Cardiotonic Agent Research Articles

A convenient synthesis of cyclopenta[b]pyridin-2,5-dione as a non- glycosidic cardiotonic agent

A straightforward synthesis of cyclopenta(b)pyridin-2,5-dione is reported starting from the commercially available 2-bromo-6-methoxypyridine. The overall route consists in a first sequence of regioselective ortho lithiation and methoxycarbonylation followed by Heck vinylation, alkene reduction, cyclization and decarboxylation.

What is the evidence for medicinal value of carnivorous plants?

Throughout history, plants have been used for medicinal purposes. Many of the modern allopathic medicines used today are either directly or indirectly derived from plants. Examples include the cardiotonic and antiarrhythmic agent digoxin (derived from the foxglove—Digitalis purpurea), antimalarial quinine (derived from the bark of the cinchona tree—Cinchona officinalis), the mydriatic (pupil dilatory) agent belladonna (derived from the nightshade Atropa belladonna), aspirin (derived from the bark of the willow tree—Salix alba, etc.), taxol (derived from the yew tree—Taxus brevifolia) and vincristine (derived from the periwinkle—Catharanthus roseus (=Vinca rosea)). Although carnivorous plants have been used medicinally, to date not a single compound derived from carnivorous plants has been widely-accepted in modern allopathic medicine. Pinguicula spp., Dionaea muscipula, Drosera spp., Sarracenia purpurea, and Nepenthes spp. are the carnivorous plants frequently touted as having therapeutic potential. We herein review the existing literature on the medical uses of these plants.

Cardiotonic Agents: Mechanisms and Characteristics of Action

Current pharmacological therapy of congestive heart failure (CHF) primarily focuses on cardioprotection by cardiac unloading and suppression of neurohumoral modulations to inhibit cardiac remodeling and cardiac pump dysfunction. However, cardiac inotropic therapy is essential for improvement of contractile dysfunction in acute CHF and aggravating phase of chronic CHF. Most of clinically available agents such as catecholamines (e.g., dobutamine), selective phosphodiesterase (PDE) 3 inhibitors (e.g., amrinone.

Basic and Clinical Characteristics of PDE 3 Inhibitors as Cardiotonic Agents

Basic and Clinical Characteristics of PDE 3 Inhibitors as Cardiotonic Agents

Myocardial Phosphodiesterases and Regulation of Cardiac Contractility in Health and Cardiac Disease

Phosphodiesterase (PDE) inhibitors are potent cardiotonic agents used for parenteral inotropic support in heart failure. Contractile effects of these agents are mediated through cAMP-protein kinase A-induced stimulation of I (Ca2+) which ultimately results in increased Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. A number of additional effects such as increases in sarcoplasmic reticulum Ca(2+) stores, stimulation of reverse mode Na(+)-Ca(2+) exchange, direct or cAMP-mediated effects on sarcoplasmic reticulum ryanodine receptor, stimulation of the voltage-sensitive sarcoplasmic reticulum Ca(2+) release mechanism, as well as A(1) adenosine receptor blockade could contribute to positive inotropic responses to PDE inhibitors. Moreover, some PDE inhibitors exhibit Ca(2+) sensitizer properties as they could increase the affinity of troponin C Ca(2+)-binding sites as well as reduce Ca(2+) threshold for thin myofilament sliding and facilitate cross-bridge cycling. Inotropic responses to PDE inhibitors are significantly reduced in cardiac disease, an effect largely attributed to downregulation of cAMP-mediated signalling due to sustained sympathetic activation. Four PDE isoenzymes (PDE1, PDE2, PDE3 and PDE4) are present in myocardial tissue of various mammalian species, of which PDE3 and PDE4 are particularly involved in regulation of cardiac myocyte contraction. PDE cAMP-hydrolysing activity is preserved in compensated cardiac hypertrophy but significantly reduced in animal models of heart failure. However, clinical studies have not revealed any changes in distribution profile as well as kinetic and regulatory properties of myocardial PDEs in failing human hearts. A reduction of PDE inhibitors-induced contractile responses in heart failure has therefore been ascribed to reduced cAMP synthesis due to uncoupling of adenylyl cyclase from beta-adrenoreceptor. In cardiac myocytes, PDEs are targeted to distinct subcellular compartments by scaffolding proteins such as myomegalin, mAKAP and beta-arrestins. Over subcellular microdomains, cAMP hydrolysis by PDE3 and PDE4 allows to control the activity of local pools of protein kinase A and therefore the extent of protein kinase A-mediated phosphorylation of cellular proteins.

Multicomponent Synthesis of Highly Substituted 2-Pyridones

A novel synthesis of polyfunctionalised pyridones, ­structurally related to cardiotonic agent milrinone is described. The procedure consists of an Ugi four-component reaction of 3-formylchromones, followed by a base-promoted ring-opening/ring-closing process. Variation of three of the four components in the Ugi ­reaction allows access to the final products with a combinatorial distribution of ­substituents.

Analysis of adverse drug reactions for preventability

Although preventability criteria have been assessed for all adverse drug reactions (ADRs) investigated at our institution over the past 12 years, a systematic evaluation of the data had not been performed. This project analysed preventability data previously collected to identify the potential areas for process improvements. A 3-year retrospective analysis was performed. All ADRs were categorised by drug, drug class, severity, probability of causality and preventability. Factors involved in preventability were assessed and tallied. Descriptive statistics was used to analyse the data. Most ADRs occurred prior to admission. In the outpatient setting, anticoagulants and anticonvulsants were associated with more preventable ADRs (pADRs) than other drug classes, followed by cardiotonic agents and non-steroidal anti-inflammatory drugs (NSAIDs). For ADRs that occurred in hospitalised patients, antibiotics and opiates were associated with approximately half of all pADRs. The preventability categories most frequently associated with ADRs prior to admission were presence of a toxic drug level and drug-drug interactions, while inappropriate dose, route or frequency was the most common preventability category for inpatient ADRs. The majority of pADRs were moderate in severity in both the in- and outpatient settings. Drugs and drug classes involved in pADRs differ in the in- and outpatient settings. Preventability categories also differ by setting. Most pADRs occur prior to admission in our healthcare system. This presents a challenge in terms of implementing the process changes to reduce the pADRs, as patients in the community are outside our control.

Activating Cardiac Myosin, a Novel Inotropic Mechanism To Improve Cardiac Function in Conscious Dogs with Congestive Heart Failure

Many cardiotonic agents are not useful in the chronic treatment of heart failure (HF), either because they increase myocardial O2 consumption (MVO2) or undergo desensitization, such that their effi...

(R)-(–)-6-(4-Aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one

The title compound, C11H13N3O, is a key intermediate in the synthesis of cardiotonic agents. The asymmetric unit consists of two molecules of the same enantiomer and the crystal packing is stabilized by intermolecular N—H...O hydrogen bonds.

Effects of MCI-154 on Vascular Reactivity and Its Mechanisms After Hemorrhagic Shock in Rats

The objectives of this study were to investigate the effects of 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate (MCI-154), a newly developed cardiotonic agent, on vascular reactivity and contractile responses to extracellular Ca2+ ([Ca2+]o) after hemorrhagic shock and primarily explore its mechanism. In vivo, the effects of MCI-154 (0.1, 0.5, 1.0, and 2.0 mg/kg) on the pressor effect of norepinephrine (NE) in rats subjected to hemorrhagic shock (30 mm Hg for 2 h) were observed and in vitro, the effects of MCI-154 (10(-7), 10(-6), 10(-5), 10(-4) mol/L) on vascular reactivity and contractile responses to [Ca2+]o of superior mesenteric artery (SMA) from hemorrhagic shock rats and its relationship to Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG) were observed. The results showed that the NE-induced pressor response after hemorrhagic shock was significantly decreased (P<0.01), and MCI-154 made it decrease further. In vitro, MCI-154 further decreased the contractile responses of SMA to NE and Ca2+ after hemorrhagic shock as compared with untreated hemorrhagic shock group (P<0.01). Angiotensin II (Ang II), with Rho-kinase stimulating action, and PMA, a PKC agonist increased the contractile responses to [Ca2+]o of SMA after hemorrhagic shock. MCI-154 (10(-5) mol/L) partly inhibited Ang II and PMA-induced increase of the contractile responses to [Ca2+]o of SMA (P<0.01). KT-5823, the PKG antagonist, antagonized MCI-154-induced decrease of the contractile responses to [Ca2+]o. Taken together, these results suggested that the vascular reactivity and contractile responses to [Ca2+]o of vascular smooth muscle after hemorrhagic shock were significantly decreased. MCI-154 worsened hemorrhagic shock-induced vascular hyporeactivity and the decrease of contractile responses to [Ca2+]o. These effects were possibly regulated by Rho-kinase, PKC, and PKG, but this needs further confirmation.

Novel Milrinone Analogues of Pyridine‐3‐carbonitrile Derivatives as Promising Cardiotonic Agents.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Prenatal diagnosis and management for a large fetal cardiac tumor complicated with hydrops fetalis

Fetal cardiac tumor is a rare disease, and its prognosis varies in relation to the complications such as arrhythmia and out-flow obstruction. Hydrops fetalis is one of severe complications that result in an unfavorable outcome. A case is presented herein of a large fetal cardiac tumor diagnosed at 28 weeks gestation. At 30 weeks gestation, the fetus complicated with hydrops fetalis because of impaired cardiac function. Increased peak systolic velocity in the ascending aorta and marked reversed flow in the ductus venosus were observed. Oral digoxin therapy was administered to the mother as a cardiotonic agent and the hydropic condition was immediately diminished. After normal delivery, the cardiac tumor gradually decreased in size and the infant developed normally, but required an antiarrhythmic drug. The case indicates that the in utero digoxin therapy could be a choice for hydrops fetalis caused by cardiac tumor.

Novel milrinone analogs of pyridine-3-carbonitrile derivatives as promising cardiotonic agents

In an attempt to design new inotropic drugs for congestive heart failure (CHF) with less proarrhythmic potential, three series of compounds analogous to milrinone were prepared, namely, 4-aryl-6-(4-pyridyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles 2a– g, 4-aryl-6-(4-pyridyl)-2-thioxo-1,2-dihydropyridine-3-carbonitriles 3a– g and 2-amino-4-aryl-6-(4-pyridyl)-pyridine-3-carbonitriles 4a– g. The first series was prepared by reacting 4-acetyl pyridine with the appropriate aldehyde, ethyl cyanoacetate and ammonium acetate in ethanol. Reaction of 2a– g with phosphorus pentasulfide afforded the second series 3a– g. The third target compounds 4a– g were prepared applying the same procedure used to synthesize 2a– g using malononitrile instead of ethyl cyanoacetate. All the newly synthesized compounds were evaluated for their cardiotonic activity and their in vivo cardiovascular effects. In addition, their oral and parentral acute toxicity were determined. Compounds 2a, 2b, 2c, 4c and 4f proved to exert cardiotonic activity comparable to that of milrinone using spontaneously beating atria model from reserpine-treated guinea pigs. In addition these compounds proved to be non-toxic and well tolerated by mice up to 250 mg kg –1 orally and up to 125 mg kg –1 through parenteral route.

Insights into structure–activity relationships from lipophilicity profiles of pyridin-2(1 H)-one analogs of the cardiotonic agent milrinone

The pH-dependent distribution profiles of a series of pyridin-2(1 H)-one analogs of the inotropic/vasodilator agent milrinone, determined in 1-octanol/water (and for a number of them also in chloroform–water) using a pH-metric technique, showed that partition coefficients of the neutral forms (log P N ) significantly encode for 2-pyridone/2-hydroxypyridine tautomerism. A comparison between experimental and calculated log P (CLOG P) values indicated that electron-withdrawing substituents, at the C(6) position, and to a lesser extent at the C(3) and C(5) positions, push up log Ps toward the values of the more lipophilic 2-hydroxypyridine tautomers. RP-HPLC parameters ( log k ′ w ) carry for large part similar information related to tautomerism-dependent lipophilicity, but they were also found to reasonably correlate with the solute molar volumes ( r 2 = 0.75). Investigating the implications of ionization and partition properties in modulating the in vitro cardiotonic activity of the examined compounds revealed that a high fraction of the neutral species at physiological pH, predominantly in the more polar pyridone (OX) tautomer, increases the positive inotropic potency.

Base catalyzed intramolecular transamidation of 2-aminoquinazoline derivatives on solid phase

A novel intramolecular cyclo-elimination via transamidation on the Rink Amide AM resin under mild basic conditions is presented. The methodology led to the synthesis of an important class of cardiotonic agents: imdiazo- and pyrimido-quinazolines from the corresponding 2-aminoquinazoline hydrobromide salt under mild basic conditions. NMR based titration studies revealed the role of hydrobromide as a molecular switch, which on removal triggers the cyclisation of aminoquinazoline to tricyclic structures. The main advantage of transamidation under basic conditions over the TFA cleavage is the recyclability of the resin obtained after cyclo-elimination. This has been demonstrated by successive synthesis of four structurally diverse imidazoquianzolin-2-ones using the same batch of resin without any cross contamination.

Pharmacological Mechanisms Contributing to the Clinical Efficacy of Levosimendan

Acute decompensation of chronic heart failure is a direct life-threatening situation with short-term mortality approaching 30%. A number of maladaptive changes are amplified within the cardiovascular system during the progression of chronic heart failure that makes the decompensation phase difficult to handle. Levosimendan is a new Ca2+-sensitizer for the treatment of acutely decompensated heart failure that has proved to be effective during the decompensation of chronic heart failure and acute myocardial infarction. Levosimendan differs from other cardiotonic agents that are used for acute heart failure in that it utilizes a unique dual mechanism of action: Ca2+-sensitization through binding to troponin C in the myocardium, and the opening of ATP-sensitive K+ channels in vascular smooth muscle. In general, these mechanisms evoke positive inotropy and vasodilation. Clinical studies suggested long-term benefits on mortality following short-term administration. It may, therefore, be inferred that levosimendan has additional effects on the cardiovascular system that are responsible for the prolongation of survival. Results of preclinical and clinical investigations suggest that the combination of levosimendan-induced cardiac and vascular changes has favorable effects on the coronary, pulmonary and peripheral circulations. Redistribution of the circulating blood offers an improved hemodynamic context for the development of a positive inotropic effect through Ca2+-sensitization of the contractile filaments, without a proportionate increase in myocardial oxygen consumption or the development of arrhythmias. Activation of ATP-sensitive K+ channels, both on sarcolemma and mitochondria, may protect against myocardial ischemia, and decreased levels of cytokines may prevent the development of further myocardial remodeling. Collectively, these effects of levosimendan shift the disturbed cardiovascular parameters towards normalization, thereby halting the perpetuation of the vicious cycle of heart failure progression. This may contribute to stabilization of the circulation and improved life expectancy of patients with chronic heart failure.

Relative Toxicity of Cardiotonic Agents: Some Induce More Cardiac and Skeletal Myocyte Apoptosis and Necrosis In Vivo Than Others

We sought to determine the relative myotoxicity of a sample of cardiotonic (catecholaminergic and PDE Inhibitory) agents currently available for clinical use. Male Wistar rats (292 +/- 24 g) were administered single subcutaneous injections of 20 mmol kg(-1) of each agent. Myocyte apoptosis (caspase-3 and annexin-V) and necrosis (anti-myosin antibody) were detected immunohistochemically on cryosections of the heart and soleus muscle. All of the cardiotonic agents except dopamine produced significant amounts of cardiomyocyte death compared with the vehicle controls, with necrosis (range 2-8%, p < 0.01) approximately one order of magnitude greater in extent than apoptosis (range 0.06-0.5%, p < 0.05). The incidence of necrosis induced by norepinephrine (8%) was approximately twice that of epinephrine and isoproterenol (4 %) and four times that of dobutamine and milrinone (2%). All agents were also toxic to the soleus muscle (range 0.1-8%), but isoproterenol (8%, p < 0.05) and epinephrine (4%, p < 0.05) were the most significant. No cell death was detected in control animals treated with only the vehicle. A majority of cardiotonic agents currently in clinical use are toxic to cardiac and skeletal myocytes. These observations suggest that judicious clinical use of such agents requires careful weighing of potential benefits against the harm via accelerated cumulative loss of myocytes.

A Na+ channel agonist: a potential cardiotonic agent with a novel mechanism?

British Journal of Pharmacology (2004) 143, 663–665. doi:10.1038/sj.bjp.0705970

Electromechanical properties of Purkinje fiber strands isolated from human ventricular endocardium

Background Abnormalities in the regulation of intracellular Ca 2+ were observed in cardiac cells obtained from failing human hearts. However, the electromechanical properties and pharmacologic responses of human ventricular Purkinje fibers have not been well characterized. Methods Strands of free-running Purkinje fibers and/or trabecular muscle fibers with a diameter of around 1.5 mm were removed from the endocardial surface of ventricles obtained from 16 transplant recipient hearts. Action potential (AP) was detected by conventional microelectrode techniques and twitch force by a force-displacement transducer. Results The human Purkinje fiber strands as revealed by histologic examination were composed of Purkinje cells and the surrounding ventricular muscle cells. In well-polarized Purkinje fibers (mean ± SE of maximum diastolic potential [MDP] = −85 ± 1 mV) showing fast-response AP (Phase 0 V̇ max >100 V/sec), the cardiotonic agents isoproterenol and strophanthidin (1 to 2 μmol/liter) accelerated the slope of diastolic depolarization and induced delayed afterdepolarization but not spontaneous APs. Steady-state contraction and the post-rest potentiation of contraction (PRPC) were similar in both Purkinje fibers and ventricular muscles, but inotropic agents induced tachyarrhythmia only in Purkinje fibers. In partially depolarized Purkinje fibers (MDP <−70 mV) with slow-response AP, isoproterenol and/or strophanthidin readily induced automatic and triggered rhythms. Conclusions Accumulation of excessive cytosolic Ca 2+ in the presence of cardiotonic agents could lead to tachyarrhythmias in Purkinje fibers, but rarely in ventricular muscles of failing human hearts.

Guidelines for acute decompensated heart failure treatment.

To describe the development of guidelines for the treatment of acute decompensated heart failure (ADHF) in the emergency department/observation unit (ED-OU) setting for hospitals that are part of a group purchasing organization (GPO). A MEDLINE search (1966-March 2003) using the following search terms: cardiotonic agents; diuretic; dobutamine; heart failure, congestive; milrinone; natriuretic peptide, brain; nesiritide; nitroglycerin; vasodilator agents, was conducted. Relevant articles in the English language were identified. All randomized studies and meta-analyses for each category of drugs were included. A group consensus method was used to develop guidelines. An expert panel reviewed and revised the guidelines. The final guidelines were approved June 1, 2003, and are described here. They are organized based upon a patient's symptomatology at the time the diagnosis of ADHF is made. Patients with evidence of volume overload require intravenous diuretics and/or intravenous vasodilators to alleviate the symptoms of ADHF. Patients with signs and symptoms of low cardiac output require inotropic support to manage their ADHF. A timeline for diagnosis, treatment, reassessment, and disposition is provided and encourages an early, aggressive approach to treating patients with ADHF. Hospitalization for ADHF is common and costly. Consensus guidelines for the treatment of ADHF did not previously exist, resulting in inconsistent and inefficient treatment. Consequently, hospitals struggling with the treatment of ADHF may find these guidelines and the process by which they were developed useful.