, crossover-design pilot study, 28 patients with ICM (ejection fraction less or equal 40% were included after providing informed consent. A total of 24 patients completed both placebo and ranolazine treatments and were analyzed. All patients were on treatment with a beta blocker, an angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker, and at least one additional antianginal drug. After randomization, patients received up to 1,000 mg ranolazine orally twice a day, as tolerated, versus placebo. The primary end point was change in angina as assessed by the Seattle Angina Questionnaire (SAQ, or in dyspnea as assessed by the Rose Dyspnea Scale (RDS. Change in the RDS and SAQ score from baseline was compared, for ranolazine and placebo, using the Wilcoxon signed rank test or paired t-test.Results: Patients had the following demographic and clinical variables: mean age of 71.5 years; male (82.1%; prior coronary bypass surgery (67.9%; prior coronary percutaneous intervention (85.7%; prior myocardial infarction (82.1%; diabetes (67.9%; and mean ejection fraction of 33.1%. No statistical difference was seen between baseline RDS score and that after placebo or ranolazine (n=20 (P≥0.05. There was however, an improvement in anginal frequency (8/10 patients (P=0.058, quality of life (8/10 patients (P=0.048, and mean score of all components of the SAQ questionnaire (n=10 (P=0.047 with ranolazine

  15. A stereoselective, catalytic strategy for the in-flow synthesis of advanced precursors of rasagiline and tamsulosin.

    Science.gov (United States)

    Brenna, Davide; Pirola, Margherita; Raimondi, Laura; Burke, Anthony J; Benaglia, Maurizio

    2017-12-01

    The diastereoselective, trichlorosilane-mediate reduction of imines, bearing different and removable chiral auxiliaries, in combination either with achiral bases or catalytic amounts of chiral Lewis bases, was investigated to afford immediate precursors of chiral APIs (Active Pharmaceutical Ingredients). The carbon-nitrogen double bond reduction was successfully performed in batch and in flow mode, in high yields and almost complete stereocontrol. By this metal-free approach, the formal synthesis of rasagiline and tamsulosin was successfully accomplished in micro(meso) flow reactors, under continuous flow conditions. The results of these explorative studies represent a new, important step towards the development of automated processes for the preparation of enantiopure biologically active compounds. Copyright © 2017 Elsevier Ltd. All rights reserved.

  16. Sinus node dysfunction in ATX-II-induced in-vitro murine model of long QT3 syndrome and rescue effect of ranolazine.

    Science.gov (United States)

    Wu, Jingjing; Cheng, Longxian; Lammers, Wim J; Wu, Lin; Wang, Xin; Shryock, John C; Belardinelli, Luiz; Lei, Ming

    2008-01-01

    The aim of this study was to characterize the role of the late Na+ current (I(Na,L)) as a mechanism for induction of both tachy and bradyarrhythmias in murine heart and sino-atrial node tissue. The sea anemone toxin ATX-II and ranolazine were used to increase and inhibit, respectively, I(Na,L). In sixteen hearts studied, exposure to 1-10nM ATX-II caused a slowing of intrinsic heart rate and prolongations of the P-R and QT intervals, the duration of the monophasic action potential, and the sinus node recovery time, accompanied by frequent occurrences of early after depolarisations, delayed after depolarisations and rapid, repetitive ventricular tachy and sino-atrial bradyarrhythmias. ATX-II also slowed sinus node pacemaking, and induced bradycardic arrhythmias in isolated sino-atrial preparations (n=5). The ATX-II-induced alteration of electrophysiological properties and occurrence of arrhythmic events were significantly attenuated by 10 microM ranolazine in intact hearts (n=11) and isolated sino-atrial preparations (n=5). In conclusion, the I(Na,L) enhancer ATX-II causes both tachy and bradyarrhythmias in the murine heart, and these arrhythmias are markedly attenuated by the I(Na,L) blocker, ranolazine (10 microM). The results suggest that I(Na,L) blockade may be the mechanism underlying the reductions of both brady and tachyarrhythmias by ranolazine that were observed during the MERLIN-TIMI clinical outcomes trial.

  17. Resolution of Angina Pectoris and Improvement of the Coronary Flow Reserve after Ranolazine Treatment in a Woman with Isolated Impaired Coronary Microcirculation

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    Alessandro Santoro

    2013-01-01

    Full Text Available In a 61-year-old woman with well controlled arterial hypertension, hypercholesterolemia, and smoke and suffering from recurrent angina pectoris despite angiographically normal epicardial coronary vessels and maximal therapy, the replacement of nitrates with novel antiangina drug ranolazine, after 6-month therapy, induced a complete relief of angina and a relevant rising of the transthoracic Doppler-derived coronary flow reserve (CFR. The present clinical case underlines therefore how in patients with chronic ischemic heart disease without epicardial coronary stenosis ranolazine can induce an improvement till the complete solution of the angina symptoms and a substantial increase of CFR as expression of the enhancement of the microvascular coronary function. The improvement of both symptoms and coronary microvascular function is strictly linked to the mechanism of action of the drug. Ranolazine induces in fact a reduction of the intracellular late sodium current that leads to a reduction of the intracellular calcium concentration thus producing a better myocardial diastolic relaxation process which in its turns enhances the myocardial perfusion. The ranolazine acts therefore as a lusitropic drug that improves the diastolic dysfunction and the segmental ischemia thus affecting one of the first steps of the ischemic cascade.

  18. Comparison of the cutaneous iontophoretic delivery of rasagiline and selegiline across porcine and human skin in vitro.

    Science.gov (United States)

    Kalaria, Dhaval R; Patel, Pratik; Patravale, Vandana; Kalia, Yogeshvar N

    2012-11-15

    The objective was to investigate the anodal iontophoresis of the MAO-B inhibitors rasagiline (RAS) and selegiline (SEL) across porcine and human skin in vitro. Passive delivery of RAS and SEL from aqueous solution was minimal; however, increasing current density from 0.1 to 0.3 and 0.5 mA/cm(2) produced a linear increase in steady-state iontophoretic flux (J(ss,RAS)=49.1i(d)+27.9 (r(2)=0.96) and J(ss,SEL)=27.8i(d)+25.8 (r(2)=0.98)). In the absence of background electrolyte, a four-fold change in donor concentration (10, 20 and 40 mM) did not produce a statistically significant increase in cumulative permeation of either drug after iontophoresis at 0.5mA/cm(2) for 7h. Co-iontophoresis of acetaminophen confirmed that electromigration was the dominant transport mechanism for both drugs (∼90%). Total iontophoretic delivery of RAS and SEL across porcine and human skin in vitro was statistically equivalent (RAS: 1512.7 ± 163.7 and 1523.6 ± 195.9 μg/cm(2), respectively, and SEL: 1268.7 ± 231.2 and 1298.3 ± 253.3 μg/cm(2), respectively). Transport efficiencies for RAS and SEL were good (ranged from 6.81 to 8.50 and 2.86 to 3.61%, respectively). Furthermore, the delivery efficiency, i.e., the fraction of the drug in the formulation that was delivered was very high (>56% at 0.5 mA/cm(2)). Cumulative permeation of RAS and SEL from carbopol gels, potential drug reservoirs for iontophoretic systems, was 891.5 ± 148.3 and 626.6 ± 162.4 μg/cm(2), respectively; this was less than from solution and was tentatively attributed to either different partitioning or slower drug diffusion in the gel matrix. The results demonstrated that therapeutic amounts of rasagiline and selegiline could be easily delivered by transdermal iontophoresis with simple gel patches of modest surface area. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Effect of synthetic protease inhibitor gabexate mesilate on attenuation of coagulant activity and cytokine release in a rat model of islet transplantation.

    Science.gov (United States)

    Tokodai, K; Goto, M; Inagaki, A; Imura, T; Satomi, S

    2011-11-01

    The instant blood-mediated inflammatory reaction (IBMIR), in which the activation of coagulation cascade plays a key role, is one of the serious obstacles to successful islet engraftment. Gabexate mesilate (GM) is well known to elicit anticoagulant and antiinflammatory effects. The aim of this study was to evaluate the effect of GM on syngeneic IBMIR. Syngeneic rat islet grafts (2.5 IEQ/g) were transplanted intraportally into 2 groups (control group and GM group; n = 10-11) of streptozotocin-induced diabetic rats. The GM group was injected intravenously with GM for 30 minutes before islet infusion to 1 hour after. The control group was injected with equivalent amount of saline solution. Plasma samples were collected before and 0.5, 1, 3, 6, and 24 hours after transplantation, and several proinflammatory mediators, including interleukin-6 and high-mobility group Box 1 were measured. Curative rate, intravenous glucose tolerance test, and insulin amount in the recipients' livers were also evaluated. Little difference was observed in any proinflammatory mediators. Whereas none of the animals in the control group became normoglycemic, 2 of 6 rats transplanted with the same number of islets in the GM group became normoglycemic during the study period. The glucose tolerance response was significantly ameliorated in the GM group compared with the control group (P < 0.001). The insulin amount in the liver of the recipients was considerably higher in the GM group (5.6 ± 4.1 vs 12.6 ± 5.3 ng/IEQ; P < .05). These data suggest that GM improves islet engraftment not through suppressing the proinflammatory cytokines but as an anticoagulant. We therefore think that GM could be a useful anticoagulant to control IBMIR induced in clinical islet transplantation, although antiinflammatory reagents are considered to be needed for the ideal regimen. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. I1 imidazoline receptor: novel potential cytoprotective target of TVP1022, the S-enantiomer of rasagiline.

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    Yaron D Barac

    Full Text Available TVP1022, the S-enantiomer of rasagiline (Azilect® (N-propargyl-1R-aminoindan, exerts cyto/cardio-protective effects in a variety of experimental cardiac and neuronal models. Previous studies have demonstrated that the protective activity of TVP1022 and other propargyl derivatives involve the activation of p42/44 mitogen-activated protein kinase (MAPK signaling pathway. In the current study, we further investigated the molecular mechanism of action and signaling pathways of TVP1022 which may account for the cyto/cardio-protective efficacy of the drug. Using specific receptor binding and enzyme assays, we demonstrated that the imidazoline 1 and 2 binding sites (I(1 & I(2 are potential targets for TVP1022 (IC(50 =9.5E-08 M and IC(50 =1.4E-07 M, respectively. Western blotting analysis showed that TVP1022 (1-20 µM dose-dependently increased the immunoreactivity of phosphorylated p42 and p44 MAPK in rat pheochromocytoma PC12 cells and in neonatal rat ventricular myocytes (NRVM. This effect of TVP1022 was significantly attenuated by efaroxan, a selective I(1 imidazoline receptor antagonist. In addition, the cytoprotective effect of TVP1022 demonstrated in NRVM against serum deprivation-induced toxicity was markedly inhibited by efaroxan, thus suggesting the importance of I(1imidazoline receptor in mediating the cardioprotective activity of the drug. Our findings suggest that the I(1imidazoline receptor represents a novel site of action for the cyto/cardio-protective efficacy of TVP1022.

  1. A randomized, placebo-controlled trial of late Na current inhibition (ranolazine) in coronary microvascular dysfunction (CMD): impact on angina and myocardial perfusion reserve.

    Science.gov (United States)

    Bairey Merz, C Noel; Handberg, Eileen M; Shufelt, Chrisandra L; Mehta, Puja K; Minissian, Margo B; Wei, Janet; Thomson, Louise E J; Berman, Daniel S; Shaw, Leslee J; Petersen, John W; Brown, Garrett H; Anderson, R David; Shuster, Jonathan J; Cook-Wiens, Galen; Rogatko, André; Pepine, Carl J

    2016-05-14

    The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling. Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD [invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI)]. Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041). In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects. clinicaltrials.gov Identifier: NCT01342029. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

  2. Role of ranolazine in the prevention and treatment of atrial fibrillation: A meta-analysis of randomized clinical trials.

    Science.gov (United States)

    Gong, Mengqi; Zhang, Zhiwei; Fragakis, Nikolaos; Korantzopoulos, Panagiotis; Letsas, Konstantinos P; Li, Guangping; Yan, Gan-Xin; Liu, Tong

    2017-01-01

    Randomized controlled trials (RCTs) on the use of ranolazine (RN) for prevention and cardioversion of atrial fibrillation (AF) have yielded conflicting results. The purpose of this study was to conduct a meta-analysis of RCTs to examine the potential role of RN in the prevention and cardioversion of AF. PubMed and EMBASE were searched until June 2016. Of 484 initially identified studies, 8 RCTs were finally analyzed. The analysis of RCTs showed that RN significantly reduced the incidence of AF compared to the control group in various clinical settings, such as after cardiac surgery, in acute coronary syndromes, and post-electrical cardioversion of AF (relative risk [RR] 0.67, 95% confidence interval [CI] 0.52-0.87, Z = 3.06, P = .002). Furthermore, a higher conversion rate of AF from the combined use of RN and amiodarone compared to amiodarone alone (RR 1.23, 95% CI 1.08-1.40, Z = 3.07, P = .002) was clear, with conversion time significantly shorter in RN plus amiodarone compared to the amiodarone group (weighted mean difference [WMD] = -10.38 hours, 95% CI -18.18 to -2.57, Z = 2.61, P = .009). Our meta-analysis suggests that RN may be effective in AF prevention, whereas it potentiates and accelerates the conversion effect of amiodarone of recent-onset AF. Larger RCTs with long-term follow-up in diverse clinical settings are needed to further clarify the impact of RN on AF therapy. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  3. The effects of inhaled nitric oxide, gabexate mesilate, and retrograde flush in the lung graft from non-heart beating minipig donors.

    Science.gov (United States)

    Luh, S P; Tsai, C C; Shau, W Y; Chen, J S; Kuo, S H; Lin-Shiau, S Y; Lee, Y C

    2000-05-27

    The use of lung grafts from non-heart-beating donors (NHBD) is one way of solving the donor organ shortage problem. In this experiment, we studied the effect of retrograde flush (RF) from the left atrium before harvest, inhaled nitric oxide (NO), and gabexate mesilate (FOY), a protease inhibitor, in the lung grafts from NHBD. Forty-eight Lee-Sung, small-ear, miniature pigs (15-20 kg) were divided into 24 pairs (donor and recipient) and four groups. The donor lungs were flushed and harvested 90 min after cardiac arrest. No i.v. heparin was administered until the time before flush and harvest. Left single lung transplantation was undertaken, and the recipients were observed for 18 hr. The grafts warm and cold ischemia times were 90 (controlled) and 183+/-23.4 min. Group 1 (untreated control, UC, n=6) had core perfusion through a Swan-Ganz catheter followed by a single, antegrade flush with modified Euro-Collin's solution containing heparin, urokinase, and PGE1. Group 2 (RF group, n=6) had the same as group 1, except that one additive retrograde flush through the left atrium was administered. Group 3 (NO group, n=6) had the same as group 1, except that 20 parts per million (ppm) inhaled NO was administered for the cadaver donors before the graft harvest, and for the recipients after the grafts reperfusion. Group 4 (FOY group, n=6) had the same as group 1, except that the recipients received FOY i.v. infusion from the beginning of the recipient's operation and continuously throughout the experiments. Compared with the group 1 (control), group 2 (RF) had significantly (Pinjury score, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 3 (NO) had significantly lower mean pulmonary arterial pressure, PVR, lung injury score, degree of tissue neutrophils infiltration (histological and myeloperoxidase assay), bronchoalveolar lavage fluid protein content and neutrophils (PMNs) percentage, and higher PaO2/FiO2 and pulmonary dynamic compliance. Group 4 (FOY) had

  4. Larger late sodium current density as well as greater sensitivities to ATX II and ranolazine in rabbit left atrial than left ventricular myocytes.

    Science.gov (United States)

    Luo, Antao; Ma, Jihua; Song, Yejia; Qian, Chunping; Wu, Ying; Zhang, Peihua; Wang, Leilei; Fu, Chen; Cao, Zhenzhen; Shryock, John C

    2014-02-01

    An increase of cardiac late sodium current (INa.L) is arrhythmogenic in atrial and ventricular tissues, but the densities of INa.L and thus the potential relative contributions of this current to sodium ion (Na(+)) influx and arrhythmogenesis in atria and ventricles are unclear. In this study, whole-cell and cell-attached patch-clamp techniques were used to measure INa.L in rabbit left atrial and ventricular myocytes under identical conditions. The density of INa.L was 67% greater in left atrial (0.50 ± 0.09 pA/pF, n = 20) than in left ventricular cells (0.30 ± 0.07 pA/pF, n = 27, P ATX II) increased INa.L with an EC50 value of 14 ± 2 nM and a Hill slope of 1.4 ± 0.1 (n = 9) in atrial myocytes and with an EC50 of 21 ± 5 nM and a Hill slope of 1.2 ± 0.1 (n = 12) in ventricular myocytes. Na(+) channel open probability (but not mean open time) was greater in atrial than in ventricular cells in the absence and presence of ATX II. The INa.L inhibitor ranolazine (3, 6, and 9 μM) reduced INa.L more in atrial than ventricular myocytes in the presence of 40 nM ATX II. In summary, rabbit left atrial myocytes have a greater density of INa.L and higher sensitivities to ATX II and ranolazine than rabbit left ventricular myocytes.

  5. Prediction of Multi-Target Networks of Neuroprotective Compounds with Entropy Indices and Synthesis, Assay, and Theoretical Study of New Asymmetric 1,2-Rasagiline Carbamates

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    Francisco J. Romero Durán

    2014-09-01

    Full Text Available In a multi-target complex network, the links (Lij represent the interactions between the drug (di and the target (tj, characterized by different experimental measures (Ki, Km, IC50, etc. obtained in pharmacological assays under diverse boundary conditions (cj. In this work, we handle Shannon entropy measures for developing a model encompassing a multi-target network of neuroprotective/neurotoxic compounds reported in the CHEMBL database. The model predicts correctly >8300 experimental outcomes with Accuracy, Specificity, and Sensitivity above 80%–90% on training and external validation series. Indeed, the model can calculate different outcomes for >30 experimental measures in >400 different experimental protocolsin relation with >150 molecular and cellular targets on 11 different organisms (including human. Hereafter, we reported by the first time the synthesis, characterization, and experimental assays of a new series of chiral 1,2-rasagiline carbamate derivatives not reported in previous works. The experimental tests included: (1 assay in absence of neurotoxic agents; (2 in the presence of glutamate; and (3 in the presence of H2O2. Lastly, we used the new Assessing Links with Moving Averages (ALMA-entropy model to predict possible outcomes for the new compounds in a high number of pharmacological tests not carried out experimentally.

  6. Multi criteria decision making to select the best method for the preparation of solid lipid nanoparticles of rasagiline mesylate using analytic hierarchy process

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    Viveksarathi Kunasekaran

    2014-01-01

    Full Text Available The objective of this study was to select best method for the development of rasagiline mesylate (RM loaded nanoscale solid lipid particles using analytic hierarchy process (AHP. Improper method selection may lead to waste of time, loss of material and financial resources. One of the possibilities to overcome these difficulties, AHP was employed to find the suitable method. In the AHP, a decision of hierarchy was constructed with a goal, criteria, sub-criteria, and alternatives. After constructing the AHP, the expert choice software was used to compute the overall priority of criteria, sub-criteria and alternatives. The best alternative selected was based on the highest priority. Nanoscale solid lipid particles of RM was formulated by the selected microemulsion method (M4 and it shows the particle size, polydispersity index and zeta potential were within acceptable limits. Drug content and entrapment efficiency of the RM-solid lipid nanoparticles were 97.26% and 86.57%, respectively. This study concludes that the AHP was viable and effective tool for selecting a most suitable method for the fabrication of RM loaded nanoscale solid lipid particles.

  7. Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade.

    Science.gov (United States)

    Jia, Shaobin; Lian, Jiangfan; Guo, Donglin; Xue, Xiaolin; Patel, Chinmay; Yang, Lin; Yuan, Zuyi; Ma, Aiqun; Yan, Gan-Xin

    2011-09-01

    Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (I(Na,L) ) could modulate the drug-induced reverse use-dependence in QT and T(p-e) (an index of dispersion of repolarization), and therefore the liability for TdP. Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an I(Na,L) enhancer), d,l-sotalol, clarithromycin and ranolazine (an I(Na,L) blocker) on rate-dependent changes in QT, T(p-e) and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and T(p-e) slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion. ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and T(p-e) intervals, steeper QT-basic cycle length (BCL) and T(p-e) -BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, T(p-e) -BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and T(p-e) without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and T(p-e) -BCL slopes and further increased TdP score. Modulation of I(Na,L) altered drug-induced reverse use-dependence related to QT as well as T(p-e) , indicating that inhibition of I(Na,L) can markedly reduce the TdP liability of agents that prolong QT intervals. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  8. Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKr blockade

    Science.gov (United States)

    Jia, Shaobin; Lian, Jiangfan; Guo, Donglin; Xue, Xiaolin; Patel, Chinmay; Yang, Lin; Yuan, Zuyi; Ma, Aiqun; Yan, Gan-Xin

    2011-01-01

    BACKGROUND AND PURPOSE Drug-induced torsades de pointes (TdP) often occurs during bradycardia due to reverse use-dependence. We tested the hypothesis that inhibition or enhancement of late sodium current (INa,L) could modulate the drug-induced reverse use-dependence in QT and Tp-e (an index of dispersion of repolarization), and therefore the liability for TdP. EXPERIMENTAL APPROACH Arterially perfused rabbit left ventricular wedge preparations were used. Action potentials from the endocardium were recorded simultaneously with a transmural ECG. The effects of Anemonia sulcata toxin (ATX-II) (an INa,L enhancer), d,l-sotalol, clarithromycin and ranolazine (an INa,L blocker) on rate-dependent changes in QT, Tp-e and proarrhythmic events were tested, either alone or in combination. Rate-dependent QT and Tp-e slopes and TdP score (a combined index of TdP liability) were calculated at control and during drug infusion. KEY RESULTS ATX-II (30 nM) and sotalol (300 µM) caused a marked increase in QT and Tp-e intervals, steeper QT-basic cycle length (BCL) and Tp-e-BCL slopes (i.e. reverse use-dependence), and TdP. Addition of ranolazine (15 µM) to ATX-II or sotalol significantly attenuated QT-BCL, Tp-e-BCL slopes and the increased TdP scores. In contrast, clarithromycin (100 µM) moderately prolonged QT and Tp-e without causing R-on-T extrasystole or TdP, but addition of ATX-II (1 nM) to clarithromycin markedly amplified the QT-BCL and Tp-e-BCL slopes and further increased TdP score. CONCLUSION AND IMPLICATIONS Modulation of INa,L altered drug-induced reverse use-dependence related to QT as well as Tp-e, indicating that inhibition of INa,L can markedly reduce the TdP liability of agents that prolong QT intervals. PMID:21182492

  9. Update on ranolazine in the management of angina

    OpenAIRE

    Codolosa JN; Acharjee S; Figueredo VM

    2014-01-01

    J Nicolás Codolosa,1 Subroto Acharjee,1 Vincent M Figueredo1,2 1Einstein Center for Heart and Vascular Health, Einstein Medical Center, 2Jefferson Medical College, Philadelphia, PA, USA Abstract: Mortality rates attributable to coronary heart disease have declined in recent years, possibly related to changes in clinical presentation patterns and use of proven secondary prevention strategies. Chronic stable angina (CSA) remains prevalent, and the goal of treatment is control of sym...

  10. Gateways to clinical trials.

    Science.gov (United States)

    Tomillero, A; Moral, M A

    2009-10-01

    [Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate. Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved.

  11. Neuropsychiatrie disorders in Parkinson's disease and their correction with the MAO-B inhibitor rasagiline (Azilect®

    Directory of Open Access Journals (Sweden)

    M R Nodel

    2011-01-01

    sleeping scale, and the PD quality of life scale (PDQ-39. Results. There were reductions in the severity of nocturnal and morning hypokinesia, daytime off periods, depression, insomnia, overfatigue and improved quality of life. The positive effect of therapy was stable within further 6 follow-up months.

  12. Dgroup: DG01967 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available de (INN) ... D00502 ... Pergolide mesylate (USP); Pergolide mesilate (JAN) ... D07836 ... Dihydroergocryptine mesilate DG00862 ... Ropini...role ... D08489 ... Ropinirole (USAN/INN) ... D00784 ... Ropinirole hydrochlo

  13. Drug: D08469 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 4728(4129) Dopaminergic synapse map07027 Antidepressants map07057 Antiparkinsonia...hibitors N04BD02 Rasagiline D08469 Rasagiline (USAN/INN) USP drug classification [BR:br08302] Antiparkinso

  14. Dgroup: DG01977 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG01977 Chemical ... DGroup Dihydroergotoxine ... D07839 ... Dihydroergotoxine D02268 ... Ergo...loid mesylates (USP); Dihydroergotoxine mesilate (JP17) Neuropsychiatric agent ... DG01964 ... Ergot alkaloid ... DG01963 ... Vasodilator, ergot alkaloid ... Vasodilator ...

  15. Synthetic antiproteases in acute pancreatitis: an experimental study.

    Science.gov (United States)

    Dobosz, M; Sledziński, Z; Babicki, A; Juszkiewicz, P; Basiński, A; Wajda, Z

    1992-01-01

    Acute pancreatitis was induced in 19 anesthetized dogs by retrograde injection of bile mixed with trypsin into the pancreatic duct. Two groups, of six animals each, were treated with intravenous infusion of synthetic antiproteases: gabexate mesilate and nafamostat mesilate in doses of 1 mg/kg per hr. One group of seven animals remained untreated. Two untreated dogs died during the experiment. All the treated dogs survived. Hemodynamic data were monitored hourly during a 6-hr observation period. In the untreated animals, cardiac output, mean arterial pressure, and left ventricular stroke volume decreased rapidly; an increase of pulmonary vascular resistance and systemic vascular resistance was observed. Synthetic antiproteases, given as a therapy, improved the hemodynamic parameters significantly and prevented the animals from developing shock. Gabexate mesilate and nafamostat mesilate seem to be of value in the treatment of experimentally produced acute pancreatitis in dogs.

  16. Dgroup: DG01964 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG01964 DGroup Ergot alkaloid ... DG01963 ... Vasodilator, ergot alkaloid ... DG01977 ... Dihydroergo...toxine ... D07839 ... Dihydroergotoxine ... D02268 ... Ergoloid mesylates (USP); Dihydroergotoxine mesilate (JP17) ... DG00283 ... Nicergo...line ... D01290 ... Nicergoline (JP17/USAN/INN) ... D08271 ... Nicergoline tartrate ... DG00284 ... Dihydroergo...cristine ... D07834 ... Dihydroergocristine (BAN) ... D07833 ... Dihydroergocri...stine mesilate (BAN) ... D07218 ... Metergoline (INN) DG00445 ... Methylergometrine ... D08207 ... Methylergometrine (INN) ... D00680 ... Methylergo

  17. Dgroup: DG01963 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG01963 DGroup Vasodilator, ergot alkaloid ... DG01977 ... Dihydroergotoxine ... D07839 ... Dihydroergo...toxine ... D02268 ... Ergoloid mesylates (USP); Dihydroergotoxine mesilate (JP17) DG00283 ... Nicergoline ... D01290 ... Nicergo...line (JP17/USAN/INN) ... D08271 ... Nicergoline tartrate DG00284 ... Dihydroergocristine ... D07834 ... Dihydroergo...cristine (BAN) ... D07833 ... Dihydroergocristine mesilate (BAN) D07218 ... Metergo...line (INN) Neuropsychiatric agent ... DG01964 ... Ergot alkaloid ATC code: C04AE Peripheral vasodilator ...

  18. Drug: D01441 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available SA:1565] map07045 Antineoplastics - protein kinases inhibitors Therapeutic catego...ry of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 42 Antineoplastics 429 Miscellaneous ... D01441 Imatinib mesilate (JAN); Imatinib mesylate (USAN) USP drug classification [BR:br08302] Antineoplastics...e kinase [HSA:25] [KO:K06619] Imatinib [ATC:L01XE01] D01441 Imatinib mesilate (JAN) Antineoplastics [BR:br08

  19. The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca2+-activated K+ channels

    DEFF Research Database (Denmark)

    Skibsbye, Lasse; Diness, Jonas; Sørensen, Ulrik S

    2011-01-01

    , whereas newer multichannel blockers such as amiodarone and ranolazine have been introduced later. This study was devoted to the evaluation of an acute pacing-induced in vivo model of AF in rats. Antiarrhythmic effects of well-known compounds such as lidocaine, dofetilide, and ranolazine were confirmed...

  20. Improved myocardial perfusion after transmyocardial laser revascularization in a patient with microvascular coronary artery disease

    Directory of Open Access Journals (Sweden)

    Peyman Mesbah Oskui

    2014-03-01

    Full Text Available We report the case of a 59-year-old woman who presented with symptoms of angina that was refractory to medical management. Although her cardiac catheterization revealed microvascular coronary artery disease, her symptoms were refractory to optimal medical management that included ranolazine. After undergoing transmyocardial revascularization, her myocardial ischemia completely resolved and her symptoms dramatically improved. This case suggests that combination of ranolazine and transmyocardial revascularization can be applied to patients with microvascular coronary artery disease.

  1. Gateways to clinical trials.

    Science.gov (United States)

    Bayés, M; Rabasseda, X; Prous, J R

    2007-01-01

    [111In]-DOTA-cG250, [131I]-Metuximab injection, [177Lu]-DOTA-cG250; Anatumomab mafenatox, AP-12009; BIBW-2992, Biricodar dicitrate; Cediranib, Cilengitide, Clevidipine, CNTO-528, CNTO-95, CP-870893; Disufenton sodium, DNK-333A; Ecallantide, Enzastaurin hydrochloride, Etravirine, Exatecan mesilate; Fingolimod hydrochloride; Human insulin, Hyaluronic acid; Indisulam, Inhaled insulin, Insulin glargine, Ipilimumab, Irofulven, Ispronicline, ITF-282; J591; KAI-9803; L-Arginine hydrochloride, Laropiprant, LY-518674; Matuzumab, MB-7133, Methylnaltrexone bromide, MVA-5T4; Nemifitide ditriflutate; Obatoclax mesylate, Oral insulin; P-276-00, PF-562271, Picolinic acid; Quercetin; R-109339, R-547, Rivaroxaban, Ruboxistaurin mesilate hydrate; Seliciclib; Terameprocol, Tilarginine hydrochloride, Tolvaptan, Uracil; Vincristine.

  2. Dgroup: DG00921 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available mesilate Neuropsychiatric agent ... DG01835 ... Benzodiazepine sedative-hypnotics ... DG01567 ... GABA-A receptor agonist ATC code: N05CD11 Benzo...diazepine sedative-hypnotics GABRA/GABRB/GABRD/GABRE/GABRG/GABRP/GABRQ [HSA:2554 25

  3. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, Ulrich-Christian; Semb, Synne; Nojgaard, Camilla

    2008-01-01

    be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  4. [A case of chronic hepatitis C with pancreas divisum and acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin].

    Science.gov (United States)

    Morio, Reona; Imamura, Michio; Fukuhara, Takayuki; Kan, Hiromi; Fujino, Hatsue; Kawaoka, Tomokazu; Hiramatsu, Akira; Aikata, Hiroshi; Sasaki, Tamito; Chayama, Kazuaki

    2014-10-01

    A 47-year-old man developed acute pancreatitis during combination treatment with telaprevir/peginterferon/ribavirin for chronic hepatitis C. Cessation of telaprevir, fasting, and gabexate mesilate improved the pancreatitis. Although peginterferon and ribavirin treatment was continued, there was no recurrence of the pancreatitis. Endoscopic retrograde cholangiopancreatography incidentally showed a pancreas divisum. We definitively diagnosed drug-induced acute pancreatitis due to telaprevir.

  5. Drug: D07836 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available kinsonian, dopaminergic; Vasodilator ATC code: N04BC03 map07057 Antiparkinsonian ag...D07836 Drug Dihydroergocryptine mesilate; Almirid (TN) C32H43N5O5. CH4SO3 673.3145 673.82 D07836.gif Antipar

  6. Drug: D00502 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 2S. CH4SO3 410.1698 410.5938 D00502.gif Antiparkinsonian, Dopamine agonist [DS:H00057] Therapeutic category:... Enzyme: CYP2D6 [HSA:1565] map07057 Antiparkinsonian agents Therapeutic category of drugs in Japan [BR:br083...ral nervous system 116 Antiparkinsonian agents 1169 Others D00502 Pergolide mesilate (JAN); Pergolide mesyla

  7. Treatment of advanced Parkinson's disease in the United States: a cost-utility model.

    Science.gov (United States)

    Groenendaal, Huybert; Tarrants, Marcy L; Armand, Christophe

    2010-01-01

    As Parkinson's disease (PD) progresses, patients and their families experience substantial health and economic burdens. Because motor fluctuations (also called 'off-time') are linked to poor quality of life and higher healthcare costs, minimizing off-time is an effective strategy for reducing costs associated with PD. To assess the cost utility of rasagiline or entacapone as adjunctive therapies to levodopa versus levodopa/carbidopa/entacapone (LCE) versus standard levodopa monotherapy in patients with advanced PD and motor fluctuations in the US. A 2-year stochastic Markov model was utilized to examine the cost effectiveness of treatments of advanced PD. The model assumed that patients transition health status every 4 months. Transition probabilities, including uncertainties, were estimated from clinical trial data. Medical costs, daily drug costs and utility weights were obtained from published literature. Over 2 years, all therapy options showed greater effectiveness than levodopa alone. Rasagiline+levodopa and LCE were cost saving from a payor perspective, while entacapone+levodopa was cost saving from a societal perspective. Mean benefits over 2 years were 0.12 (90% credibility interval [CI] 0.07, 0.18) additional quality-adjusted life-years (QALYs) for rasagiline+levodopa, entacapone+levodopa and LCE, 5.08 (90% CI 3.87, 6.28) additional months with treatment of advanced PD patients. Results from this cost-utility model and prior adjunctive clinical data provide ongoing support for the adjunctive use of rasagiline in advanced PD patients with motor fluctuations.

  8. Freezing of Gait in Parkinsonism and its Potential Drug Treatment

    Science.gov (United States)

    Zhang, Li-Li; Canning, S. Duff; Wang, Xiao-Ping

    2016-01-01

    Freezing of gait (FOG) is a heterogeneous symptom. Studies of treatment for FOG are scarce. Levodopa and monoamine oxidase inhibitors (rasagiline and selegiline) have shown effective improvement for FOG. Other drugs, such as L-threo-3, 4-dihydroxyphenylserine, amantadine, and botulinum toxin have exhibited some beneficial effects. The present review summarizes the potential drug treatment for FOG in Parkinsonism. PMID:26635194

  9. The new inhibitor of monoamine oxidase, M30, has a neuroprotective effect against dexamethasone-induced brain cell apoptosis

    Directory of Open Access Journals (Sweden)

    Shakevia Johnson

    2010-11-01

    Full Text Available Stress detrimentally affects the brain and body and can lead to or be accompanied by depression. Although stress and depression may contribute to each other, the exact molecular mechanism underlying the effects is unclear. However, there is a correlation between stress and an increase in glucocorticoid secretion which causes a subsequent increase in monoamine oxidase (MAO activity during stress. Consequently, MAO inhibitors have been used as traditional antidepressant drugs. Cellular treatment with the synthetic glucocorticoid, dexamethasone (a cellular stressor, has been reported to markedly increase both MAO A and MAO B catalytic activities, as well as apoptosis. This study compares the neuroprotective abilities of M30 (a new generation inhibitor of both MAO A and MAO B with rasagiline (Azilect®, another new MAO B inhibitor and selegiline (Deprenyl®, a traditional MAO B inhibitor in the prevention of dexamethasone-induced brain cell death and MAO activity in human neuroblastoma cells, SH-SY5Y. M30 demonstrated the highest inhibitory effect on MAO A; however, M30 showed the lowest inhibitory effect on MAO B enzymatic activity in comparison to rasagiline and selegiline. Although, M30 exhibited the greatest neuroprotective effect by decreasing cell death rates and apoptotic DNA damage compared to rasagiline and selegiline, these neuroprotective effects of M30 were, overall, similar to rasagiline. Summarily, M30 has a generally greater impact on neuroprotection than the MAO B inhibitors, selegiline and rasagiline. Our results suggest that M30 may have great potential in alleviating disorders involving increases in both MAO A and MAO B, such as stress-induced disorders.

  10. Oral lesions associated with hydroxyurea treatment

    Directory of Open Access Journals (Sweden)

    Regina Mendonça

    2011-01-01

    Full Text Available Hydroxyurea (HU is an antimetabolic agent commonly used in myeloproliferative disorders and hematological diseases as well as in severe psoriasis. Despite of usually be well tolerated, sometimes it can induce immunosuppression and mucocutaneous adverse effects associated with discomfort or pain. Nevertheless, oral mucosal adverse reactions are extremely uncommon and present as ulcers, tongue depapilation and dyschromia. Complete remission of adverse effects is usually observed after withdrawal of the medication. The aim of this paper is to report two patients with oral lesions related to HU treatment. T0 he patients were adequately managed by changing hydroxyurea with imatinib mesilate. Oral lesions are rare complications of long-term hydroxyurea treatment and may be an indication of stopping therapy and substitution with imatinib mesilate.

  11. Dgroup: DG01982 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available DG01982 DGroup Antimigraine, ergot alkaloid -erg- ... DG00833 ... Dihydroergotamine ... D07837 ... Dihydroergo...tamine (INN) ... D02211 ... Dihydroergotamine mesylate (USP); Dihydroergotamine mesilate (JP17) ... D07838 ... Dihydroergo...tamine tartrate DG00834 ... Ergotamine ... D07906 ... Ergotamine (INN) ... D00679 ... Ergotamine tartr... Methysergide maleate (USP) DG00453 ... Lisuride ... D08132 ... Lisuride (INN) ... D01462 ... Lisuride maleate (JAN) D05829 ... Sergo...lexole maleate (USAN) D07585 ... Isopropylantipyrine - ergotamine tartrate - anhydrous caffeine mixt ... Neuropsychiatric agent ATC code: N02CA ...

  12. Synergistic antiarrhythmic effect of combining inhibition of Ca(2+)-activated K(+) (SK) channels and voltage-gated Na(+) channels in an isolated heart model of atrial fibrillation

    DEFF Research Database (Denmark)

    Kirchhoff, Jeppe Egedal; Goldin Diness, Jonas; Sheykhzade, Majid

    2015-01-01

    )thiazol-2-amine (ICA) in a Langendorff-perfused guinea pig heart model in which AF was induced after acetylcholine application and burst pacing. RESULTS: AF duration was reduced when both flecainide and ranolazine were combined with ICA in doses that did not reduce AF as monotherapy. At higher...

  13. ATX-II-induced pulmonary vein arrhythmogenesis related to atrial fibrillation and long QT syndrome.

    Science.gov (United States)

    Lu, Yen-Yu; Cheng, Chen-Chuan; Chen, Yao-Chang; Chen, Shih-Ann; Chen, Yi-Jen

    2012-08-01

    Long QT syndrome (LQTS) is associated with a high incidence of atrial fibrillation (AF), but the underlying mechanisms are unclear. Pulmonary veins (PVs) play a critical role in AF genesis. Type 3 LQTS increases late sodium current (I(Na,L) ), which may increase PV arrhythmogenesis and AF. Therefore, this study examines PV arrhythmogenesis in anemonia sulcata toxin II (ATX-II)-induced type 3 LQTS and evaluates whether the I(Na,L) inhibitor ranolazine can suppress PV arrhythmogenesis. Conventional microelectrodes were used to record the action potentials (AP) and contractility in isolated rabbit PV specimens before and after ATX-II administration with or without ranolazine. Anemonia sulcata toxin II (100 nM) increased the PV spontaneous rates from 2·0 ± 0·1 to 2·9 ± 0·2 Hz (n = 7), induced PV burst firing (100%) with the genesis of early afterdepolarization (EAD) (86%) and prolonged the AP duration. Ranolazine (0·1, 1 and 10 μM) dose dependently reduced the PV spontaneous rates from 2·5 ± 0·2 to 2·3 ± 0·2 Hz, 1·9 ± 0·2 and 1·5 ± 0·3 Hz (P ATX-II (100 nM) further increased the AP duration. However, ATX-II neither increased the PV spontaneous rates (1·6 ± 0·1 vs. 1·7 ± 0·2 Hz, n = 7) nor induced PV burst firing or EAD. Moreover, ranolazine (10 μM) reduced ATX-II-induced PV acceleration and EAD. The I(Na,L) enhancer ATX-II can increase PV arrhythmogenesis, which can be attenuated or blocked by ranolazine. This suggests that AF may be related to type 3 LQTS through increased I(Na,L) . © 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.

  14. Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Bradley J Robottom

    2011-01-01

    Full Text Available Bradley J RobottomDepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD, USAAbstract: Parkinson's disease (PD is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors.Keywords: monoamine oxidase inhibitors, rasagiline, selegiline, Parkinson's disease, efficacy, safety

  15. Drug-printing by flexographic printing technology--a new manufacturing process for orodispersible films.

    Science.gov (United States)

    Janssen, Eva Maria; Schliephacke, Ralf; Breitenbach, Armin; Breitkreutz, Jörg

    2013-01-30

    Orodispersible films (ODFs) are intended to disintegrate within seconds when placed onto the tongue. The common way of manufacturing is the solvent casting method. Flexographic printing on drug-free ODFs is introduced as a highly flexible and cost-effective alternative manufacturing method in this study. Rasagiline mesylate and tadalafil were used as model drugs. Printing of rasagiline solutions and tadalafil suspensions was feasible. Up to four printing cycles were performed. The possibility to employ several printing cycles enables a continuous, highly flexible manufacturing process, for example for individualised medicine. The obtained ODFs were characterised regarding their mechanical properties, their disintegration time, API crystallinity and homogeneity. Rasagiline mesylate did not recrystallise after the printing process. Relevant film properties were not affected by printing. Results were comparable to the results of ODFs manufactured with the common solvent casting technique, but the APIs are less stressed through mixing, solvent evaporation and heat. Further, loss of material due to cutting jumbo and daughter rolls can be reduced. Therefore, a versatile new manufacturing technology particularly for processing high-potent low-dose or heat sensitive drugs is introduced in this study. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure.

    Science.gov (United States)

    Dalal, Jamshed J; Mishra, Sundeep

    The combined and relative contribution of glucose and fatty acid oxidation generates myocardial energy, which regulates the cardiac function and efficiency. Any dysregulation in this metabolic homeostasis can adversely affect the function of heart and contribute to cardiac conditions such as angina and heart failure. Metabolic agents ameliorate this internal metabolic anomaly, by shifting the energy production pathway from free fatty acids to glucose, resulting in a better performance of the heart. Metabolic therapy is relatively a new modality, which functions through optimization of cardiac substrate metabolism. Among the metabolic therapies, trimetazidine and ranolazine are the agents presently available in India. In the present review, we would like to present the metabolic perspective of pathophysiology of coronary artery disease and heart failure, and metabolic therapy by using trimetazidine and ranolazine. Copyright © 2017. Published by Elsevier B.V.

  17. Modulation of myocardial energetics: An important category of agents in the multimodal treatment of coronary artery disease and heart failure

    Directory of Open Access Journals (Sweden)

    Jamshed J. Dalal

    2017-05-01

    Full Text Available The combined and relative contribution of glucose and fatty acid oxidation generates myocardial energy, which regulates the cardiac function and efficiency. Any dysregulation in this metabolic homeostasis can adversely affect the function of heart and contribute to cardiac conditions such as angina and heart failure. Metabolic agents ameliorate this internal metabolic anomaly, by shifting the energy production pathway from free fatty acids to glucose, resulting in a better performance of the heart. Metabolic therapy is relatively a new modality, which functions through optimization of cardiac substrate metabolism. Among the metabolic therapies, trimetazidine and ranolazine are the agents presently available in India. In the present review, we would like to present the metabolic perspective of pathophysiology of coronary artery disease and heart failure, and metabolic therapy by using trimetazidine and ranolazine.

  18. Hypertensive crisis due to contrast-enhanced computed tomography in a patient with malignant pheochromocytoma.

    Science.gov (United States)

    Nakano, Sachiko; Tsushima, Yoshito; Taketomi-Takahashi, Ayako; Higuchi, Tetsuya; Amanuma, Makoto; Oriuchi, Noboru; Endo, Keigo

    2011-07-01

    A 63-year-old man underwent computed tomography (CT) using intravenous low-osmolar iodine contrast medium (LOCM) 6 days after undergoing high-dose (131)I-MIBG therapy for metastatic pheochromocytoma. Immediately after the CT examination, his blood pressure increased to 260/160 mmHg (from 179/101 mmHg before the examination). Phentolamine mesilate was administered, and the blood pressure rapidly went back to normal. Although hypertensive crisis after administration of LOCM is rare, this case suggests that high-dose (131)IMIBG therapy may be a risk factor for hypertensive crisis after administration of intravenous LOCM.

  19. Pharmacological approach to acute pancreatitis

    DEFF Research Database (Denmark)

    Bang, U.C.; Semb, S.; Nøjgaard, Camilla

    2008-01-01

    The aim of the present review is to summarize the current knowledge regarding pharmacological prevention and treatment of acute pancreatitis (AP) based on experimental animal models and clinical trials. Somatostatin (SS) and octreotide inhibit the exocrine production of pancreatic enzymes and may...... be useful as prophylaxis against post endoscopic retrograde cholangiopancreatography pancreatitis (PEP). The protease inhibitor gabexate mesilate (GM) is used routinely as treatment to AP in some countries, but randomized clinical trials and a meta-analysis do not support this practice. Nitroglycerin (NGL...

  20. The autocrine role of tryptase in pressure overload-induced mast cell activation, chymase release and cardiac fibrosis

    Directory of Open Access Journals (Sweden)

    Jianping Li

    2016-03-01

    Results and conclusion: The results indicate the presence of PAR-2 on MCs and that tryptase inhibition and nedocromil prevented TAC-induced fibrosis and increases in MC density, activation, and chymase release. Tryptase also significantly increased chymase concentration in ventricular slice culture media, which was prevented by the tryptase inhibitor. Hydroxyproline concentration in culture media was significantly increased with tryptase incubation as compared to the control group and the tryptase group incubated with nafamostat mesilate or chymostatin. We conclude that tryptase contributes to TAC-induced cardiac fibrosis primarily via activation of MCs and the amplified release of chymase.

  1. Sarcoendoplasmic reticulum Ca(2+) ATPase. A critical target in chlorine inhalation-induced cardiotoxicity.

    Science.gov (United States)

    Ahmad, Shama; Ahmad, Aftab; Hendry-Hofer, Tara B; Loader, Joan E; Claycomb, William C; Mozziconacci, Olivier; Schöneich, Christian; Reisdorph, Nichole; Powell, Roger L; Chandler, Joshua D; Day, Brian J; Veress, Livia A; White, Carl W

    2015-04-01

    Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation-induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration-approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia-reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure.

  2. Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

    Science.gov (United States)

    Ahmad, Aftab; Hendry-Hofer, Tara B.; Loader, Joan E.; Claycomb, William C.; Mozziconacci, Olivier; Schöneich, Christian; Reisdorph, Nichole; Powell, Roger L.; Chandler, Joshua D.; Day, Brian J.; Veress, Livia A.; White, Carl W.

    2015-01-01

    Autopsy specimens from human victims or experimental animals that die due to acute chlorine gas exposure present features of cardiovascular pathology. We demonstrate acute chlorine inhalation–induced reduction in heart rate and oxygen saturation in rats. Chlorine inhalation elevated chlorine reactants, such as chlorotyrosine and chloramine, in blood plasma. Using heart tissue and primary cardiomyocytes, we demonstrated that acute high-concentration chlorine exposure in vivo (500 ppm for 30 min) caused decreased total ATP content and loss of sarcoendoplasmic reticulum calcium ATPase (SERCA) activity. Loss of SERCA activity was attributed to chlorination of tyrosine residues and oxidation of an important cysteine residue, cysteine-674, in SERCA, as demonstrated by immunoblots and mass spectrometry. Using cardiomyocytes, we found that chlorine-induced cell death and damage to SERCA could be decreased by thiocyanate, an important biological antioxidant, and by genetic SERCA2 overexpression. We also investigated a U.S. Food and Drug Administration–approved drug, ranolazine, used in treatment of cardiac diseases, and previously shown to stabilize SERCA in animal models of ischemia–reperfusion. Pretreatment with ranolazine or istaroxime, another SERCA activator, prevented chlorine-induced cardiomyocyte death. Further investigation of responsible mechanisms showed that ranolazine- and istaroxime-treated cells preserved mitochondrial membrane potential and ATP after chlorine exposure. Thus, these studies demonstrate a novel critical target for chlorine in the heart and identify potentially useful therapies to mitigate toxicity of acute chlorine exposure. PMID:25188881

  3. The Effect of Serine Protease Inhibitors on Airway Inflammation in a Chronic Allergen-Induced Asthma Mouse Model

    Directory of Open Access Journals (Sweden)

    Chih-Che Lin

    2014-01-01

    Full Text Available Serine protease inhibitors reportedly attenuated airway inflammation and had antioxidant in multiorgan. However, the effects of the serine protease inhibitors nafamostat mesilate (FUT, gabexate mesilate (FOY, and ulinastatin (UTI on a long-term challenged mouse model of chronic asthma are unclear. BALB/c mice (6 mice/group were intratracheally inoculated with five doses of Dermatophagoides pteronyssinus (Der p; 50 μL, 1 mg/mL at one-week intervals. Therapeutic doses of FUT (0.0625 mg/kg, FOY (20 mg/kg, or UTI (10,000 U/kg were, respectively, injected intraperitoneally into these mice. Control mice received sterile PBS. At 3 days after the last challenge, mice were sacrificed to assess airway hyperresponsiveness (AHR, remodeling, and inflammation; lung histological features; and cytokine expression profiles. Compared with untreated controls, mice treated with FUT, FOY, and UTI had decreased AHR and goblet cell hyperplasia, decreased eosinophil and neutrophil infiltration, decreased Der p-induced IL-4 levels in serum and IL-5, IL-6, IL-13, and IL-17 levels in bronchoalveolar lavage fluid, and inhibited nuclear factor (NF-κB activity in lung tissues. The serine protease inhibitors FUT, FOY, and UTI have potential therapeutic benefits for treating asthma by downregulating Th2 cytokines and Th17 cell function and inhibiting NF-κB activation in lung tissue.

  4. Gateways to clinical trials.

    Science.gov (United States)

    Bayés, M; Rabasseda, X; Prous, J R

    2007-11-01

    1-Octanol, 9vPnC-MnCc; Abiraterone acetate, Adalimumab, Adefovir dipivoxil, Alemtuzumab, Aliskiren fumarate, Aminolevulinic acid hexyl ester, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, Aripiprazole, ARRY-520, AS-1404, Asimadoline, Atazanavir sulfate, AVE-0277, Azelnidipine; Bevacizumab, Bimatoprost, Boceprevir, Bortezomib, Bosentan, Botulinum toxin type B; Certolizumab pegol, Cetuximab, Clevudine, Contusugene ladenovec, CP-751871, Crofelemer, Cypher, CYT006-AngQb; Darbepoetin alfa, Desmopressin, Dexlansoprazole, DG-041; E-5555, Ecogramostim, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Everolimus, Ezetimibe, Ezetimibe/simvastatin; Falecalcitriol, Fampridine, Fesoterodine fumarate, Fingolimod hydrochloride; Gefitinib, Ghrelin (human), GS-7904L, GV-1001; HT-1001; Insulin detemir, ISIS-112989, Istradefylline; Laquinimod sodium, Latanoprost/timolol maleate, Lenalidomide, Levobetaxolol hydrochloride, Liposomal doxorubicin, Liposomal morphine sulfate, Lubiprostone, Lumiracoxib, LY-518674; MEM-1003, Mesna disulfide, Mipomersen sodium, MM-093, Mycophenolic acid sodium salt; Naptumomab estafenatox, Natalizumab; Olmesartan medoxomil, Olmesartan medoxomil/hydrochlorothiazide; Paclitaxel nanoparticles, Paclitaxel poliglumex, Pasireotide, Pazufloxacin mesilate, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimagedine, Pimecrolimus, Pramlintide acetate, Prasterone, Pregabalin, Prulifloxacin; QAE-397; Rec-15/2615, RFB4(dsFv)-PE38, rhGAD65, Roflumilast, Romiplostim, Rosuvastatin calcium, Rotigotine, Rupatadine fumarate; Safinamide mesilate, SIR-Spheres, Sitagliptin phosphate, Sodium phenylacetate, Sodium phenylacetate/Sodium benzoate, Sorafenib, SSR-244738; Taribavirin hydrochloride, Taxus, Teduglutide, Tegaserod maleate, Telaprevir, Telbivudine, Tenofovir disoproxil fumarate, Tigecycline, Tiotropium bromide, Trabectedin, Travoprost

  5. Monoamine oxidase B inhibitors for the treatment of Parkinson's disease: a review of symptomatic and potential disease-modifying effects.

    Science.gov (United States)

    Schapira, Anthony H V

    2011-12-01

    Parkinson's disease is a disorder characterized pathologically by progressive neurodegeneration of the dopaminergic cells of the nigrostriatal pathway. Although the resulting dopamine deficiency is the cause of the typical motor features of Parkinson's disease (bradykinesia, rigidity, tremor), additional non-motor symptoms appear at various timepoints and are the result of non-dopamine nerve degeneration. Monoamine oxidase B (MAO-B) inhibitors are used in the symptomatic treatment of Parkinson's disease as they increase synaptic dopamine by blocking its degradation. Two MAO-B inhibitors, selegiline and rasagiline, are currently licensed in Europe and North America for the symptomatic improvement of early Parkinson's disease and to reduce off-time in patients with more advanced Parkinson's disease and motor fluctuations related to levodopa. A third MAO-B inhibitor (safinamide), which also combines additional non-dopaminergic properties of potential benefit to Parkinson's disease, is currently under development in phase III clinical trials as adjuvant therapy to either a dopamine agonist or levodopa. MAO-B inhibitors have also been studied extensively for possible neuroprotective or disease-modifying actions. There is considerable laboratory evidence that MAO-B inhibitors do exert some neuroprotective properties, at least in the Parkinson's disease models currently available. However, these models have significant limitations and caution is required in assuming that such results may easily be extrapolated to clinical trials. Rasagiline 1 mg/day has been shown to provide improved motor control in terms of Unified Parkinson's Disease Rating Scale (UPDRS) score at 18 months in those patients with early disease who began the drug 9 months before a second group. There are a number of possible explanations for this effect that may include a disease-modifying action; however, the US FDA recently declined an application for the licence of rasagiline to be extended to cover

  6. Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease: Two Randomized Clinical Trials and Lessons Learned.

    Science.gov (United States)

    Hauser, Robert A; Stocchi, Fabrizio; Rascol, Olivier; Huyck, Susan B; Capece, Rachel; Ho, Tony W; Sklar, Peter; Lines, Christopher; Michelson, David; Hewitt, David

    2015-12-01

    Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials. To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations. Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations. In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio. The primary outcome measure was change in off time from baseline to week 12. In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for

  7. Drug: D02562 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ate (USAN) USP drug classification [BR:br08302] Antiparkinson Agents Monoamine Ox...D02562 Drug Rasagiline mesylate (USAN); Azilect (TN) C12H13N. CH4SO3 267.0929 267.344 D02562.gif Antiparkins... cytochrome P450 hsa04726(4129) Serotonergic synapse hsa04728(4129) Dopaminergic synapse map07027 Antidepressants map07057 Antiparkin...sonian agents map07216 Catecholamine transferase inhibit...onian [DS:H00057] ATC code: N04BD02 monoamine oxidase B (MAO-B) inhibitor [HSA:4129

  8. Late sodium current inhibition reverses electromechanical dysfunction in human hypertrophic cardiomyopathy.

    Science.gov (United States)

    Coppini, Raffaele; Ferrantini, Cecilia; Yao, Lina; Fan, Peidong; Del Lungo, Martina; Stillitano, Francesca; Sartiani, Laura; Tosi, Benedetta; Suffredini, Silvia; Tesi, Chiara; Yacoub, Magdi; Olivotto, Iacopo; Belardinelli, Luiz; Poggesi, Corrado; Cerbai, Elisabetta; Mugelli, Alessandro

    2013-02-05

    Hypertrophic cardiomyopathy (HCM), the most common mendelian heart disorder, remains an orphan of disease-specific pharmacological treatment because of the limited understanding of cellular mechanisms underlying arrhythmogenicity and diastolic dysfunction. We assessed the electromechanical profile of cardiomyocytes from 26 HCM patients undergoing myectomy compared with those from nonfailing nonhypertrophic surgical patients by performing patch-clamp and intracellular Ca(2+) (Ca(2+)(i)) studies. Compared with controls, HCM cardiomyocytes showed prolonged action potential related to increased late Na(+) (I(NaL)) and Ca(2+) (I(CaL)) currents and decreased repolarizing K(+) currents, increased occurrence of cellular arrhythmias, prolonged Ca(2+)(i) transients, and higher diastolic Ca(2+)(i). Such changes were related to enhanced Ca(2+)/calmodulin kinase II (CaMKII) activity and increased phosphorylation of its targets. Ranolazine at therapeutic concentrations partially reversed the HCM-related cellular abnormalities via I(NaL) inhibition, with negligible effects in controls. By shortening the action potential duration in HCM cardiomyocytes, ranolazine reduced the occurrence of early and delayed afterdepolarizations. Finally, as a result of the faster kinetics of Ca(2+)(i) transients and the lower diastolic Ca(2+)(i), ranolazine accelerated the contraction-relaxation cycle of HCM trabeculae, ameliorating diastolic function. We highlighted a specific set of functional changes in human HCM myocardium that stem from a complex remodeling process involving alterations of CaMKII-dependent signaling, rather than being a direct consequence of the causal sarcomeric mutations. Among the several ion channel and Ca(2+)(i) handling proteins changes identified, an enhanced I(NaL) seems to be a major contributor to the electrophysiological and Ca(2+)(i) dynamic abnormalities of ventricular myocytes and trabeculae from patients with HCM, suggesting potential therapeutic implications of

  9. Phenotypic variability in LQT3 human induced pluripotent stem cell-derived cardiomyocytes and their response to antiarrhythmic pharmacologic therapy: An in silico approach.

    Science.gov (United States)

    Paci, Michelangelo; Passini, Elisa; Severi, Stefano; Hyttinen, Jari; Rodriguez, Blanca

    2017-07-27

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are in vitro models with the clear advantages of their human origin and suitability for human disease investigations. However, limitations include their incomplete characterization and variability reported in different cell lines and laboratories. The purpose of this study was to investigate in silico ionic mechanisms potentially explaining the phenotypic variability of hiPSC-CMs in long QT syndrome type 3 (LQT3) and their response to antiarrhythmic drugs. Populations of in silico hiPSC-CM models were constructed and calibrated for control (n = 1,463 models) and LQT3 caused by INaL channelopathy (n = 1,401 models), using experimental recordings for late sodium current (INaL) and action potentials (APs). Antiarrhythmic drug therapy was evaluated by simulating mexiletine and ranolazine multichannel effects. As in experiments, LQT3 hiPSC-CMs yield prolonged action potential duration at 90% repolarization (APD90) (+34.3% than controls) and large electrophysiological variability. LQT3 hiPSC-CMs with symptomatic APs showed overexpression of ICaL, IK1, and INaL, underexpression of IKr, and increased sensitivity to both drugs compared to asymptomatic LQT3 models. Simulations showed that both mexiletine and ranolazine corrected APD prolongation in the LQT3 population but also highlighted differences in drug response. Mexiletine stops spontaneous APs in more LQT3 hiPSC-CMs models than ranolazine (784/1,401 vs 53/1,401) due to its stronger action on INa. In silico simulations demonstrate our ability to recapitulate variability in LQT3 and control hiPSC-CM phenotypes, and the ability of mexiletine and ranolazine to reduce APD prolongation, in agreement with experiments. The in silico models also identify potential ionic mechanisms of phenotypic variability in LQT3 hiPSC-CMs, explaining APD prolongation in symptomatic vs asymptomatic LQT3 hiPSC-CMs. Copyright © 2017 The Authors. Published by Elsevier Inc

  10. Novel analytical method development for some amide group containing drugs using Bougainvillea spectabilis bract extracts.

    Science.gov (United States)

    Killedar, Suresh; Pawar, Anuja; Nadaf, Sameer; Nale, Ashwini; Tamboli, Umarfarukh; Pishawikar, Sachin

    2014-09-01

    To develop and validate a simple, accurate and precise colorimetric method using Bougainvillea spectabilis (B. spectabilis) bract color previously not exploited for estimation of amide group containing drugs i.e. lidocaine and ranolazine in pharmaceutical formulations. Methanolic extract of B. spectabilis was prepared and evaluated for stability of its color at different pH and temperature for a period of 3 weeks. The accuracy and reliability of the proposed method was ascertained by evaluating various validation parameters like linearity, precision, limit of detection, limit of quantitation and specificity according to International Conference on Harmonization guidelines. About 0.5% of B. spectabilis bract color was added to the working standard solutions of the drugs separately and after formation of color complex, and absorbances were noted at 418 nm. For color complexes of lidocaine and ranolazine, linearity was found to be in the range of 4 to 24 and 5 to 25 μg/mL respectively. The % relative standard deviation was found to be within specification limits. Presence of lone pair of electron on nitrogen of amide group of both drugs shows basic nature, contributed in formation of color complex between amide and the color pigment obtained from B. spectabilis bracts. It can be concluded that the method is simple, accurate, economic, and rapid hence can be employed for routine analysis. Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  11. Pharmacokinetic and pharmacodynamic profile of dronedarone , a new antiarrhythmic agent for the treatment of atrial fibrillation.

    Science.gov (United States)

    Rosa, Gian Marco; Bianco, Daniele; Parodi, Antonello; Valbusa, Alberto; Zawaideh, Camilla; Bizzarri, Nicolò; Ferrero, Simone; Brunelli, Claudio

    2014-12-01

    Atrial fibrillation (AF) is the most common arrhythmia and is associated with increased morbidity and mortality. Dronedarone is a recent antiarrhythmic drug that has been developed for treatment of AF, with electrophysiological properties similar to amiodarone but with a lower incidence of side effects. This review evaluates the efficacy, safety, tolerability and side effects of dronedarone in the treatment of AF. In particular, the review includes studies comparing: dronedarone and placebo (ANDROMEDA, ATHENA, DAFNE, ERATO, EURIDIS/ADONIS, HESTIA, PALLAS trials), dronedarone and amiodarone (DIONYSOS trial), ranolazine and dronedarone given alone and in combination (HARMONY trial). Dronedarone is an interesting antiarrhythmic agent in well-selected groups of patients. It also has several other pleiotropic effects that may potentially be beneficial in clinical practice, such as the reduction of the risk of stroke and acute coronary syndromes. In addition, combination therapies such as those with dronedarone and ranolazine, currently being investigated in the HARMONY trial, may provide another interesting approach to increase the antiarrhythmic efficacy and further reduce the incidence of side effects. A better understanding of the mechanisms underlying dronedarone's pleiotropic actions is expected to facilitate the selection of patients benefiting from dronedarone, as well as the development of novel antiarrhythmic drugs for AF.

  12. Management of stable angina: A commentary on the European Society of Cardiology guidelines.

    Science.gov (United States)

    Ambrosio, Giuseppe; Komajda, Michel; Mugelli, Alessandro; Lopez-Sendón, José; Tamargo, Juan; Camm, John

    2016-09-01

    In 2013 the European Society of Cardiology (ESC) released new guidelines on the management of stable coronary artery disease. These guidelines update and replace the previous ESC guidelines on the management of stable angina pectoris, issued in 2006. There are several new aspects in the 2013 ESC guidelines compared with the 2006 version. This opinion paper provides an in-depth interpretation of the ESC guidelines with regard to these issues, to help physicians in making evidence-based therapeutic choices in their routine clinical practice. The first new element is the definition of stable coronary artery disease itself, which has now broadened from a 'simple' symptom, angina pectoris, to a more complex disease that can even be asymptomatic. In the first-line setting, the major changes in the new guidelines are the upgrading of calcium channel blockers, the distinction between dihydropyridines and non-dihydropyridine calcium channel blockers, and the presence of important statements regarding the combination of calcium channel blockers with beta-blockers. In the second-line setting, the 2013 ESC guidelines recommend the addition of long-acting nitrates, ivabradine, nicorandil or ranolazine to first-line agents. Trimetazidine may also be considered. However, no clear distinction is made among different second-line drugs, despite different quality of evidence in favour of these agents. For example, the use of ranolazine is supported by strong and recent evidence, while data supporting the use of the traditional agents appear relatively scanty. © The European Society of Cardiology 2016.

  13. Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson's Disease.

    Science.gov (United States)

    Kasai, Satoka; Yoshihara, Toru; Lopatina, Olga; Ishihara, Katsuhiko; Higashida, Haruhiro

    2017-01-01

    Parkinson's disease (PD), a neurodegenerative disorder, is accompanied by various non-motor symptoms including depression and anxiety, which may precede the onset of motor symptoms. Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor, and is widely used in the treatment of PD and major depression. However, there are few reports about the effects of selegiline on non-motor symptoms in PD. The aim of this study was to explore the antidepressant and anxiolytic effects of selegiline, using CD157/BST1 knockout (CD157 KO) mouse, a PD-related genetic model displaying depression and anxiety, compared with other antiparkinsonian drugs and an antidepressant, and was to investigate the effects of selegiline on biochemical parameters in emotion-related brain regions. A single administration of selegiline (1-10 mg/kg) dose-dependently reduced immobility time in the forced swimming test (FST) in CD157 KO mice, but not C57BL/6N wild-type (WT) mice. At 10 mg/kg, but not 3 mg/kg, selegiline significantly increased climbing time in CD157 KO mice. A single administration of the antiparkinsonian drugs pramipexole (a dopamine (DA) D2/D3 receptor agonist) or rasagiline (another MAO-B inhibitor), and repeated injections of a noradrenergic and specific serotonergic antidepressant (NaSSA), mirtazapine, also decreased immobility time, but did not increase climbing time, in CD157 KO mice. The antidepressant-like effects of 10 mg/kg selegiline were comparable to those of 10 mg/kg rasagiline, and tended to be stronger than those of 1 mg/kg rasagiline. After the FST, CD157 KO mice showed decreases in striatal and hippocampal serotonin (5-HT) content, cortical norepinephrine (NE) content, and plasma corticosterone concentration. A single administration of selegiline at 10 mg/kg returned striatal 5-HT, cortical NE, and plasma corticosterone levels to those observed in WT mice. In the open field test (OFT), repeated administration of mirtazapine had anxiolytic effects, and

  14. Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease

    Science.gov (United States)

    Kasai, Satoka; Yoshihara, Toru; Lopatina, Olga; Ishihara, Katsuhiko; Higashida, Haruhiro

    2017-01-01

    Parkinson’s disease (PD), a neurodegenerative disorder, is accompanied by various non-motor symptoms including depression and anxiety, which may precede the onset of motor symptoms. Selegiline is an irreversible monoamine oxidase-B (MAO-B) inhibitor, and is widely used in the treatment of PD and major depression. However, there are few reports about the effects of selegiline on non-motor symptoms in PD. The aim of this study was to explore the antidepressant and anxiolytic effects of selegiline, using CD157/BST1 knockout (CD157 KO) mouse, a PD-related genetic model displaying depression and anxiety, compared with other antiparkinsonian drugs and an antidepressant, and was to investigate the effects of selegiline on biochemical parameters in emotion-related brain regions. A single administration of selegiline (1–10 mg/kg) dose-dependently reduced immobility time in the forced swimming test (FST) in CD157 KO mice, but not C57BL/6N wild-type (WT) mice. At 10 mg/kg, but not 3 mg/kg, selegiline significantly increased climbing time in CD157 KO mice. A single administration of the antiparkinsonian drugs pramipexole (a dopamine (DA) D2/D3 receptor agonist) or rasagiline (another MAO-B inhibitor), and repeated injections of a noradrenergic and specific serotonergic antidepressant (NaSSA), mirtazapine, also decreased immobility time, but did not increase climbing time, in CD157 KO mice. The antidepressant-like effects of 10 mg/kg selegiline were comparable to those of 10 mg/kg rasagiline, and tended to be stronger than those of 1 mg/kg rasagiline. After the FST, CD157 KO mice showed decreases in striatal and hippocampal serotonin (5-HT) content, cortical norepinephrine (NE) content, and plasma corticosterone concentration. A single administration of selegiline at 10 mg/kg returned striatal 5-HT, cortical NE, and plasma corticosterone levels to those observed in WT mice. In the open field test (OFT), repeated administration of mirtazapine had anxiolytic effects, and

  15. Selegiline Ameliorates Depression-Like Behavior in Mice Lacking the CD157/BST1 Gene, a Risk Factor for Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Satoka Kasai

    2017-05-01

    Full Text Available Parkinson’s disease (PD, a neurodegenerative disorder, is accompanied by various non-motor symptoms including depression and anxiety, which may precede the onset of motor symptoms. Selegiline is an irreversible monoamine oxidase-B (MAO-B inhibitor, and is widely used in the treatment of PD and major depression. However, there are few reports about the effects of selegiline on non-motor symptoms in PD. The aim of this study was to explore the antidepressant and anxiolytic effects of selegiline, using CD157/BST1 knockout (CD157 KO mouse, a PD-related genetic model displaying depression and anxiety, compared with other antiparkinsonian drugs and an antidepressant, and was to investigate the effects of selegiline on biochemical parameters in emotion-related brain regions. A single administration of selegiline (1–10 mg/kg dose-dependently reduced immobility time in the forced swimming test (FST in CD157 KO mice, but not C57BL/6N wild-type (WT mice. At 10 mg/kg, but not 3 mg/kg, selegiline significantly increased climbing time in CD157 KO mice. A single administration of the antiparkinsonian drugs pramipexole (a dopamine (DA D2/D3 receptor agonist or rasagiline (another MAO-B inhibitor, and repeated injections of a noradrenergic and specific serotonergic antidepressant (NaSSA, mirtazapine, also decreased immobility time, but did not increase climbing time, in CD157 KO mice. The antidepressant-like effects of 10 mg/kg selegiline were comparable to those of 10 mg/kg rasagiline, and tended to be stronger than those of 1 mg/kg rasagiline. After the FST, CD157 KO mice showed decreases in striatal and hippocampal serotonin (5-HT content, cortical norepinephrine (NE content, and plasma corticosterone concentration. A single administration of selegiline at 10 mg/kg returned striatal 5-HT, cortical NE, and plasma corticosterone levels to those observed in WT mice. In the open field test (OFT, repeated administration of mirtazapine had anxiolytic effects

  16. The Promise of Neuroprotective Agents in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Judith ePotashkin

    2011-11-01

    Full Text Available Parkinson’s Disease is characterized by loss of dopamine neurons in the substantia nigra of the brain. Since there are limited treatment options for PD, neuroprotective agents are currently being tested as a means to slow disease progression. Agents targeting oxidative stress, mitochondrial dysfunction and inflammation are prime candidates for neuroprotection. This review identifies Rasagiline, Minocycline and creatine, as the most promising neuroprotective agents for PD, and they are all currently in phase III trials. Other agents possessing protective characteristics in delaying PD include stimulants, vitamins, supplements, and other drugs. Additionally, combination therapies also show benefits in slowing PD progression. The identification of neuroprotective agents for PD provides us with therapeutic opportunities for modifying the course of disease progression and, perhaps, reducing the risk of onset when preclinical biomarkers become available.

  17. Type A and B monoamine oxidases distinctly modulate signal transduction pathway and gene expression to regulate brain function and survival of neurons.

    Science.gov (United States)

    Naoi, Makoto; Maruyama, Wakako; Shamoto-Nagai, Masayo

    2017-12-26

    Type A and B monoamine oxidases (MAO-A, -B) mediate and modulate intracellular signal pathways for survival or death of neuronal cells. MAO-A is associated with development of neuronal architecture, synaptic activity, and onset of psychiatric disorders, including depression, and antisocial aggressive impulsive behaviors. MAO-B produces hydrogen peroxide and plays a vital role in neuronal loss of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. This review presents a novel role of MAO-A and B, their substrates and inhibitors, and hydrogen peroxide in brain function and neuronal survival and death. MAO-A activity is regulated not only by genetic factor, but also by environmental factors, including stress, hormonal deregulation, and food factors. MAO-A activity fluctuates by genetic-environmental factors, modulates the neuronal response to the stimuli, and affects behavior and emotional activities. MAO-B inhibitors selegiline and rasagiline protect neurons via increase expression of anti-apoptotic Bcl-2 and pro-survival neurotrophic factors in human neuroblastoma SH-SY5Y and glioblastoma U118MG cell lines. MAO-A knockdown suppressed the rasagiline-induced gene expression in SH-SY5Y cells, whereas MAO-B silencing enhanced the basal- and selegiline-induced gene expression in U118MG cells. MAO-A and B were shown to function as a mediator or repressor of gene expression, respectively. Further study on cellular mechanism underlying regulation of signal pathways by MAO-A and B may bring us a new insight on the role of MAOs in decision of neuronal fate and the development of novel therapeutic strategy may be expected for neuropsychiatric disorders.

  18. Polycyclic propargylamine and acetylene derivatives as multifunctional neuroprotective agents.

    Science.gov (United States)

    Zindo, Frank T; Barber, Quinton R; Joubert, Jacques; Bergh, Jacobus J; Petzer, Jacobus P; Malan, Sarel F

    2014-06-10

    The aim of this study was to design drug-like molecules with multiple neuroprotective mechanisms which would ultimately inhibit N-methyl-D-aspartate (NMDA) receptors, block L-type voltage gated calcium channels (VGCC) and inhibit apoptotic processes as well as the monoamine oxidase-B (MAO-B) enzyme in the central nervous system. These types of compounds may act as neuroprotective and symptomatic drugs for disorders such as Alzheimer's and Parkinson's disease. In designing the compounds we focused on the structures of rasagiline and selegiline, two well known MAO-B inhibitors and proposed neuroprotective agents. Based on this consideration, the compounds synthesised all contain the propargylamine functional group of rasagiline and selegiline or a derivative thereof, conjugated to various polycyclic cage moieties. Being non-polar, these polycyclic moieties have been shown to aid in the transport of conjugated compounds across the blood-brain barrier, as well as cell membranes and have secondary positive neuroprotective effects. All novel synthesised polycyclic derivatives proved to have significant anti-apoptotic activity (p < 0.05) which was comparable to the positive control, selegiline. Four compounds (12, 15 and 16) showed promising VGCC and NMDA receptor channel inhibitory activity ranging from 18% to 59% in micromolar concentrations and compared favourably to the reference compounds. In the MAO-B assay, 8-phenyl-ethynyl-8-hydroxypentacycloundecane (10), exhibited MAO-B inhibition of 73.32% at 300 μM. This compound also reduced the percentage of apoptotic cells by as much as 40% when compared to the control experiments. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  19. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. One For All? Hitting multiple Alzheimer’s Disease targets with one drug

    Directory of Open Access Journals (Sweden)

    Rebecca Ellen Hughes

    2016-04-01

    Full Text Available Alzheimer’s disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs. Intended as a introduction for non-experts, this review describes the key multi-target drug design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch and also the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer’s Disease are rasagiline, originally developed for the treatment of Parkinson’s Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

  1. One for All? Hitting Multiple Alzheimer's Disease Targets with One Drug.

    Science.gov (United States)

    Hughes, Rebecca E; Nikolic, Katarina; Ramsay, Rona R

    2016-01-01

    HIGHLIGHTS Many AD target combinations are being explored for multi-target drug design.New databases and models increase the potential of computational drug designLiraglutide and other antidiabetics are strong candidates for repurposing to AD.Donecopride a dual 5-HT/AChE inhibitor shows promise in pre-clinical studies Alzheimer's Disease is a complex and multifactorial disease for which the mechanism is still not fully understood. As new insights into disease progression are discovered, new drugs must be designed to target those aspects of the disease that cause neuronal damage rather than just the symptoms currently addressed by single target drugs. It is becoming possible to target several aspects of the disease pathology at once using multi-target drugs (MTDs). Intended as an introduction for non-experts, this review describes the key MTD design approaches, namely structure-based, in silico, and data-mining, to evaluate what is preventing compounds progressing through the clinic to the market. Repurposing current drugs using their off-target effects reduces the cost of development, time to launch, and the uncertainty associated with safety and pharmacokinetics. The most promising drugs currently being investigated for repurposing to Alzheimer's Disease are rasagiline, originally developed for the treatment of Parkinson's Disease, and liraglutide, an antidiabetic. Rational drug design can combine pharmacophores of multiple drugs, systematically change functional groups, and rank them by virtual screening. Hits confirmed experimentally are rationally modified to generate an effective multi-potent lead compound. Examples from this approach are ASS234 with properties similar to rasagiline, and donecopride, a hybrid of an acetylcholinesterase inhibitor and a 5-HT4 receptor agonist with pro-cognitive effects. Exploiting these interdisciplinary approaches, public-private collaborative lead factories promise faster delivery of new drugs to the clinic.

  2. Role of ST2 in Non–ST-Elevation Acute Coronary Syndrome in the MERLIN-TIMI 36 Trial

    Science.gov (United States)

    Kohli, Payal; Bonaca, Marc P.; Kakkar, Rahul; Kudinova, Anastacia Y.; Scirica, Benjamin M.; Sabatine, Marc S.; Murphy, Sabina A.; Braunwald, Eugene; Lee, Richard T.; Morrow, David A.

    2014-01-01

    OBJECTIVE We investigated the prognostic performance of ST2 with respect to cardiovascular death (CVD) and heart failure (HF) in patients with non–ST-elevation acute coronary syndrome (NSTE-ACS) in a large multinational trial. BACKGROUND Myocytes that are subjected to mechanical stress secrete ST2, a soluble interleukin-1 receptor family member that is associated with HF after STE-ACS. METHODS We measured ST2 with a high-sensitivity assay in all available baseline samples (N = 4426) in patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in the Non–ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocar-dial Infarction 36 (MERLIN-TIMI 36), a placebo-controlled trial of ranolazine in NSTE-ACS. All events, including cardiovascular death and new or worsening HF, were adjudicated by an independent events committee. RESULTS Patients with ST2 concentrations in the top quartile (>35 μg/L) were more likely to be older and male and have diabetes and renal dysfunction. ST2 was only weakly correlated with troponin and B-type natriuretic peptide. High ST2 was associated with increased risk for CVD/HF at 30 days (6.6% vs 1.6%, P <0.0001) and 1 year (12.2% vs 5.2%, P <0.0001). The risk associated with ST2 was significant after adjustment for clinical covariates and biomarkers (adjusted hazard ratio CVD/HF 1.90, 95% CI 1.15–3.13 at 30 days, P = 0.012; 1.51, 95% CI 1.15–1.98 at 1 year, P = 0.003), with a significant integrated discrimination improvement (P < 0.0001). No significant interaction was found between ST2 and ranolazine (Pinteraction = 0.15). CONCLUSIONS ST2 correlates weakly with biomarkers of acute injury and hemodynamic stress but is strongly associated with the risk of HF after NSTE-ACS. This biomarker and related pathway merit further investigation as potential therapeutic targets for patients with ACS at risk for cardiac remodeling. PMID:22096031

  3. [New pharmacological approaches to ischemic heart disease].

    Science.gov (United States)

    Raddino, Riccardo; Della Pina, Paolo; Gorga, Elio; Brambilla, Giulio; Regazzoni, Valentina; Gavazzoni, Mara; Dei Cas, Livio

    2012-10-01

    Major steps have been made in the treatment of ischemic heart disease from the discovery of nitrates as antianginal medication to the techniques of percutaneous angioplasty. This incredible therapeutic progress has resulted in a reduced incidence of ischemic heart disease and related mortality and morbidity. However, statistical and epidemiological data indicate that in ischemic heart disease, despite the achievement of great success, there is a necessity for a further step toward treatment, considering the fact that the characteristics of this population are changing (increased prevalence of subendocardial infarction compared with classic transmural infarction, especially in the elderly population). Furthermore, the need for alternative therapeutic approaches to traditional ones is recognized. Ranolazine is a selective inhibitor of Na channels that prevents pathological extension of late Na current developing in the ischemic myocardial cell. This current is responsible for calcium overload, with consequent impairment of diastolic relaxation. Ranolazine reduces Na overload induced by calcium and improves diastolic relaxation and coronary subendocardial flow, without affecting hemodynamic parameters such as blood pressure, heart rate, or inotropic state of the heart, avoiding undesirable side effects. Efficacy of ranolazine has been evaluated in several trials, using clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). Ivabradine acts through the inhibition of late Na current (also known as If), which controls the spontaneous diastolic depolarization of sinus node cells. The partial inhibition of these channels reduces the frequency of sinus node action potential initiation, resulting in decreased heart rate without effects on contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL trial has tested whether the effect of ivabradine in lowering

  4. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

    Science.gov (United States)

    Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

    2016-10-03

    Late sodium current (late INa) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Nav 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late INa, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late INa inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late INa inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

  5. Eleclazine exhibits enhanced selectivity for long QT syndrome type 3-associated late Na(+) current.

    Science.gov (United States)

    El-Bizri, Nesrine; Xie, Cheng; Liu, Lynda; Limberis, James; Krause, Michael; Hirakawa, Ryoko; Nguyen, Steven; Tabuena, Dennis R; Belardinelli, Luiz; Kahlig, Kristopher M

    2017-10-07

    Eleclazine (GS-6615) is a sodium channel blocker designed to improve the selectivity for cardiac late Na(+) current (INa) over peak INa. The goals of this study were to investigate the inhibition of late INa by eleclazine using a sample of long QT syndrome type 3 (LQT3) and overlap LQT3/Brugada syndrome mutant channels; to compare the apparent binding rates for eleclazine with those for other class 1 antiarrhythmic agents; and to investigate the binding site. Wild-type human cardiac voltage-gated sodium channel (hNaV1.5) and 21 previously reported variants were studied using patch clamp recordings from a heterologous expression system. Eleclazine inhibited anemone toxin II-enhanced late INa from wild-type hNaV1.5 with a drug concentration that causes 50% block of 0.62 ± 0.12 μM (84-fold selectivity over peak INa). The drug concentration that causes 50% block of eleclazine to inhibit the enhanced late INa from LQT3 mutant channels ranged from 0.33 to 1.7 μM. At predicted therapeutic concentrations, eleclazine and ranolazine inhibited peak INa to a similar degree as assessed with 4 overlap LQT3/Brugada syndrome mutations. Eleclazine was found to interact with hNaV1.5 significantly faster than ranolazine and 6 other class 1 antiarrhythmic agents. Engineered mutations (F1760A/Y1767A) located within the local anesthetic binding site decreased the inhibition of late INa and peak INa by eleclazine. At predicted therapeutic concentrations, eleclazine elicits potent inhibition of late INa across a cohort of NaV1.5 mutant channels. These properties are consistent with a class 1b antiarrhythmic agent that associates with unusually rapid binding/unbinding rates. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  6. New drugs vs. old concepts: a fresh look at antiarrhythmics.

    Science.gov (United States)

    Thireau, Jérôme; Pasquié, Jean-Luc; Martel, Eric; Le Guennec, Jean-Yves; Richard, Sylvain

    2011-11-01

    Common arrhythmias, particularly atrial fibrillation (AF) and ventricular tachycardia/fibrillation (VT/VF) are a major public health concern. Classic antiarrhythmic (AA) drugs for AF are of limited effectiveness, and pose the risk of life-threatening VT/VF. For VT/VF, implantable cardiac defibrillators appear to be the unique, yet unsatisfactory, solution. Very few AA drugs have been successful in the last few decades, due to safety concerns or limited benefits in comparison to existing therapy. The Vaughan-Williams classification (one drug for one molecular target) appears too restrictive in light of current knowledge of molecular and cellular mechanisms. New AA drugs such as atrial-specific and/or multichannel blockers, upstream therapy and anti-remodeling drugs, are emerging. We focus on the cellular mechanisms related to abnormal Na⁺ and Ca²⁺ handling in AF, heart failure, and inherited arrhythmias, and on novel strategies aimed at normalizing ionic homeostasis. Drugs that prevent excessive Na⁺ entry (ranolazine) and aberrant diastolic Ca²⁺ release via the ryanodine receptor RyR2 (rycals, dantrolene, and flecainide) exhibit very interesting antiarrhythmic properties. These drugs act by normalizing, rather than blocking, channel activity. Ranolazine preferentially blocks abnormal persistent (vs. normal peak) Na⁺ currents, with minimal effects on normal channel function (cell excitability, and conduction). A similar "normalization" concept also applies to RyR2 stabilizers, which only prevent aberrant opening and diastolic Ca²⁺ leakage in diseased tissues, with no effect on normal function during systole. The different mechanisms of action of AA drugs may increase the therapeutic options available for the safe treatment of arrhythmias in a wide variety of pathophysiological situations. Copyright © 2011 Elsevier Inc. All rights reserved.

  7. Osteoprotegerin and cardiovascular mortality in patients with non-ST elevation acute coronary syndromes

    Science.gov (United States)

    Røysland, Ragnhild; Bonaca, Marc P; Sabatine, Marc; Murphy, Sabina A; Scirica, Benjamin M; Bjerre, Mette; Flyvbjerg, Allan; Braunwald, Eugene; Morrow, David A

    2012-01-01

    Objective To assess the relationship between osteoprotegerin (OPG) and cardiovascular death, and the pathobiological mechanisms contributing to the association, in acute coronary syndromes (ACS). Design Prospective observational. Setting Biomarker substudy of MERLIN-TIMI 36, a randomised, placebo controlled trial of ranolazine in non-ST elevation (NSTE)-ACS. Patients 4463 patients with NSTE-ACS. Interventions Ranolazine or placebo. Main outcome measures Incidence of cardiovascular death (CV death); additionally, heart failure (HF), cardiac arrhythmias, inhospital ischaemia, severe recurrent ischaemia or recurrent myocardial infarction (MI). Results During a median follow-up of 341 days, 208 patients died of cardiovascular causes. The OPG baseline concentration was strongly associated with both 30 day and 1 year incidence of CV death. After adjustment for conventional risk markers, OPG concentrations (log transformed) remained a significant predictor of CV death by 30 days (HR (95% CI) 2.32 (1.30 to 4.17); p=0.005) and by 1 year (HR 1.85 (1.33 to 2.59); p<0.001). Baseline levels of OPG were also an independent predictor of new or worsening HF at 30 days (HR 2.25 (1.38 to 3.69); p=0.001) and 1 year (HR 1.81 (1.26 to 2.58) p=0.001). By univariable analysis, higher OPG was associated with both early ischaemic and arrhythmic events. Although OPG levels were associated with recurrent MI within 12 months, this association was attenuated and no longer significant after multivariable adjustment. Conclusions OPG is independently associated with 30 day and 1 year risk of cardiovascular mortality and HF development after NSTE-ACS. As no independent relationship between OPG levels and recurrent ischaemia or MI was observed, myocardial dysfunction may be a more important stimulus for OPG production than ischaemia in ACS. PMID:22373720

  8. Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain.

    Science.gov (United States)

    Hoyer, Kirsten; Song, Yejia; Wang, Desuo; Phan, Dillon; Balschi, James; Ingwall, Joanne S; Belardinelli, Luiz; Shryock, John C

    2011-05-01

    Inhibition by cardiac glycosides of Na(+), K(+)-ATPase reduces sodium efflux from myocytes and may lead to Na(+) and Ca(2+) overload and detrimental effects on mechanical function, energy metabolism, and electrical activity. We hypothesized that inhibition of sodium persistent inward current (late I(Na)) would reduce ouabain's effect to cause cellular Na(+) loading and its detrimental metabolic (decrease of ATP) and functional (arrhythmias, contracture) effects. Therefore, we determined effects of ouabain on concentrations of intracellular sodium (Na(+)(i)) and high-energy phosphates using (23)Na and (31)P NMR, the amplitude of late I(Na) using the whole-cell patch-clamp technique, and contractility and electrical activity of guinea pig isolated hearts, papillary muscles, and ventricular myocytes in the absence and presence of inhibitors of late I(Na). Ouabain (1-1.3 μM) increased Na(+)(i) and late I(Na) of guinea pig isolated hearts and myocytes by 3.7- and 4.2-fold, respectively. The late I(Na) inhibitors ranolazine and tetrodotoxin significantly reduced ouabain-stimulated increases in Na(+)(i) and late I(Na). Reductions of ATP and phosphocreatine contents and increased diastolic tension in ouabain-treated hearts were also markedly attenuated by ranolazine. Furthermore, the ouabain-induced increase of late I(Na) was also attenuated by the Ca(2+)-calmodulin-dependent kinase I inhibitors KN-93 [N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide] and autocamide-2 related inhibitory peptide, but not by KN-92 [2-[N-(4'-methoxybenzenesulfonyl)]amino-N-(4'-chlorophenyl)-2-propenyl-N-methylbenzylamine phosphate]. We conclude that ouabain-induced Na(+) and Ca(2+) overload is ameliorated by the inhibition of late I(Na).

  9. Regulation of Adrenal Aldosterone Production by Serine Protease Prostasin

    Directory of Open Access Journals (Sweden)

    Takehiro Ko

    2010-01-01

    Full Text Available A serine protease prostasin has been demonstrated to have a pivotal role in the activation of the epithelial sodium channel. Systemic administration of adenovirus carrying human prostasin gene in rats resulted in an increase in plasma prostasin and aldosterone levels. However, the mechanism by which the elevation of prostasin levels in the systemic circulation stimulated the plasma aldosterone levels remains unknown. Therefore, we examined if prostasin increases the aldosterone synthesis in a human adrenocortical cell line (H295R cells. Luciferase assay using CYP11B2 promoter revealed that prostasin significantly increased the transcriptional activity of CYP11B2. Prostasin significantly increased both CYP11B2 mRNA expression and aldosterone production in a dose-dependent manner. Surprisingly, treatment with camostat mesilate, a potent prostasin inhibitor, had no effect on the aldosterone synthesis by prostasin and also a protease-dead mutant of prostasin significantly stimulated the aldosterone production. A T-type/L-type calcium channel blocker and a protein kinase C (PKC inhibitor significantly reduced the aldosterone synthesis by prostasin. Our findings suggest a stimulatory effect of prostasin on the aldosterone synthesis by adrenal gland through the nonproteolytic action and indicate a new role of prostasin in the systemic circulation.

  10. A Case of Idiopathic Acute Pancreatitis in the First Trimester of Pregnancy

    Directory of Open Access Journals (Sweden)

    Tomomi Hara

    2015-01-01

    Full Text Available Acute pancreatitis is rare in pregnancy, with an estimated incidence of approximately 1 in 1000 to 1 in 10,000 pregnancies. Acute pancreatitis in pregnancy usually occurs in the third trimester. Here, we report a case of acute pancreatitis in the first trimester. A 36-year-old primigravida at 11 weeks of gestation complained of severe lower abdominal pain. The pain gradually worsened and migrated toward the epigastric region. She had no history of chronic alcoholism. Blood investigations showed elevated level of C-reactive protein (9.58 mg/dL, pancreatic amylase (170 IU/L, and lipase (332 IU/L. There was no gallstone and no abnormality in the pancreatic and biliary ducts on ultrasonography. Antinuclear antibody and IgG4 were negative and no evidence of hyperlipidemia or diabetes was found. There was also no evidence of viral infection. On the third day of hospitalization, she was diagnosed with severe acute pancreatitis on magnetic resonance imaging. Medical interventions were initiated with nafamostat mesilate and ulinastatin, and parenteral nutrition was administered through a central venous catheter. On the eighth day of hospitalization, her condition gradually improved with a decreased level of pancreatic amylase and the pain subsided. After conservative management, she did not have any recurrence during her pregnancy.

  11. Extensive hemorrhagic erosive gastritis associated with acute pancreatitis successfully treated with a somatostatin analog.

    Science.gov (United States)

    Yabuki, Kiyotaka; Maekawa, Takeo; Satoh, Koichi; Tamasaki, Yoshihisa; Maekawa, Hiroshi; Kudoh, Keizo; Aoki, Eizaburo

    2002-01-01

    In massive hemorrhage from acute gastric mucosal lesions, it is occasionally difficult to control the bleeding with nonsurgical therapy. We used the somatostatin analog, octreotide, which suppresses gastric and pancreatic function, to treat severe hemorrhagic erosive gastritis in a patient with acute pancreatitis. A 22-year-old man presented with epigastralgia and melena. Blood levels of pancreatitis markers were elevated. Computed tomography revealed diffuse enlargement of the pancreas, without fluid collection around the organ. An endoscopic examination showed extensive hemorrhagic erosions over almost the whole gastric mucosa. We diagnosed extensive hemorrhagic erosive gastritis with acute pancreatitis. A protease inhibitor (nafamostat mesilate 50 mg/day) and an H(2) receptor antagonist (famotidine 40 mg/day) were administered by injection for 6 days; the patient's serum and urine amylase levels fell, but the gastric erosions with hemorrhage were not attenuated. Octreotide was given subcutaneously, at a daily dose of 100 microg for 5 days, without famotidine administration. His melena disappeared, and the gastric erosions were markedly decreased. Administration of the somatostatin analog, octreotide, proved to be effective treatment in a patient with severe hemorrhagic erosive gastritis associated with acute pancreatitis.

  12. A reductive aminase from Aspergillus oryzae

    Science.gov (United States)

    Aleku, Godwin A.; France, Scott P.; Man, Henry; Mangas-Sanchez, Juan; Montgomery, Sarah L.; Sharma, Mahima; Leipold, Friedemann; Hussain, Shahed; Grogan, Gideon; Turner, Nicholas J.

    2017-10-01

    Reductive amination is one of the most important methods for the synthesis of chiral amines. Here we report the discovery of an NADP(H)-dependent reductive aminase from Aspergillus oryzae (AspRedAm, Uniprot code Q2TW47) that can catalyse the reductive coupling of a broad set of carbonyl compounds with a variety of primary and secondary amines with up to >98% conversion and with up to >98% enantiomeric excess. In cases where both carbonyl and amine show high reactivity, it is possible to employ a 1:1 ratio of the substrates, forming amine products with up to 94% conversion. Steady-state kinetic studies establish that the enzyme is capable of catalysing imine formation as well as reduction. Crystal structures of AspRedAm in complex with NADP(H) and also with both NADP(H) and the pharmaceutical ingredient (R)-rasagiline are reported. We also demonstrate preparative scale reductive aminations with wild-type and Q240A variant biocatalysts displaying total turnover numbers of up to 32,000 and space time yields up to 3.73 g l-1 d-1.

  13. Apathy and associated factors in Mexican patients with Parkinson's disease.

    Science.gov (United States)

    Rodríguez-Violante, Mayela; González-Latapi, Paulina; Cervantes-Arriaga, Amin; Martínez-Ramírez, Daniel; Velázquez-Osuna, Salvador; Camacho-Ordoñez, Azyadeh

    2014-05-01

    Apathy is one of the most common behavioral disturbances in Parkinson's disease (PD) with a reported prevalence of 17-51 %. Apathy has been associated with depression, cognitive deficits, and poor quality of life. The objective of this study was to determine the prevalence of apathy in Mexican subjects with PD and its correlation with clinical and demographic characteristics. A cross-sectional, descriptive, and analytic study was carried out. Consecutive subjects with PD attending the National Institute of Neurology and Neurosurgery in Mexico City were included. Demographic and other relevant clinical data were collected. The Apathy Scale was applied to all subjects. A cut-off score of ≥ 14 was used. A total of 241 non-demented patients (52.7 % male) were included. Apathy was found in 43 % of subjects. Lower body mass index, older age of PD onset, cognitive decline and disease severity were all related to apathy. The use of dopamine agonists or rasagiline was more common in patients with low apathy scores. Our results show that the prevalence of apathy in Mexican subjects with PD is similar to other reports.

  14. Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology

    Directory of Open Access Journals (Sweden)

    John Paul Maurice Finberg

    2016-10-01

    Full Text Available Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines (cheese effect. A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinson’s disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge of the enzyme’s binding site structure should lead to future developments with these drugs.

  15. Drugs with potential cardiac adverse effects: Retrospective study in a large cohort of parkinsonian patients.

    Science.gov (United States)

    Heranval, A; Lefaucheur, R; Fetter, D; Rouillé, A; Le Goff, F; Maltête, D

    2016-01-01

    Drugs with potential cardiac adverse effects are commonly prescribed in Parkinson's disease (PD). To describe demographic and clinical characteristics in a group of PD patients with cardiac events and to evaluate risk factors. We sampled 506 consecutive PD patients (211 women/295 men), median age 68.3±10.6 years (range 36-95) and median disease duration 11.2±6.5 years (range 1-49). Medications with potential cardiac effects, i.e. QT prolongation (citalopram, escitalopram, venlafaxine, sertraline, domperidone, amantadine, solifenacin), ventricular arrhythmia (rivastigmine, clozapine, midodrine, sildenafil, tadalafil) and ischemic heart disease (rasagiline, entacapone, tadalafil) were recorded. Demographic and clinical data were collected prospectively; cardiac events were obtained retrospectively. Twenty-four patients (4.7%) (9 women/15 men) presented a cardiac event. Fifteen (62.5%) patients had dysautonomia, 4 (16.6%) a history of heart disease and 8 (33.3%) were taking one or more drugs with a definite potential cardiac adverse effect. Age (75.9±6.6 yr vs. 67.8±11 yr), disease duration (14.7±3.6 yr vs. 11±6.5 yr), dysautonomia (62.5% vs. 24.5%) and dementia associated with PD (37.5% vs. 14.6%) were significantly higher in the group with cardiac events (PParkinson's disease is associated with a higher risk of cardiovascular complications. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. Late cardiac sodium current can be assessed using automated patch-clamp [v1; ref status: indexed, http://f1000r.es/4kj

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    Morgan Chevalier

    2014-10-01

    Full Text Available The cardiac late Na+ current is generated by a small fraction of voltage-dependent Na+ channels that undergo a conformational change to a burst-gating mode, with repeated openings and closures during the action potential (AP plateau. Its magnitude can be augmented by inactivation-defective mutations, myocardial ischemia, or prolonged exposure to chemical compounds leading to drug-induced (di-long QT syndrome, and results in an increased susceptibility to cardiac arrhythmias. Using CytoPatch™ 2 automated patch-clamp equipment, we performed whole-cell recordings in HEK293 cells stably expressing human Nav1.5, and measured the late Na+ component as average current over the last 100 ms of 300 ms depolarizing pulses to -10 mV from a holding potential of -100 mV, with a repetition frequency of 0.33 Hz. Averaged values in different steady-state experimental conditions were further corrected by the subtraction of current average during the application of tetrodotoxin (TTX 30 μM. We show that ranolazine at 10 and 30 μM in 3 min applications reduced the late Na+ current to 75.0 ± 2.7% (mean ± SEM, n = 17 and 58.4 ± 3.5% (n = 18 of initial levels, respectively, while a 5 min application of veratridine 1 μM resulted in a reversible current increase to 269.1 ± 16.1% (n = 28 of initial values. Using fluctuation analysis, we observed that ranolazine 30 μM decreased mean open probability p from 0.6 to 0.38 without modifying the number of active channels n, while veratridine 1 μM increased n 2.5-fold without changing p. In human iPSC-derived cardiomyocytes, veratridine 1 μM reversibly increased APD90 2.12 ± 0.41-fold (mean ± SEM, n = 6. This effect is attributable to inactivation removal in Nav1.5 channels, since significant inhibitory effects on hERG current were detected at higher concentrations in hERG-expressing HEK293 cells, with a 28.9 ± 6.0% inhibition (mean ± SD, n = 10 with 50 μM veratridine.      

  17. The Use of Ratiometric Fluorescence Measurements of the Voltage Sensitive Dye Di-4-ANEPPS to Examine Action Potential Characteristics and Drug Effects on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

    Science.gov (United States)

    Hortigon-Vinagre, M P; Zamora, V; Burton, F L; Green, J; Gintant, G A; Smith, G L

    2016-12-01

    Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD 90 : 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10-90% rise time of the AP (T rise ) was ∼6 ms and was normally distributed when expressed as 1/[Formula: see text] in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations. © The Author 2016. Published by Oxford University Press on behalf of the Society of

  18. Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

    Science.gov (United States)

    Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Ray; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

    2017-04-04

    Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r=0.55; 95% confidence interval, 0.09-0.81; P=0.02), 23% in response to quinidine (r=0.48; 95% confidence interval, -0.03 to 0.79; P=0.06), and 27% in response to ranolazine (r=0.52; 95% confidence interval, 0.05-0.80; P=0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls (r2=12%, P=1×10-7). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve

  19. Recent advances in the management of chronic stable angina II. Anti-ischemic therapy, options for refractory angina, risk factor reduction, and revascularization

    Directory of Open Access Journals (Sweden)

    Richard Kones

    2010-08-01

    Full Text Available Richard KonesThe Cardiometabolic Research Institute, Houston, Texas, USAAbstract: The objectives in treating angina are relief of pain and prevention of disease ­progression through risk reduction. Mechanisms, indications, clinical forms, doses, and side effects of the traditional antianginal agents – nitrates, ß-blockers, and calcium channel ­blockers – are reviewed. A number of patients have contraindications or remain unrelieved from anginal discomfort with these drugs. Among newer alternatives, ranolazine, recently approved in the United States, indirectly prevents the intracellular calcium overload involved in cardiac ischemia and is a welcome addition to available treatments. None, however, are disease-modifying agents. Two options for refractory angina, enhanced external counterpulsation and spinal cord stimulation (SCS, are presented in detail. They are both well-studied and are effective means of treating at least some patients with this perplexing form of angina. Traditional modifiable risk factors for coronary artery disease (CAD – smoking, hypertension, dyslipidemia, ­diabetes, and obesity – account for most of the population-attributable risk. Individual therapy of high-risk patients differs from population-wide efforts to prevent risk factors from appearing or reducing their severity, in order to lower the national burden of disease. Current American College of Cardiology/American Heart Association guidelines to lower risk in patients with chronic angina are reviewed. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE trial showed that in patients with stable angina, optimal medical therapy alone and percutaneous coronary intervention (PCI with medical therapy were equal in preventing myocardial infarction and death. The integration of COURAGE results into current practice is discussed. For patients who are unstable, with very high risk, with left main coronary artery lesions, in

  20. [A 50-year history of new drugs in Japan-the development and trends of hemostatics and antithrombotic drugs].

    Science.gov (United States)

    Ozawa, Hikaru; Abiko, Yasushi; Akimoto, Takeshi

    2003-01-01

    The developments and trends of hemostatic and antithrombotic drugs in Japan were investigated chronologically for the last 50 years after the 2nd World War. 1. Hemostatic drugs are classified into three groups ; capillary stabilizers, blood coagulants and antifibrinolytics. l) As to capillary stabilizers, flavonoid (rutin, 1949), adrenochrome derivative (carbazochrome, 1954) and conjugated estrogen (Premarin, 1964) were introduced therapeutically. Especially, the soluble types of adrenochrome compounds (Adona 1956, S-Adchnon, 1962) were devised and used widely in Japan. 2) Drugs concerning blood coagulation, thrombin, introduced in 1953, and hemocoagulase, a snake venom introduced in 1966, were used clinically. V.K. groups producing various coagulation factors were introduced as V.K1 (Phytonadione, 1962) and V.K2 (rnenatetrenone,1972), and they were admitted in "The Japanese Pharmacopoeia"editions 8 and 14, respectively). 3) Regarding antifibrinolytic drugs, Japanese researchers have made remarkable contributions. e-Aminocapronic acid (Ipsilon, 1962) and tranexamic acid (Transamin, 1965) were developed and used for various abnormal bleedings or hemorrhage associated with plasmin over-activation. tranexamic acid also proved to suppress inflammations of the throat such as tonsillitis, pharyngitis or laryngitis. 2. Antithrombotic drugs are also divided into three groups; anticoagulants, antiplatelet drugs and fibrinolytics.1) The anticoagulants used therapeutically by injection are heparins (Na-salt, 1951; Ca-salt, 1962) and low-molecular-weight heparins such as dalteparin (1992), parnaparin (1994) and reviparin (1999). The low molecule compounds are superior to the original heparins in reducing the risk of bleeding. As oral anticoagulants, coumarin derivatives, dicumarol (1950), ethylbiscoumacetate (1954), phenylindandione (1956) and warfarin (1962) are known. Warfarin potassium is the main drug for oral therapy of thromboembolism lately. Gabexate mesilate (1989) and

  1. Pretreatment of Mesenchymal Stem Cells and Stromal-derived Factor-1α Delivery from Chitosan-based Injectable Hydrogels for Better Cell Guidance and Retention

    Directory of Open Access Journals (Sweden)

    Hojjat Naderi-Meshkin

    2014-05-01

    Full Text Available Clinical applications of mesenchymal stem cells (MSCs rely on their capacity to home and engraft in the appropriate target tissues for a long time. Homing and engraftment capacity of these stem cells depend on the expression of Chemokines and their receptors. Ex vivo expanded MSCs exhibit homing potential when grafted to injury tissue but their homing efficiency has been observed very poor because of modifications in homing receptor expression and/or functions during culture and/or preparation steps. Hence, this study was designed to investigate the expression of surface CXCR4 by flow cytometric analysis (FACS and in vitro modified Boyden chamber assay in adipose-derive MSCs (ASCs stimulated with a hypoxia mimicking agents such as desferrioxamine mesilate (DFX, cobalt chloride (CoCl2, lithium chloride (LiCl, valproic acid (VPA and hypoxia. Intracellular CXCR4 were also evaluated by conventional and real-time PCR. Then we evaluated the homing ability of DFX-pretreated human DiI-labeled ASCs in vivo, 2 weeks after intravenous (IV, local infusion towards subcutaneously implanted chitosan-glycerophophate-hydroxyethyl cellulose (CH-GP-HEC injectable hydrogels releasing SDF1 in dorsum of Wistar Rats. Presence of human ASCs in the CH-GP-HEC injectable, spleen, and lung were analyzed histologically by fluorescent microscope, and also quantified by PCR for human specific CXCR4 gene, 2 weeks after transplantation in recipients' Rats. Results showed that short-term (24 hours pretreatment to ASCs with the hypoxia mimicking agents up-regulate the CXCR4, increase in vitro migration capacity toward 100ng/ml SDF-1 (P

  2. Mechanism of metal-mediated DNA damage induced by metabolites of carcinogenic 2-nitropropane.

    Science.gov (United States)

    Sakano, K; Oikawa, S; Murata, M; Hiraku, Y; Kojima, N; Kawanishi, S

    2001-08-08

    2-Nitropropane (2-NP), a widely used industrial solvent, is carcinogenic to rats. To clarify the mechanism of carcinogenesis by 2-NP, we investigated DNA damage by 2-NP metabolites, N-isopropylhydroxylamine (IPHA) and hydroxylamine-O-sulfonic acid (HAS), using 32P-5'-end-labelled DNA fragments obtained from genes that are relevant to human cancer. In the presence of Fe(III) EDTA, both IPHA and HAS caused DNA damage at every nucleotide position without marked site preference. The damage was inhibited by free hydroxyl radical (-*OH) scavengers, catalase and deferoxamine mesilate, an iron chelating agent. These results suggest that the DNA damage was caused by -*OH generated via H(2)O(2) by both IPHA and HAS. In contrast, in the presence of Cu(II), IPHA frequently caused DNA damage at thymine. The Cu(II)-mediated DNA damage caused by IPHA was inhibited by catalase, methional and bathocuproine, a Cu(I)-specific chelator, suggesting the involvement of H(2)O(2) and Cu(I). These results suggest that the DNA damage induced by IPHA in the presence of Cu(II) was caused by a reactive oxygen species like the Cu(I)-hydroperoxo complex. On the other hand, HAS most frequently induced DNA damage at 5'-TG-3', 5'-GG-3' and 5'-GGG-3' sequences. Catalase and methional only partly inhibited the Cu(II)-mediated DNA damage caused by HAS, suggesting that the reactive oxygen species and another reactive species participate in this process. Formation of 8-oxodG by IPHA or HAS increased in the presence of metal ions. This study suggests that metal-mediated DNA damage caused by 2-NP metabolites plays an important role in the mutagenicity and the carcinogenicity of 2-NP.

  3. Novel anti-arrhythmic medications in the treatment of atrial fibrillation.

    Science.gov (United States)

    Saklani, Pradyot; Skanes, Allan

    2012-11-01

    Atrial fibrillation (AF) is a prevalent condition particularly amongst the elderly, which contributes to both morbidity and mortality. The burden of disease has lead to significant increases in health care utilization and cost in recent years. Treatment of Atrial fibrillation consists of either a rate or rhythm control strategy. Rhythm control is achieved using medical management and/or catheter ablation. In spite of major strides in catheter ablation, this procedure remains a second line treatment of AF. Anti-arrhythmic medications represent the main treatment modality for the maintenance of sinus rhythm. Amiodarone has been used for decades because of its efficacy and lack of pro-arrhythmia despite numerous extracardiac side effects. Novel agents such as Dronedarone were designed to emulate Amiodarone without the extra-cardiac side effects. Unfortunately recent trials have raised concerns for the safety of this medication in certain patients. Other agents such as Vernakalant and Ranolazine are in development that promise to be more atrial selective in their action, thereby potentially avoiding pro-arrhythmia and heart failure side effects. It remains to be seen however if one or more of these agents achieves the required high efficacy and safety threshold. This review summarizes the main anti-arrhythmic clinical trials, early phase trials involving novel agents and examines the conflicting data relating to Dronedarone.

  4. New antiarrhythmic drugs for treatment of atrial fibrillation.

    Science.gov (United States)

    Dobrev, Dobromir; Nattel, Stanley

    2010-04-03

    Inadequacies in current therapies for atrial fibrillation have made new drug development crucial. Conventional antiarrhythmic drugs increase the risk of ventricular proarrhythmia. In drug development, the focus has been on favourable multichannel-blocking profiles, atrial-specific ion-channels, and novel non-channel targets (upstream therapy). Molecular modification of the highly effective multichannel blocker, amiodarone, to improve safety and tolerability has produced promising analogues such as dronedarone, although this drug seems less effective than does amiodarone. Vernakalant, an atrial-selective drug with reduced proarrhythmic risk, might be useful for cardioversion in atrial fibrillation. Ranolazine, another atrial-selective agent initially developed as an antianginal, has efficacy for atrial fibrillation and is being tested in prospective clinical trials. So-called upstream therapy with angiotensin-converting enzyme and angiotensin-receptor inhibitors, statins, or omega-3 fatty acids and fish oil that target atrial remodelling could be effective, but need further clinical validation. We focus on the basic and clinical pharmacology of newly emerging antiarrhythmic drugs and non-traditional approaches such as upstream therapy for atrial fibrillation. Copyright 2010 Elsevier Ltd. All rights reserved.

  5. One pot phytosynthesis of gold nanoparticles using Genipa americana fruit extract and its biological applications.

    Science.gov (United States)

    Kumar, Brajesh; Smita, Kumari; Cumbal, Luis; Camacho, Javier; Hernández-Gallegos, Elisabeth; de Guadalupe Chávez-López, María; Grijalva, Marcelo; Andrade, Kleber

    2016-05-01

    In this article, rapid one pot synthesis of gold nanoparticles (GNPs) using an eco-friendly extract of Genipa americana L. fruit is described. Electrospray ionization mass spectrometry (ESI-MS) and Fourier transform infrared (FTIR) spectroscopic studies demonstrated that small molecules such as genipin, genipaol, geniposide and ranolazine can act as reducer as well as stabilizers. The monodispersed, spherical GNPs were further characterized by UV-vis spectroscopy at λmax=535 nm, transmission electron microscopy (TEM), dynamic light scattering (DLS) and X-ray diffraction (XRD) analysis. This synthetic approach offers a greener and alternate route to the preparation of GNPs free from toxic chemical components and stable for 6-7 months under room temperature. The green synthesized GNPs showed weak antioxidant efficacy against 1,1-diphenyl-2-picrylhydrazyl and no cytotoxicity against A-549 and HeLa human cancer cell lines, from lung and cervix. This study opens a new industrial scope of G. americana fruit in nanoscience and as surface modified GNPs can be developed into a successful drug carrier for future pharmaceutical products. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. One pot phytosynthesis of gold nanoparticles using Genipa americana fruit extract and its biological applications

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Brajesh, E-mail: krmbraj@gmail.com [Centro de Nanociencia y Nanotecnologia, Universidad de las Fuerzas Armadas ESPE, Av. Gral. Rumiñahui s/n, Sangolqui, P.O. BOX 171-5-231B (Ecuador); Smita, Kumari; Cumbal, Luis [Centro de Nanociencia y Nanotecnologia, Universidad de las Fuerzas Armadas ESPE, Av. Gral. Rumiñahui s/n, Sangolqui, P.O. BOX 171-5-231B (Ecuador); Camacho, Javier [Centro de Nanociencia y Nanotecnologia, Universidad de las Fuerzas Armadas ESPE, Av. Gral. Rumiñahui s/n, Sangolqui, P.O. BOX 171-5-231B (Ecuador); Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Departamento de Farmacología, C.P. 07360 Mexico City (Mexico); Hernández-Gallegos, Elisabeth; Guadalupe Chávez-López, María de [Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Departamento de Farmacología, C.P. 07360 Mexico City (Mexico); Grijalva, Marcelo; Andrade, Kleber [Centro de Nanociencia y Nanotecnologia, Universidad de las Fuerzas Armadas ESPE, Av. Gral. Rumiñahui s/n, Sangolqui, P.O. BOX 171-5-231B (Ecuador)

    2016-05-01

    In this article, rapid one pot synthesis of gold nanoparticles (GNPs) using an eco-friendly extract of Genipa americana L. fruit is described. Electrospray ionization mass spectrometry (ESI-MS) and Fourier transform infrared (FTIR) spectroscopic studies demonstrated that small molecules such as genipin, genipaol, geniposide and ranolazine can act as reducer as well as stabilizers. The monodispersed, spherical GNPs were further characterized by UV–vis spectroscopy at λ{sub max} = 535 nm, transmission electron microscopy (TEM), dynamic light scattering (DLS) and X-ray diffraction (XRD) analysis. This synthetic approach offers a greener and alternate route to the preparation of GNPs free from toxic chemical components and stable for 6–7 months under room temperature. The green synthesized GNPs showed weak antioxidant efficacy against 1,1-diphenyl-2-picrylhydrazyl and no cytotoxicity against A-549 and HeLa human cancer cell lines, from lung and cervix. This study opens a new industrial scope of G. americana fruit in nanoscience and as surface modified GNPs can be developed into a successful drug carrier for future pharmaceutical products. - Highlights: • Gold nanoparticles can be synthesized by Genipa americana fruit extract. • TEM-DLS analysis confirmed that the average particle size is 30.4 ± 14.9 nm. • Nanoparticles showed weak antioxidant and no cytotoxicity activity.

  7. [Optimal Diagnostics and Therapy for Microvascular Angina Pectoris].

    Science.gov (United States)

    Ong, Peter; Sechtem, Udo

    2017-10-01

    Patients with microvascular angina are characterized by angina pectoris with proof of myocardial ischemia in the absence of any relevant epicardial stenosis and without myocardial disease (type 1 coronary microvascular dysfunction according to Crea and Camici). Structural and functional alterations of the coronary microvessels (diameter < 500 µm) are the reason for this phenomenon. Frequently such alterations are associated with cardiovascular risk factors. Patients with angina pectoris without epicardial stenoses represent for 10 - 50 % of all patients undergoing coronary angiography depending on the clinical presentation. Diagnostic approaches include non-invasive (e. g. combination of coronary CT-angiography and positron emission tomography/echo Doppler-based coronary flow reserve measurements) as well as invasive procedures (coronary flow reserve measurements in response to adenosine, intracoronary acetylcholine testing). Pharmacological treatment of these patients is often challenging and should be based on the characterization of the underlying mechanisms. Moreover, strict risk factor control and individually titrated combinations of antianginal substances (e. g. beta blockers, calcium channel blockers, nitrates, ranolazine, ivabradine etc.) are recommended. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism.

    Science.gov (United States)

    Pollak, Yulia; Mechlovich, Danit; Amit, Tamar; Bar-Am, Orit; Manov, Irena; Mandel, Silvia A; Weinreb, Orly; Meyron-Holtz, Esther G; Iancu, Theodore C; Youdim, Moussa B H

    2013-01-01

    Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.

  9. Controversies in Neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Reichmann Heinz

    2011-09-01

    Full Text Available Abstract Background Early initiation of pharmacotherapy in Parkinson's disease (PD is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease. Discussion In multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease. Summary MAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

  10. Parkinson's Disease: From Pathogenesis to Pharmacogenomics.

    Science.gov (United States)

    Cacabelos, Ramón

    2017-03-04

    Parkinson's disease (PD) is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer's disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson's disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson's disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS) structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin-proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone). The chronic administration of antiparkinsonian drugs currently induces the "wearing-off phenomenon", with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in addition to enhancing

  11. Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.

    Science.gov (United States)

    Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin

    2016-04-12

    Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

  12. Treatment of psychosis and dementia in Parkinson's disease.

    Science.gov (United States)

    Goldman, Jennifer G; Holden, Samantha

    2014-03-01

    Parkinson's disease (PD) has been increasingly recognized as having a multitude of nonmotor symptoms including psychosis, cognitive impairment and dementia, mood disturbances, fatigue, apathy, and sleep disorders. Psychosis and dementia, in particular, greatly affect quality of life for both patients and caregivers and are associated with poor outcomes. Safe and effective treatment options for psychosis and dementia in PD are much needed. Antipsychotics with dopamine-blocking properties can worsen parkinsonian motor features and have been associated with increased morbidity and mortality in elderly, dementia patients. For treating PD psychosis, a first step would be eliminating confounding variables, such as delirium, infections, or toxic-metabolic imbalances, followed by simplifying parkinsonian medications as tolerated. If additional treatment is warranted after such interventions, clozapine or quetiapine can be implemented at the low dose levels typically needed by PD patients. Although quetiapine is easy-to-use in clinical settings, does not require blood count monitoring like clozapine, and is anecdotally beneficial, it remains "investigational" in evidence-based medicine reviews. Though not currently available, the novel 5-HT2a inverse agonist, pimavanserin has shown promise in the treatment of PD psychosis. Current treatments for PD dementia are mostly derived from those utilized in Alzheimer's disease, focusing mainly on cholinesterase inhibitors and memantine, a NMDA receptor antagonist. Rivastigmine, the only Food and Drug Administration approved medication for PD dementia, is a reasonable first choice. Other cholinesterase inhibitors and memantine have not yet achieved recommendation status in evidence-based medicine reviews but are well tolerated in studies of PD dementia patients. At present, there are no approved treatments for mild cognitive impairment in PD, but rasagiline, a selective MAO-B inhibitor, and atomoxetine, a serotonin norepinephrine

  13. Parkinson’s Disease: From Pathogenesis to Pharmacogenomics

    Directory of Open Access Journals (Sweden)

    Ramón Cacabelos

    2017-03-01

    Full Text Available Parkinson’s disease (PD is the second most important age-related neurodegenerative disorder in developed societies, after Alzheimer’s disease, with a prevalence ranging from 41 per 100,000 in the fourth decade of life to over 1900 per 100,000 in people over 80 years of age. As a movement disorder, the PD phenotype is characterized by rigidity, resting tremor, and bradykinesia. Parkinson’s disease -related neurodegeneration is likely to occur several decades before the onset of the motor symptoms. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. Parkinson’s disease neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta, with widespread involvement of other central nervous system (CNS structures and peripheral tissues. Pathogenic mechanisms associated with genomic, epigenetic and environmental factors lead to conformational changes and deposits of key proteins due to abnormalities in the ubiquitin–proteasome system together with dysregulation of mitochondrial function and oxidative stress. Conventional pharmacological treatments for PD are dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina, and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, monoamine oxidase (MAO inhibitors (selegiline, rasagiline, and catechol-O-methyltransferase (COMT inhibitors (entacapone, tolcapone. The chronic administration of antiparkinsonian drugs currently induces the “wearing-off phenomenon”, with additional psychomotor and autonomic complications. In order to minimize these clinical complications, novel compounds have been developed. Novel drugs and bioproducts for the treatment of PD should address dopaminergic neuroprotection to reduce premature neurodegeneration in

  14. Late Sodium Current in Human Atrial Cardiomyocytes from Patients in Sinus Rhythm and Atrial Fibrillation.

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    Claire Poulet

    Full Text Available Slowly inactivating Na+ channels conducting "late" Na+ current (INa,late contribute to ventricular arrhythmogenesis under pathological conditions. INa,late was also reported to play a role in chronic atrial fibrillation (AF. The objective of this study was to investigate INa,late in human right atrial cardiomyocytes as a putative drug target for treatment of AF. To activate Na+ channels, cardiomyocytes from transgenic mice which exhibit INa,late (ΔKPQ, and right atrial cardiomyocytes from patients in sinus rhythm (SR and AF were voltage clamped at room temperature by 250-ms long test pulses to -30 mV from a holding potential of -80 mV with a 100-ms pre-pulse to -110 mV (protocol I. INa,late at -30 mV was not discernible as deviation from the extrapolated straight line IV-curve between -110 mV and -80 mV in human atrial cells. Therefore, tetrodotoxin (TTX, 10 μM was used to define persistent inward current after 250 ms at -30 mV as INa,late. TTX-sensitive current was 0.27±0.06 pA/pF in ventricular cardiomyocytes from ΔKPQ mice, and amounted to 0.04±0.01 pA/pF and 0.09±0.02 pA/pF in SR and AF human atrial cardiomyocytes, respectively. With protocol II (holding potential -120 mV, pre-pulse to -80 mV TTX-sensitive INa,late was always larger than with protocol I. Ranolazine (30 μM reduced INa,late by 0.02±0.02 pA/pF in SR and 0.09±0.02 pA/pF in AF cells. At physiological temperature (37°C, however, INa,late became insignificant. Plateau phase and upstroke velocity of action potentials (APs recorded with sharp microelectrodes in intact human trabeculae were more sensitive to ranolazine in AF than in SR preparations. Sodium channel subunits expression measured with qPCR was high for SCN5A with no difference between SR and AF. Expression of SCN8A and SCN10A was low in general, and lower in AF than in SR. In conclusion, We confirm for the first time a TTX-sensitive current (INa,late in right atrial cardiomyocytes from SR and AF patients at room

  15. Particulate matter induces cardiac arrhythmias via dysregulation of carotid body sensitivity and cardiac sodium channels.

    Science.gov (United States)

    Wang, Ting; Lang, Gabriel D; Moreno-Vinasco, Liliana; Huang, Yong; Goonewardena, Sascha N; Peng, Ying-Jie; Svensson, Eric C; Natarajan, Viswanathan; Lang, Roberto M; Linares, Jered D; Breysse, Patrick N; Geyh, Alison S; Samet, Jonathan M; Lussier, Yves A; Dudley, Samuel; Prabhakar, Nanduri R; Garcia, Joe G N

    2012-04-01

    The mechanistic links between exposure to airborne particulate matter (PM) pollution and the associated increases in cardiovascular morbidity and mortality, particularly in people with congestive heart failure (CHF), have not been identified. To advance understanding of this issue, genetically engineered mice (CREB(A133)) exhibiting severe dilated cardiomyopathic changes were exposed to ambient PM collected in Baltimore. CREB(A133) mice, which display aberrant cardiac physiology and anatomy reminiscent of human CHF, displayed evidence of basal autonomic aberrancies (compared with wild-type mice) with PM exposure via aspiration, producing significantly reduced heart rate variability, respiratory dysynchrony, and increased ventricular arrhythmias. Carotid body afferent nerve responses to hypoxia and hyperoxia-induced respiratory depression were pronounced in PM-challenged CREB(A133) mice, and denervation of the carotid bodies significantly reduced PM-mediated cardiac arrhythmias. Genome-wide expression analyses of CREB(A133) left ventricular tissues demonstrated prominent Na(+) and K(+) channel pathway gene dysregulation. Subsequent PM challenge increased tyrosine phosphorylation and nitration of the voltage-gated type V cardiac muscle α-subunit of the Na(+) channel encoded by SCN5A. Ranolazine, a Na(+) channel modulator that reduces late cardiac Na(+) channel currents, attenuated PM-mediated cardiac arrhythmias and shortened PM-elongated QT intervals in vivo. These observations provide mechanistic insights into the epidemiologic findings in susceptibility of human CHF populations to PM exposure. Our results suggest a multiorgan pathobiology inherent to the CHF phenotype that is exaggerated by PM exposure via heightened carotid body sensitivity and cardiac Na(+) channel dysfunction.

  16. Particulate Matter Induces Cardiac Arrhythmias via Dysregulation of Carotid Body Sensitivity and Cardiac Sodium Channels

    Science.gov (United States)

    Wang, Ting; Lang, Gabriel D.; Moreno-Vinasco, Liliana; Huang, Yong; Goonewardena, Sascha N.; Peng, Ying–Jie; Svensson, Eric C.; Natarajan, Viswanathan; Lang, Roberto M.; Linares, Jered D.; Breysse, Patrick N.; Geyh, Alison S.; Samet, Jonathan M.; Lussier, Yves A.; Dudley, Samuel; Prabhakar, Nanduri R.

    2012-01-01

    The mechanistic links between exposure to airborne particulate matter (PM) pollution and the associated increases in cardiovascular morbidity and mortality, particularly in people with congestive heart failure (CHF), have not been identified. To advance understanding of this issue, genetically engineered mice (CREBA133) exhibiting severe dilated cardiomyopathic changes were exposed to ambient PM collected in Baltimore. CREBA133 mice, which display aberrant cardiac physiology and anatomy reminiscent of human CHF, displayed evidence of basal autonomic aberrancies (compared with wild-type mice) with PM exposure via aspiration, producing significantly reduced heart rate variability, respiratory dysynchrony, and increased ventricular arrhythmias. Carotid body afferent nerve responses to hypoxia and hyperoxia-induced respiratory depression were pronounced in PM-challenged CREBA133 mice, and denervation of the carotid bodies significantly reduced PM-mediated cardiac arrhythmias. Genome-wide expression analyses of CREBA133 left ventricular tissues demonstrated prominent Na+ and K+ channel pathway gene dysregulation. Subsequent PM challenge increased tyrosine phosphorylation and nitration of the voltage-gated type V cardiac muscle α-subunit of the Na+ channel encoded by SCN5A. Ranolazine, a Na+ channel modulator that reduces late cardiac Na+ channel currents, attenuated PM-mediated cardiac arrhythmias and shortened PM-elongated QT intervals in vivo. These observations provide mechanistic insights into the epidemiologic findings in susceptibility of human CHF populations to PM exposure. Our results suggest a multiorgan pathobiology inherent to the CHF phenotype that is exaggerated by PM exposure via heightened carotid body sensitivity and cardiac Na+ channel dysfunction. PMID:22108299

  17. Relaxation and the Role of Calcium in Isolated Contracting Myocardium From Patients With Hypertensive Heart Disease and Heart Failure With Preserved Ejection Fraction.

    Science.gov (United States)

    Runte, K Elisabeth; Bell, Stephen P; Selby, Donald E; Häußler, Tim N; Ashikaga, Takamuru; LeWinter, Martin M; Palmer, Bradley M; Meyer, Markus

    2017-08-01

    Relaxation characteristics and Ca(2+) homeostasis have not been studied in isolated myocardium from patients with hypertensive heart disease (HHD) and heart failure with preserved ejection fraction (HFpEF). Prolonged myocardial relaxation is believed to play an important role in the pathophysiology of these conditions. In this study, we evaluated relaxation parameters, myocardial calcium (Ca(2+)), and sodium (Na(+)) handling, as well as ion transporter expression and tested the effect of Na(+)-influx inhibitors on relaxation in isolated myocardium from patients with HHD and HFpEF. Relaxation characteristics were studied in myocardial strip preparations under physiological conditions at stimulation rates of 60 and 180 per minute. Intracellular Ca(2+) and Na(+) were simultaneously assessed using Fura-2 and AsanteNATRIUMGreen-2, whereas elemental analysis was used to measure total myocardial concentrations of Ca, Na, and other elements. Quantitative polymerase chain reaction was used to measure expression levels of key ion transport proteins. The lusitropic effect of Na(+)-influx inhibitors ranolazine, furosemide, and amiloride was evaluated. Myocardial left ventricular biopsies were obtained from 36 control patients, 29 HHD and 19 HHD+HFpEF. When compared with control patients, half maximal relaxation time (RT50) at 60 per minute was prolonged by 13% in HHD and by 18% in HHD+HFpEF (both Pmyocardium from patients with HHD and HHD+HFpEF. This leads to incomplete relaxation at higher rates. Elevated calcium levels in HFpEF are neither a result of an impaired Na(+) gradient nor expression changes in key ion transporters and regulatory proteins. © 2017 American Heart Association, Inc.

  18. Stable ischemic heart disease in women: current perspectives

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    Samad F

    2017-09-01

    Full Text Available Fatima Samad,1 Anushree Agarwal,2 Zainab Samad3 1Aurora Cardiovascular Services, Aurora Sinai/Aurora St Luke’s Medical Centers, University of Wisconsin School of Medicine and Public Health, Milwaukee, WI, 2Division of Cardiology, Department of Medicine, University of California San Francisco, San Francisco, CA, 3Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA Abstract: Cardiovascular disease is the leading cause of death in women accounting for 1 in every 4 female deaths. Pathophysiology of ischemic heart disease in women includes epicardial coronary artery, endothelial dysfunction, coronary vasospasm, plaque erosion and spontaneous coronary artery dissection. Angina is the most common presentation of stable ischemic heart disease (SIHD in women. Risk factors for SIHD include traditional risks such as older age, obesity (body mass index [BMI] >25 kg/m2, smoking, hypertension, dyslipidemia, cerebrovascular and peripheral vascular disease, sedentary lifestyle, family history of premature coronary artery disease, metabolic syndrome and diabetes mellitus, and nontraditional risk factors, such as gestational diabetes, insulin resistance/polycystic ovarian disease, pregnancy-induced hypertension, pre-eclampsia, eclampsia, menopause, mental stress and autoimmune diseases. Diagnostic testing can be used effectively to risk stratify women. Guidelines-directed medical therapy including aspirin, statins, beta-blocker therapy, calcium channel blockers and ranolazine should be instituted for symptom and ischemia management. Despite robust evidence regarding the adverse outcomes seen in women with ischemic heart disease, knowledge gaps exist in several areas. Future research needs to be directed toward a greater understanding of the role of nontraditional risk factors for SIHD in women, gaining deeper insights into the sex differences in therapeutic effects and formulating a sex-specific algorithm for the

  19. CSAHi study: Detection of drug-induced ion channel/receptor responses, QT prolongation, and arrhythmia using multi-electrode arrays in combination with human induced pluripotent stem cell-derived cardiomyocytes.

    Science.gov (United States)

    Kitaguchi, Takashi; Moriyama, Yuta; Taniguchi, Tomohiko; Maeda, Sanae; Ando, Hiroyuki; Uda, Takaaki; Otabe, Koji; Oguchi, Masao; Shimizu, Shigekazu; Saito, Hiroyuki; Toratani, Atsushi; Asayama, Mahoko; Yamamoto, Wataru; Matsumoto, Emi; Saji, Daisuke; Ohnaka, Hiroki; Miyamoto, Norimasa

    The use of multi-electrode arrays (MEA) in combination with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provides a promising method to predict comprehensive cardiotoxicity, including drug-induced QT prolongation and arrhythmia. We previously demonstrated that MEA in combination with hiPSC-CMs could provide a generalizable platform by using 7 reference drugs at 10 testing facilities. Using this approach, we evaluated responses to reference drugs that modulate a range of cardiac ion currents and have a range of arrhythmogenic effects. We used the MEA system (MED64) and commercially available hiPSC-CMs (iCell cardiomyocytes) to evaluate drug effects on the beat rate, field potential duration (FPD), FPD corrected by Fridericia's formula (FPDc), and the incidence of arrhythmia-like waveforms. This assay detected the repolarization effects of Bay K8644, mibefradil, NS1643, levcromakalim, and ouabain; and the chronotropic effects of isoproterenol, ZD7288, and BaCl2. Chronotropy was also affected by K(+) and Ca(2+) current modulation. This system detected repolarization delays and the arrhythmogenic effects of quinidine, cisapride, thioridazine, astemizole, bepridil, and pimozide more sensitively than the established guinea pig papillary muscle action potential assay. It also predicted clinical QT prolongation by drugs with multiple ion channel effects (fluoxetine, amiodarone, tolterodine, vanoxerine, alfuzosin, and ranolazine). MEA in combination with hiPSC-CMs may provide a powerful method to detect various cardiac electrophysiological effects, QT prolongation, and arrhythmia during drug discovery. However, the data require careful interpretation to predict chronotropic effects and arrhythmogenic effects of candidate drugs with multiple ion channel effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Mechanism of As2O3-Induced Action Potential Prolongation and Using hiPS-CMs to Evaluate the Rescue Efficacy of Drugs With Different Rescue Mechanism.

    Science.gov (United States)

    Yan, Meng; Feng, Lifang; Shi, Yanhui; Wang, Junnan; Liu, Yan; Li, Fengmei; Li, Baoxin

    2017-08-01

    Arsenic trioxide (As2O3) has been verified as a breakthrough in the management of acute promyelocytic leukemia in recent decades. However, cardiotoxicity, especially long QT syndrome (LQTS) has become the most important issue during As2O3 treatment. The characterized mechanisms behind this adverse effect are inhibition of cardiac hERG channel trafficking and increase of cardiac calcium currents. In our study, we found a new pathway underlying As2O3-induced cardiotoxicity that As2O3 accelerates lysosomal degradation of hERG on plasma membrane after using brefeldin A (BFA) to block protein trafficking. Then we explored pharmacological rescue strategies on As2O3-induced LQTS, and found that 4 therapeutic agents exert rescue efficacy via 3 different pathways: fexofenadine and astemizole facilitate hERG trafficking via promotion of channel-chaperone formation after As2O3 incubation; ranolazine slows hERG degradation in the presence of As2O3; and resveratrol shows significant attenuation on calcium current increase triggered by As2O3. Moreover, we used human-induced pluripotent stem cell derived cardiomyocytes (hiPS-CMs) to evaluate the rescue effects of the above agents on As2O3-induced prolongation of action potential duration (APD) and demonstrated that fexofenadine and resveratrol significantly ameliorate the prolonged APD. These observations suggested that pharmacological chaperone like fexofenadine and resveratrol might have the potential to protect against the cardiotoxicity of As2O3. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. Different pH-sensitivity patterns of 30 sodium channel inhibitors suggest chemically different pools along the access pathway.

    Directory of Open Access Journals (Sweden)

    Alexandra eLazar

    2015-09-01

    Full Text Available The major drug binding site of sodium channels is inaccessible from the extracellular side, drug molecules can only access it either from the membrane phase, or from the intracellular aqueous phase. For this reason, ligand-membrane interactions are as important determinants of inhibitor properties, as ligand-protein interactions. One way to probe this is to modify the pH of the extracellular fluid, which alters the ratio of charged vs. uncharged forms of some compounds, thereby changing their interaction with the membrane. In this electrophysiology study we used three different pH values: 6.0, 7.3 and 8.6 to test the significance of the protonation-deprotonation equilibrium in drug access and affinity. We investigated drugs of several different indications: carbamazepine, lamotrigine, phenytoin, lidocaine, bupivacaine, mexiletine, flecainide, ranolazine, riluzole, memantine, ritanserin, tolperisone, silperisone, ambroxol, haloperidol, chlorpromazine, clozapine, fluoxetine, sertraline, paroxetine, amitriptyline, imipramine, desipramine, maprotiline, nisoxetine, mianserin, mirtazapine, venlafaxine, nefazodone and trazodone. We recorded the pH-dependence of potency, reversibility, as well as onset/offset kinetics. As expected, we observed a strong correlation between the acidic dissociation constant (pKa of drugs and the pH-dependence of their potency. Unexpectedly, however, the pH-dependence of reversibility or kinetics showed diverse patterns, not simple correlation. Our data are best explained by a model where drug molecules can be trapped in at least two chemically different environments: A hydrophilic trap (which may be the aqueous cavity within the inner vestibule, which favors polar and less lipophilic compounds, and a lipophilic trap (which may be the membrane phase itself, and/or lipophilic binding sites on the channel. Rescue from the hydrophilic and lipophilic traps can be promoted by alkalic and acidic extracellular pH, respectively.

  2. Increment of late sodium currents in the left atrial myocytes and its potential contribution to increased susceptibility of atrial fibrillation in castrated male mice.

    Science.gov (United States)

    Zhang, Yang; Wang, Hui-Min; Wang, Ying-Zhe; Zhang, Yi-Yuan; Jin, Xue-Xin; Zhao, Yue; Wang, Jin; Sun, Yi-Lin; Xue, Gen-Long; Li, Peng-Hui; Huang, Qi-He; Yang, Bao-Feng; Pan, Zhen-Wei

    2017-07-01

    The incidence of atrial fibrillation (AF) is correlated with decreased levels of testosterone in elderly men. Late sodium current may exert a role in AF pathogenesis. The purpose of this study was to explore the effect of testosterone deficiency on AF susceptibility and the therapeutic effect of late sodium current inhibitors in mice. Male ICR mice (5 weeks old) were castrated to establish a testosterone deficiency model. One month after castration, dihydrotestosterone 5 mg/kg was administered subcutaneously for 2 months. Serum total testosterone level was assessed by enzyme-linked immunosorbent assay. High-frequency electrical stimulation was used to induce atrial arrhythmias. Whole-cell patch-clamp technique was used to for single-cell electrophysiologic study. Serum dihydrotestosterone levels of castration mice declined significantly but recovered with administration of exogenous dihydrotestosterone. In comparison with sham mice, the number of AF episodes significantly increased by 13.5-fold, AF rate increased by 3.75-fold, and AF duration prolonged in castrated mice. Dihydrotestosterone administration alleviated the occurrence of AF. Action potential duration at both 50% and 90% repolarization were markedly increased in castrated mice compared to sham controls. The late sodium current was enhanced in castrated male mice. These alterations were alleviated by treatment with dihydrotestosterone. Systemic application of the INa-L inhibitors ranolazine, eleclazine, and GS967 inhibited the occurrence of AF in castrated mice. Testosterone deficiency contributed to the increased late sodium current, prolonged action potential repolarization, and increased susceptibility to AF. Blocking of late sodium current is beneficial against the occurrence of AF in castrated mice. Copyright © 2017. Published by Elsevier Inc.

  3. Larger rate dependence of late sodium current in cardiac Purkinje cells: A potential link to arrhythmogenesis.

    Science.gov (United States)

    Li, Wei; Yu, Ying; Hou, Jian-Wen; Zhou, Zhi-Wen; Guo, Kai; Zhang, Peng-Pai; Wang, Zhi-Quan; Yan, Jian-Hua; Sun, Jian; Zhou, Qing; Wang, Yue-Peng; Li, Yi-Gang

    2017-03-01

    Purkinje cells (PCs) have a steeper rate dependence of repolarization and are more susceptible to arrhythmic activity than do ventricular myocytes (VMs). Late sodium current (INaL) is rate dependent and contributes to rate dependence of repolarization. This study sought to test our hypothesis that PCs have a larger rate dependence of INaL, contributing to their steeper rate dependence of repolarization and higher susceptibility to arrhythmic activity, than do VMs. INaL was recorded in isolated rabbit PCs and VMs with the whole-cell patch clamp technique. Action potential was examined using the microelectrode technique. Compared with VMs, PCs exhibited a significantly larger rate dependence of INaL with a larger INaL to basic cycle length (BCL) slope. Moreover, PCs had a larger rate dependence of INaL decay and slower recovery kinetics. Interestingly, the larger rate dependence of INaL matched to a steeper rate dependence of action potential duration (APD) in PCs. The INaL blocker tetrodotoxin significantly blunted, while the INaL enhancer anemone toxin (ATX-II) significantly increased, the rate dependence of INaL and APD in PCs and VMs. In the presence of ATX-II, the rate dependence of INaL in PCs was markedly larger than that in VMs, causing a much steeper rate dependence of APD in PCs. Accordingly, PCs exhibited greater rate-dependent electrical instability and were more prone to ATX-II-induced early afterdepolarizations, which were completely inhibited by the INaL inhibitor ranolazine. PCs have a significantly larger rate dependence of INaL than do VMs because of distinctive INaL decay and recovery kinetics, which contributes to their larger rate adaptation, and simultaneously predisposes them to a higher risk of arrhythmogenesis. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

  4. Late sodium current and intracellular ionic homeostasis in acute ischemia.

    Science.gov (United States)

    Ronchi, Carlotta; Torre, Eleonora; Rizzetto, Riccardo; Bernardi, Joyce; Rocchetti, Marcella; Zaza, Antonio

    2017-03-01

    Blockade of the late Na+ current (I NaL) protects from ischemia/reperfusion damage; nevertheless, information on changes in I NaL during acute ischemia and their effect on intracellular milieu is missing. I NaL, cytosolic Na+ and Ca2+ activities (Nacyt, Cacyt) were measured in isolated rat ventricular myocytes during 7 min of simulated ischemia (ISC); in all the conditions tested, effects consistently exerted by ranolazine (RAN) and tetrodotoxin (TTX) were interpreted as due to I NaL blockade. The results indicate that I NaL was enhanced during ISC in spite of changes in action potential (AP) contour; I NaL significantly contributed to Nacyt rise, but only marginally to Cacyt rise. The impact of I NaL on Cacyt was markedly enhanced by blockade of the sarcolemmal(s) Na+/Ca2+ exchanger (NCX) and was due to the presence of (Na+-sensitive) Ca2+ efflux through mitochondrial NCX (mNCX). sNCX blockade increased Cacyt and decreased Nacyt, thus indicating that, throughout ISC, sNCX operated in the forward mode, in spite of the substantial Nacyt increment. Thus, a robust Ca2+ source, other than sNCX and including mitochondria, contributed to Cacyt during ISC. Most, but not all, of RAN effects were shared by TTX. (1) The paradigm that attributes Cacyt accumulation during acute ischemia to decrease/reversal of sNCX transport may not be of general applicability; (2) I NaL is enhanced during ISC, when the effect of Nacyt on mitochondrial Ca2+ transport may substantially contribute to I NaL impact on Cacyt; (3) RAN may act mostly, but not exclusively, through I NaL blockade during ISC.

  5. Voltage-gated sodium channels contribute to action potentials and spontaneous contractility in isolated human lymphatic vessels.

    Science.gov (United States)

    Telinius, Niklas; Majgaard, Jens; Kim, Sukhan; Katballe, Niels; Pahle, Einar; Nielsen, Jørn; Hjortdal, Vibeke; Aalkjaer, Christian; Boedtkjer, Donna Briggs

    2015-07-15

    Voltage-gated sodium channels (VGSC) play a key role for initiating action potentials (AP) in excitable cells. VGSC in human lymphatic vessels have not been investigated. In the present study, we report the electrical activity and APs of small human lymphatic collecting vessels, as well as mRNA expression and function of VGSC in small and large human lymphatic vessels. The VGSC blocker TTX inhibited spontaneous contractions in six of 10 spontaneously active vessels, whereas ranolazine, which has a narrower VGSC blocking profile, had no influence on spontaneous activity. TTX did not affect noradrenaline-induced contractions. The VGSC opener veratridine induced contractions in a concentration-dependent manner (0.1-30 μm) eliciting a stable tonic contraction and membrane depolarization to -18 ± 0.6 mV. Veratridine-induced depolarizations and contractions were reversed ∼80% by TTX, and were dependent on Ca(2+) influx via L-type calcium channels and the sodium-calcium exchanger in reverse mode. Molecular analysis determined NaV 1.3 to be the predominantly expressed VGSC isoform. Electrophysiology of mesenteric lymphatics determined the resting membrane potential to be -45 ± 1.7 mV. Spontaneous APs were preceded by a slow depolarization of 5.3 ± 0.6 mV after which a spike was elicited that almost completely repolarized before immediately depolarizing again to plateau. Vessels transiently hyperpolarized prior to returning to the resting membrane potential. TTX application blocked APs. We have shown that VGSC are necessary for initiating and maintaining APs and spontaneous contractions in human lymphatic vessels and our data suggest the main contribution from comes NaV 1.3. We have also shown that activation of these channels augments the contractile activity of the vessels. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  6. Role of late sodium current as a potential arrhythmogenic mechanism in the progression of pressure-induced heart disease.

    Science.gov (United States)

    Toischer, Karl; Hartmann, Nico; Wagner, Stefan; Fischer, Thomas H; Herting, Jonas; Danner, Bernhard C; Sag, Can M; Hund, Thomas J; Mohler, Peter J; Belardinelli, Luiz; Hasenfuss, Gerd; Maier, Lars S; Sossalla, Samuel

    2013-08-01

    The aim of the study was to determine the characteristics of the late Na current (INaL) and its arrhythmogenic potential in the progression of pressure-induced heart disease. Transverse aortic constriction (TAC) was used to induce pressure overload in mice. After one week the hearts developed isolated hypertrophy with preserved systolic contractility. In patch-clamp experiments both, INaL and the action potential duration (APD90) were unchanged. In contrast, after five weeks animals developed heart failure with prolonged APDs and slowed INaL decay time which could be normalized by addition of the INaL inhibitor ranolazine (Ran) or by the Ca/calmodulin-dependent protein kinase II (CaMKII) inhibitor AIP. Accordingly the APD90 could be significantly abbreviated by Ran, tetrodotoxin and the CaMKII inhibitor AIP. Isoproterenol increased the number of delayed afterdepolarizations (DAD) in myocytes from failing but not sham hearts. Application of either Ran or AIP prevented the occurrence of DADs. Moreover, the incidence of triggered activity was significantly increased in TAC myocytes and was largely prevented by Ran and AIP. Western blot analyses indicate that increased CaMKII activity and a hyperphosphorylation of the Nav1.5 at the CaMKII phosphorylation site (Ser571) paralleled our functional observations five weeks after TAC surgery. In pressure overload-induced heart failure a CaMKII-dependent augmentation of INaL plays a crucial role in the AP prolongation and generation of cellular arrhythmogenic triggers, which cannot be found in early and still compensated hypertrophy. Inhibition of INaL and CaMKII exerts potent antiarrhythmic effects and might therefore be of potential therapeutic interest. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates.

    Science.gov (United States)

    Comtois, Philippe; Sakabe, Masao; Vigmond, Edward J; Munoz, Mauricio; Texier, Anne; Shiroshita-Takeshita, Akiko; Nattel, Stanley

    2008-10-01

    Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding Na(+) channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding I(Na) blockers affect AF, we developed realistic mathematical models of state-dependent Na(+) channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two- and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulated-receptor theory and maximum affinity for activated Na(+) channels. Lidocaine produced frequency-dependent Na(+) channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum approximately 89% at 60 microM). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source Na(+) current in the face of large ACh-sensitive K(+) current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF.

  8. Correlation between serum tryptase, mast cells positive to tryptase and microvascular density in colo-rectal cancer patients: possible biological-clinical significance.

    Directory of Open Access Journals (Sweden)

    Michele Ammendola

    Full Text Available BACKGROUND: Tryptase is a serin protease stored and released from mast cells (MCs that plays a role in tumour angiogenesis. In this study we aimed to evaluate serum tryptase levels in colo-rectal cancer (CRC patients before (STLBS and after (STLAS radical surgical resection. We also evaluated mast cell density positive to tryptase (MCDPT and microvascular density (MVD in primary tumour tissue. METHODS: A series of 61 patients with stage B and C CRC (according to the Astler and Coller staging system were selected. Serum blood samples were collected from patients one day before and one day after surgery. Tryptase levels were measured using the UniCAP Tryptase Fluoroenzymeimmunoassay (Pharmacia, Uppsala, Sweden. Tumour sections were immunostained with a primary anti-tryptase antibody (clone AA1; Dako, Glostrup, Denmark and an anti CD-34 antibody (QB-END 10; Bio-Optica Milan, Italy by means of immunohistochemistry and then evaluated by image analysis methods. RESULTS: The mean ± s.d. STLBS and STLAS was 5.63±2.61 µg/L, and 3.39±1.47 µg/L respectively and a significant difference between mean levels was found: p = 0.000 by t-test. The mean ± s.d. of MCDPT and MVD was 8.13±3.28 and 29.16±7.39 respectively. A strong correlation between STLBS and MVD (r = 0.83, p = 0.000; STLBS and MCDPT (r = 0.60, p = 0.003; and MCDPT and MVD (r = 0.73; p = 0.001 was found. CONCLUSION: Results demonstrated higher STLBS in CRC patients, indicating an involvement of MC tryptase in CRC angiogenesis. Data also indicated lower STLAS, suggesting the release of tryptase from tumour-infiltrating MCs. Serum tryptase levels may therefore play a role as a novel bio-marker predictive of response to radical surgery. In this context tryptase inhibitors such as Gabexate and Nafamostat Mesilate might be evaluated in adjuvant clinical trials as a new anti-angiogenic approach.

  9. MIND-BEST: Web server for drugs and target discovery; design, synthesis, and assay of MAO-B inhibitors and theoretical-experimental study of G3PDH protein from Trichomonas gallinae.

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    González-Díaz, Humberto; Prado-Prado, Francisco; García-Mera, Xerardo; Alonso, Nerea; Abeijón, Paula; Caamaño, Olga; Yáñez, Matilde; Munteanu, Cristian R; Pazos, Alejandro; Dea-Ayuela, María Auxiliadora; Gómez-Muñoz, María Teresa; Garijo, M Magdalena; Sansano, José; Ubeira, Florencio M

    2011-04-01

    Many drugs with very different affinity to a large number of receptors are described. Thus, in this work, we selected drug-target pairs (DTPs/nDTPs) of drugs with high affinity/nonaffinity for different targets. Quantitative structure-activity relationship (QSAR) models become a very useful tool in this context because they substantially reduce time and resource-consuming experiments. Unfortunately, most QSAR models predict activity against only one protein target and/or they have not been implemented on a public Web server yet, freely available online to the scientific community. To solve this problem, we developed a multitarget QSAR (mt-QSAR) classifier combining the MARCH-INSIDE software for the calculation of the structural parameters of drug and target with the linear discriminant analysis (LDA) method in order to seek the best model. The accuracy of the best LDA model was 94.4% (3,859/4,086 cases) for training and 94.9% (1,909/2,012 cases) for the external validation series. In addition, we implemented the model into the Web portal Bio-AIMS as an online server entitled MARCH-INSIDE Nested Drug-Bank Exploration & Screening Tool (MIND-BEST), located at http://miaja.tic.udc.es/Bio-AIMS/MIND-BEST.php . This online tool is based on PHP/HTML/Python and MARCH-INSIDE routines. Finally, we illustrated two practical uses of this server with two different experiments. In experiment 1, we report for the first time a MIND-BEST prediction, synthesis, characterization, and MAO-A and MAO-B pharmacological assay of eight rasagiline derivatives, promising for anti-Parkinson drug design. In experiment 2, we report sampling, parasite culture, sample preparation, 2-DE, MALDI-TOF and -TOF/TOF MS, MASCOT search, 3D structure modeling with LOMETS, and MIND-BEST prediction for different peptides as new protein of the found in the proteome of the bird parasite Trichomonas gallinae, which is promising for antiparasite drug targets discovery.

  10. Serum potassium levels, cardiac arrhythmias, and mortality following non-ST-elevation myocardial infarction or unstable angina: insights from MERLIN-TIMI 36.

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    Patel, Ravi B; Tannenbaum, Sara; Viana-Tejedor, Ana; Guo, Jianping; Im, KyungAh; Morrow, David A; Scirica, Benjamin M

    2017-02-01

    In acute coronary syndrome (ACS), potassium levels 4.0 mEq/L in ACS. Our study evaluated the association between potassium levels, cardiac arrhythmias, and cardiovascular death in patients with non-ST-segment elevation myocardial infarction or unstable angina. Potassium levels were measured in 6515 patients prior to randomization to receive either ranolazine or a placebo in the MERLIN-TIMI 36 trial. A seven-day continuous electrocardiographic assessment was obtained to determine the incidence of non-sustained ventricular tachycardia (NSVT) and ventricular pauses. The association between potassium levels and cardiovascular death was evaluated using a Cox proportional hazards regression model with multivariable adjustment. NSVT lasting for at least eight consecutive beats occurred more frequently at potassium levels 3 s, which occurred more frequently at potassium levels ⩾5 mEq/L than at potassium levels <3.5 mEq/L (5.9 vs. 2.0%, p=0.03 for trend). There was a U-shaped relationship between the potassium level at admission and both early and late risk of cardiovascular death. Compared with patients with potassium levels of 3.5 to <4 mEq/L, a potassium level <3.5 mEq/L was associated with an increased risk of cardiovascular death at day 14 (2.4 vs. 0.8%, HRadj 3.1, p=0.02) and at one year (6.4 vs. 3.0%, HRadj 2.2, p=0.01). The risk of cardiovascular death at one year was also significantly increased at potassium levels ⩾4.5 mEq/L and a similar trend was noted at potassium levels ⩾5 mEq/L. The lowest risk of cardiovascular death was observed in patients with admission potassium levels between 3.5 and 4.5 mEq/L. Both lower and higher levels of potassium were associated with tachyarrhythmias and bradyarrhythmias, suggesting a potential mechanistic explanation for the increased risk of cardiovascular death at the extremes of potassium homeostasis.

  11. Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig.

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    Guns, P-J; Johnson, D M; Weltens, E; Lissens, J

    2012-09-01

    Assessment of the propensity of novel drugs to cause proarrhythmia is essential in the drug development process. It is increasingly recognized, however, that QT prolongation alone is an imperfect surrogate marker for Torsades de Pointes (TdP) arrhythmia prediction. In the present study we investigated the behavior of a novel surrogate marker for TdP, the electro-mechanical (E-M) window, prior to triggering of TdP episodes with sympathetic stimulation after administration of a number of reference compounds. Experiments were carried out in closed chest pentobarbital anesthetized guinea pigs. Test compounds were administered intravenously together with a specific I(Ks) blocker (JNJ303; 0.2 mgkg(-1)min(-1) for 3 min) and adrenaline (0.06 mgkg(-1)min(-1) for 2 min) was applied to trigger TdP. ECG, blood- and left ventricular pressure signals were measured continuously throughout the experiments. The E-M window i.e. the duration of the mechanical systole (QLVP(end) interval) minus the duration of the electrical activity (QT interval) was assessed for individual beats. Drugs with documented TdP liability (quinidine, haloperidol, domperidone, terfenadine, moxifloxacin, ciprofloxacin and dofetilide) produced TdP in the protocol after adrenaline infusion, whereas negative control compounds (verapamil, ranolazine, amiodarone and saline) did not cause TdP arrhythmia, even though increases in repolarization times were observed. TdP were typically preceded by large (greater than -50 ms) negative electro-mechanical windows and were accompanied by aftercontractions. The present study in anesthetized guinea pigs indicates that negative E-M windows are a prerequisite for sympathetically-driven TdP induction after the administration of various agents with known proarrhythmic potential. These data are a first step in the validation of this novel protocol; however we believe that this proarrhythmia model in small animals might be a valuable additional tool in the prediction of TdP risk

  12. [Modifications in myocardial energy metabolism in diabetic patients

    Science.gov (United States)

    Grynberg, A.

    2001-01-01

    The capacity of cardiac myocyte to regulate ATP production to face any change in energy demand is a major determinant of cardiac function. Because FA is the main heart fuel (although the most expensive one in oxygen, and prompt to induce deleterious effects), this process is based on a balanced fatty acid (FA) metabolism. Several pathological situations are associated with an accumulation of FA or derivatives, or with an excessive b-oxidation. The diabetic cardiomyocyte is characterised by an over consumption of FA. The control of the FA/glucose balance clearly appears as a new strategy for cytoprotection, particularly in diabetes and requires a reduced FA contribution to ATP production. Cardiac myocytes can control FA mitochondrial entry, but display weak ability to control FA uptake, thus the fate of non beta-oxidized FA appear as a new impairment for the cell. Both the trigger and the regulation of cardiac contraction result from membrane activity, and the other major FA function in the myocardium is their role in membrane homeostasis, through the phospholipid synthesis and remodeling pathways. Sudden death, hypercatecholaminemia, diabetes and heart failure have been associated with an altered PUFA content in cardiac membranes. Experimental data suggest that the 2 metabolic pathways involved in membrane homeostasis may represent therapeutic targets for cytoprotection. The drugs that increase cardiac phospholipid turnover (trimetazidine, ranolazine,...) display anti-ischemic non hemodynamic effect. This effect is based on a redirection of FA utilization towards phospholipid synthesis, which decrease their availability for energy production. A nutritional approach gave also promising results. Besides its anti-arrhythmic effect, the dietary docosahexaenoic acid is able to reduce FA energy consumption and hence oxygen demand. The cardiac metabolic pathways involving FA should be considered as a whole, precariously balanced. The diabetic heart being characterised by

  13. Serum potassium levels, cardiac arrhythmias, and mortality following non-ST-elevation myocardial infarction or unstable angina: insights from MERLIN-TIMI 36

    Science.gov (United States)

    Patel, Ravi B; Tannenbaum, Sara; Viana-Tejedor, Ana; Guo, Jianping; Im, KyungAh; Morrow, David A; Scirica, Benjamin M

    2017-01-01

    Background In acute coronary syndrome (ACS), potassium levels 4.0 mEq/L in ACS. Our study evaluated the association between potassium levels, cardiac arrhythmias, and cardiovascular death in patients with non-ST-segment elevation myocardial infarction or unstable angina. Methods Potassium levels were measured in 6515 patients prior to randomization to receive either ranolazine or a placebo in the MERLIN-TIMI 36 trial. A seven-day continuous electrocardiographic assessment was obtained to determine the incidence of non-sustained ventricular tachycardia (NSVT) and ventricular pauses. The association between potassium levels and cardiovascular death was evaluated using a Cox proportional hazards regression model with multivariable adjustment. Results NSVT lasting for at least eight consecutive beats occurred more frequently at potassium levels 3 s, which occurred more frequently at potassium levels ⩾5 mEq/L than at potassium levels <3.5 mEq/L (5.9 vs. 2.0%, p=0.03 for trend). There was a U-shaped relationship between the potassium level at admission and both early and late risk of cardiovascular death. Compared with patients with potassium levels of 3.5 to <4 mEq/L, a potassium level <3.5 mEq/L was associated with an increased risk of cardiovascular death at day 14 (2.4 vs. 0.8%, HRadj 3.1, p=0.02) and at one year (6.4 vs. 3.0%, HRadj 2.2, p=0.01). The risk of cardiovascular death at one year was also significantly increased at potassium levels ⩾4.5 mEq/L and a similar trend was noted at potassium levels ⩾5 mEq/L. Conclusions The lowest risk of cardiovascular death was observed in patients with admission potassium levels between 3.5 and 4.5 mEq/L. Both lower and higher levels of potassium were associated with tachyarrhythmias and bradyarrhythmias, suggesting a potential mechanistic explanation for the increased risk of cardiovascular death at the extremes of potassium homeostasis. PMID:26714972

  14. Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII

    Science.gov (United States)

    Fischer, Thomas H.; Herting, Jonas; Mason, Fleur E.; Hartmann, Nico; Watanabe, Saera; Nikolaev, Viacheslav O.; Sprenger, Julia U.; Fan, Peidong; Yao, Lina; Popov, Aron-Frederik; Danner, Bernhard C.; Schöndube, Friedrich; Belardinelli, Luiz; Hasenfuss, Gerd; Maier, Lars S.; Sossalla, Samuel

    2015-01-01

    Aims Enhanced cardiac late Na current (late INa) and increased sarcoplasmic reticulum (SR)-Ca2+-leak are both highly arrhythmogenic. This study seeks to identify signalling pathways interconnecting late INa and SR-Ca2+-leak in atrial cardiomyocytes (CMs). Methods and results In murine atrial CMs, SR-Ca2+-leak was increased by the late INa enhancer Anemonia sulcata toxin II (ATX-II). An inhibition of Ca2+/calmodulin-dependent protein kinase II (Autocamide-2-related inhibitory peptide), protein kinase A (H89), or late INa (Ranolazine or Tetrodotoxin) all prevented ATX-II-dependent SR-Ca2+-leak. The SR-Ca2+-leak induction by ATX-II was not detected when either the Na+/Ca2+ exchanger was inhibited (KBR) or in CaMKIIδc-knockout mice. FRET measurements revealed increased cAMP levels upon ATX-II stimulation, which could be prevented by inhibition of adenylyl cyclases (ACs) 5 and 6 (NKY 80) but not by inhibition of phosphodiesterases (IBMX), suggesting PKA activation via an AC-dependent increase of cAMP levels. Western blots showed late INa-dependent hyperphosphorylation of CaMKII as well as PKA target sites at ryanodine receptor type-2 (-S2814 and -S2808) and phospholamban (-Thr17, -S16). Enhancement of late INa did not alter Ca2+-transient amplitude or SR-Ca2+-load. However, upon late INa activation and simultaneous CaMKII inhibition, Ca2+-transient amplitude and SR-Ca2+-load were increased, whereas PKA inhibition reduced Ca2+-transient amplitude and load and additionally slowed Ca2+ elimination. In atrial CMs from patients with atrial fibrillation, inhibition of late INa, CaMKII, or PKA reduced the SR-Ca2+-leak. Conclusion Late INa exerts distinct effects on Ca2+ homeostasis in atrial myocardium through activation of CaMKII and PKA. Inhibition of late INa represents a potential approach to attenuate CaMKII activation and decreases SR-Ca2+-leak in atrial rhythm disorders. The interconnection with the cAMP/PKA system further increases the antiarrhythmic potential of late

  15. Ethyl methanesulfonate toxicity in Viracept--a comprehensive human risk assessment based on threshold data for genotoxicity.

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    Müller, Lutz; Gocke, Elmar; Lavé, Thierry; Pfister, Thomas

    2009-11-12

    Based on a production accident Viracept (nelfinavir mesilate) tablets, an HIV protease inhibitor supplied by Roche outside the US, Canada and Japan was contaminated with relatively high levels of ethyl methanesulfonate (EMS) for at most 3 months in spring of 2007. On the basis of a wide variety of toxicological data including critical experiments for mutation induction under chronic exposure conditions and cross-species exposure scaling experiments to extrapolate to humans, we estimate the added risk of adverse effects (cancer, birth abnormalities, heritable defects) in any individual patient accidentally exposed to EMS via contaminated Viracept tablets in the context of this production accident as essentially zero. Of critical important for this risk assessment are pivotal in vivo genotoxicity studies (MNT, MutaMouse) providing evidence for 'hockey-stick', like dose-response relationships for the risk defining induction of gene mutations and chromosomal damage by EMS [Gocke, E., Müller, L., Pfister, T., Buergin, H., 2009a. Literature review on the genotoxicity, reproductive toxicity, and carcinogenicity of ethyl methanesulfonate. Toxicol. Lett.; Gocke, E., Müller, L., Pfister, T., 2009b. EMS in Viracept-initial ('traditional') assessment of risk to patients based on linear dose response relations. Toxicol. Lett.; Gocke, E., Müller, L., Ballantyne, M., Whitwell, J., Müller, L., 2009c. MNT and MutaMouse studies to definde the in vivo dose-response relations of the genotoxicity of EMS and ENU. Toxicol. Lett.]. As outlined in Gocke and Wall [Gocke, E., Wall, M., 2009. In vivo genotoxicity of EMS: Statistical assessment of the dose response curves. Toxicol. Lett.], several statistical approaches are in support of a threshold model to best fit the data. The presence of clear no effect levels in bone marrow, liver and GI-tract tissue with several dose levels tested below the NOEL permits the calculation of safety factors with considerable confidence. In calculating

  16. Crotalaria (Crotalaria juncea L.) Heavy Metal Uptake in Eastern Hungary

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    László Phd, M., ,, Dr.

    2009-04-01

    Summary: Soil condition, plant production and ecological protection are most important parts of the sustainable agricultural activity on all over the world nowadays. Soils, their fertility, their content of different macro-, mezo-, micro-, trace elements have almost always dictated the spread of agricultural farmlands, including the plant production-, yield harvest levels and yield element contents possible. The success of agriculturists in the 20th and 21th century, particularly in the Europe has relied on inproved soil fertility managements, appropriate crop production and environmental protection. We can test and improve the situations by using different plant species (Crotalaria juncea L.) x macro nutrients (nitrogen) x chelating agents (Desferal as deferoxamine-mesilate: C25H48N6O8-CH4O3S) methods. Crotalaria has a very potential and important role in soil fertility as a green manure crop in the design of plant rotation to field plant production, in the animal foraging as a fodder-crop with a high protein content (30%) and in the pytoremediation possibilities. Field experiment was carried out on a calcareous chernozem meadow soil (Kunság-region of Hungary, Kunmadaras) in partly of crotalaria experiment series (5 years) in 2001. The agrochemical parameters of the ploughed layer of the region soils were as follows: humus 2.5-3.0%, pH (H2O) 7.7, pH (KCl) 7.0, LE (Lakanen & Erviö 1971 [3])-P2O5 183-218 mg kg-1, LE-K2O 82-115 mg kg-1, LE-Ca 1.3%, LE-Mg 56-60 mg kg-1, LE-Mn 45 mg kg-1 according to soil analysis. Nitrogen (N) x Desferal ("D"-Novartis Pharma AG Basie [7], Switzerland, Suiza 500 mg) x Genotype ("G"-India-University of Agricultural Sciences, Bangalore) x Time (T) experiment involved The N levels were 0, 100, 200 and 300 kg ha-1 year-1, and Desferal 0 and 20 kg ha-1 year-1. The plot size had an area of 4x2=8 m2. Experimental datas were estimated by MANOVA of SPSS. The main results can be summarised as follows: a., At harvest, total air dry phytomass