Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the course of diagnostic cardiac catheterisation in 6 patients suspected of having coronary heart disease 2-[(2-methoxy)-4-methylsulfinyl)phenyl]-1H-imidazol[4,5-b]pyridine (AR-L 115 BS) was administered to see whether an improvement in left ventricular function could be achieved. 30 min after oral administration of the drug there was an increase in the ejection fraction (EF) and in the rate of circumferential fibre shortening (FSR) and a decrease in the end-systolic volume (ESV) and end-diastolic pressure (EDP). There was no significant change in heart rate (HR) and systolic blood pressure. The investigation confirmed the positive inotropic effect of AR-L 115 BS following oral administration: this substance could, therefore, be of value in the treatment of cardiac insufficiency.
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PMID:A new orally active positive inotropic substance: AR-L 115 BS. 719 40

In 11 patients with New York Heart Association (NYHA) functional class III-IV symptoms we monitored the effect of 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazo[4.5-b]pyridine (AR-L 115 BS). Heart rate (HR), pulmonary arterial mean pressure (PAM), aortic systolic pressure (AoSP) and thermodilution cardiac output (CO) were measured before and up to 25 min after a bolus of AR-L 115 BS, 3 mg/kg body weight, i.v. The oral effect of AR-L 115, 200 mg, 3 times daily, was monitored in 18 patients with congestive cardiomyopathy (CC) over a period of 4 days. AR-L 115 BS is also orally active and thus is a very promising inotropic agent for the treatment of chronic heart failure in man.
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PMID:A new non-glycoside, non-adrenergic cardiotonic agent AR-L 115 BS. Hemodynamic proof of its efficacy after both i.v. and oral administration. 719 41

Calcium (Ca) agonists like Bay k 8644 ((-)-S-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl) pyridine-5-carboxylate (CAS 93468-89-4), may represent a new principle in the treatment of heart failure. Because of marked vasoconstrictive properties, these agents may have a deleterious effect on myocardial ischemia (MI). It was however demonstrated that contractility enhancement and coronary flow (CF) reduction do not automatically enlarge MI. Therefore, we investigated the influence of Bay k 8644 (10(-8) mol/l) in comparison to ouabain (1.5 x 10(-7) mol/l) in non-arrhythmogenic concentrations on MI in electrically paced isolated rabbit hearts (Langendorff, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l, 180 beats/min). MI was induced by coronary artery ligation and quantified by epicardial NADH-fluorescence. Left ventricular pressure (LVP) was significantly increased by ouabain (+10-20%) but slightly diminished by Bay k 8644 (-10%) (p < 0.05). CF reduction after Bay k 8644 (-30%) was more pronounced than after ouabain (-10%) (p < 0.05), but both substances did reduce relative CF (CF/LVP x heart rate) to the same extent (-20-30%) (p > 0.05). Nevertheless, ouabain did not significantly influence epicardial NADH-fluorescence area or intensity (p > 0.05), whereas MI was significantly enlarged by Bay k 8644 (+30%) (p < 0.05). It is concluded that in isolated rabbit hearts ouabain and Bay k 8644 might influence CF-distribution differently with a more pronounced diminuation of the nutritive CF induced by Bay k 8644.
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PMID:Influence of dihydropyridine-type calcium agonists on hemodynamics and myocardial ischemia in isolated rabbit hearts. 750 84

The pharmacokinetic profile and pharmacodynamic activities of torasemide, a new pyridine sulfonylurea acting on the loop of Henle, are described. Absorption of the drug was unchanged in patients with congestive heart failure, though maximum concentrations occurred at 1.7 h compared with 0.9 h in healthy subjects. The volume of distribution after oral administration was also unchanged in patients with heart failure, but oral clearance was reduced by 50%, consistent with the increase in elimination half-life; renal clearance and maximum urinary torasemide excretion rate were also reduced by 50%. Thus, the primary pharmacokinetic alteration in patients with heart failure compared with healthy subjects was a reduction in the rate of delivery of torasemide to its site of action in the loop of Henle. Fractional sodium excretion and urinary torasemide excretion rate were similar in patients with heart failure and healthy subjects, though the relationship between the excretion rates of sodium and torasemide was depressed in the patients with heart failure. Thus, the primary pharmacodynamic alteration in patients with heart failure compared with healthy subjects was less total sodium excretion per molecule of torasemide reaching the renal tubule. Torasemide was effective in inducing loss of body weight and increased sodium excretion in patients with congestive heart failure. Single intravenous and oral doses of 20 mg both produced similar significant increases in total sodium excretion. Torasemide, 5-20 mg once daily for up to 6 weeks, produced significant loss of body weight and increased total sodium excretion confirming the diuretic effectiveness of torasemide in patients with congestive heart failure.
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PMID:Pharmacokinetics and pharmacodynamics of torasemide in congestive heart failure. 795 32

2-Amino-1,4-dihydro-4-(2-[-4[4-(2-methoxyphenyl)-1-piperazinyl]- butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513) was designed to combine the calcium agonistic and alpha-1 adrenergic receptor antagonistic properties in the same molecule. It inhibited the specific binding of [3H] nitrendipine in rat cardiac ventricular membranes with an IC50 of 1.2 microM, which is 20-fold greater than the standard calcium agonist Bay K 8644. It displaced [3H]prazosin in rat brain membranes with an IC50 of 29 nM. XB513 caused concentration-dependent positive inotropic responses in isolated electrically paced guinea pig left atria with an EC50 of 1.2 microM and was 10 times less potent than Bay K 8644. In rabbit aorta, XB513 inhibited the contractile effect of 16 nM norepinephrine with an IC50 of 89 nM. In an acute heart failure dog model produced by an overdose of propranolol, XB513 at 0.3 to 3 mg/kg i.v. dose-dependently reversed the decreased mean arterial pressure, cardiac output and dP/dt as well as the increased left ventricular end diastolic pressure induced by propranolol. In conscious instrumented dogs, XB513 at 0.1 and 0.3 mg/kg i.v. increased dP/dt and heart rate significantly, with a minor effect on mean arterial pressure. In summary, this study demonstrates that XB513 is a novel chemical entity possessing both calcium agonistic and alpha-1 adrenergic receptor blocking properties and thus may represent a new class of agents for the treatment of congestive heart failure.
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PMID:Pharmacology of 2-amino-1,4-dihydro-4-(2-[4-[4-(2-methoxyphenyl)-1- piperazinyl]butylsulfinyl]phenyl)-6-methyl-5-nitro-3-pyridine carboxylic acid methyl ester (XB513), a novel calcium agonist with alpha-1 adrenergic receptor antagonistic. 809 16

The effects of HN-10200 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo(4,5-c)-pyridine HCl) and its derivatives HN-10201-sulfide and HN-10202-sulfone on the activities of the phosphodiesterase (PDE) isoenzyme activities isolated from ventricular myocardium of failing human hearts (end-stage myocardial failure, NYHA IV) were investigated. Four PDE isoenzymes (PDE I-IV) were separated by DEAE-sepharose chromatography. Milrinone, 3-isobutyl-1-methylxanthine (IBMX), and a derivative of pimobendan (2-(4-hydroxyphenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl)- benzimidazole HCl, PiD) were studied for comparison. Furthermore, the influence of HN-10200 on force of contraction and cAMP content of ventricular trabeculae of these hearts were determined. HN-10200 inhibited the activities of PDE I-IV concentration-dependently. The IC50 values were (mumol/l): 218.7, 283.1, 119.6, and 85.8 for PDE I-IV, respectively. The IC50 values of its derivatives were in the same range, i.e. the parent compound or its derivatives inhibited the PDE isoenzymes nonselectively. IBMX also inhibited PDE I-IV nonselectively, but was about ten times more potent based on IC50 values. In contrast, PiD was the most selective and potent PDE III inhibitor tested. Milrinone inhibited both, PDE III and IV, up to two orders of magnitude more potently than PDE I and II, HN-10200 (30 mumol/l) only marginally and insignificantly increased force of contraction and cAMP content of the ventricular trabeculae. Thus, HN-10200 and it's derivatives HN-10201-sulfide and HN-10202-sulfone are nonselective inhibitors of myocardial PDE I-IV. HN-10200 revealed only neglectable positive inotropic effects in preparations from failing human heart.
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PMID:Characterization of the phosphodiesterase inhibition by 2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo-(4,5-c)-pyridine HCl and its sulfide- and sulfone derivatives in myocardial preparations from failing human hearts. 857 20

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.
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PMID:Skeletal muscle metabolism in experimental heart failure. 893 80

The action of medical drugs obtained from many vegetables aroused a great interest of naturalists and physicians in all time. Moreover, it was always required that those persons destined to medical practice have a good knowledge of botany. Among the medicinal plants utilized by ancient peoples of the Anahuac, yoloxochitl or heart flower (Talauma mexicana) is mentioned, which seems to have a digitalis-like action. Research in our century demonstrated a positive inotropic and bradycardic effect of the leavels of Magnolia grandiflora or Talauma mexicana extract. Since the end of the XVIII century, digitalis was employed. It was considered initially as a diuretic and later as a cardiotonic agent. The action of digitalic glycosides upon the cardiac tissues was studied experimentally in Mexico. At the present-time there are positive inotropic agents derived from pyridine, as is the case of Milrinone, which have a beneficial action on the failing human myocardium. However, following the opinion of distinguished pharmacologists, "in the case of heart failure associated to atrial fibrillation, digitalis cannot be substituted".
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PMID:[Digitalic therapy. Historical outline]. 1108 Sep 35

Drugs acting on beta(1)- and beta(2)-adrenergic receptors are widely used for the clinical management of a large number of cardiovascular and respiratory pathologies. In the last decade, the discovery of the third subtype of beta receptors, the beta(3)-adrenoceptor, gave a further pharmacological target for the development of new selective drugs. Initially, a potential therapeutic use of beta(3)-selective agents seemed to be restricted to agonists, for the treatment of metabolic diseases, such as obesity, non-insulin-dependent diabetes, urinary frequency and incontinence. More recently, some interesting theories about a negative role played by the cardio-depressant activity of myocardial beta(3)-adrenoceptors in heart failure, seemed to justify a clinical use of beta(3)-antagonists in the last phases of this cardiac disease. Following the indications deriving from previous experimental work, the beta-antagonist properties of newly-synthesised (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and of 2,3-dihydrothiopyrano[2,3-b]pyridine were evaluated, in order to identify some useful structure-activity relationships, which might account for selectivity towards the three beta-subtypes and, in particular, the beta(3)-adrenoceptor. Among the various observations regarding possible structure-activity relationships, able to explain the pharmacodynamic patterns of the synthesised compounds on the three subtypes of beta-adrenoceptors, the most significant data derived from the evaluation of the beta(3)-blocking properties of some oximeethers of 1,8-naphthyridine derivatives. In these molecules, although the presence of the large substituents in position 7, such as 4-chloro-phenoxy- or 4-t-butyl-phenoxy groups determined a dramatic decline in both the beta(1)- and beta(2)-activities, this structural characteristic had a modest influence on the beta(3)-affinity, which was only slightly lower. Hence, this last structural requirement of oximeethers of 1,8-naphthyridine derivatives seems to represent a useful expedient to induce an appreciable selectivity towards the beta(3)-receptor, through a markedly negative effect on the beta(1)- and beta(2)-activities rather than an increase in the beta(3)-affinity.
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PMID:Synthesis and beta-blocking activity of (R,S)-(E)-oximeethers of 2,3-dihydro-1,8-naphthyridine and 2,3-dihydrothiopyrano[2,3-b]pyridine: identification of beta 3-antagonists. 1460 53

Adriamycin (doxorubicin) is a potent and broad-spectrum antineoplastic agent, the clinical utility of which is limited by the development of a cumulative and irreversible cardiomyopathy. Although the drug affects numerous structures in different cell types, the mitochondrion appears to a principal subcellular target for the development of cardiomyopathy. This review describes evidence demonstrating that adriamycin redox cycles on complex I of the mitochondrial electron transport chain to liberate highly reactive free radical species of molecular oxygen. The primary effect of adriamycin on mitochondrial performance is the interference with oxidative phosphorylation and inhibition of ATP synthesis. Free radicals liberated from adriamycin redox cycling are thought to be responsible for many of the secondary effects of adriamycin, including lipid peroxidation, the oxidation of both proteins and DNA, and the depletion of glutathione and pyridine nucleotide reducing equivalents in the cell. It is this altered redox status that is believed to cause assorted changes in intracellular regulation, including the induction of the mitochondrial permeability transition and complete loss of mitochondrial integrity and function. Associated with this is the interference with mitochondrial-mediated cell calcium signaling, which is implicated as essential to the capacity of mitochondria to participate in bioenergetic regulation in response to external signals reflecting changes in metabolic demand. If taken to an extreme, this loss of mitochondrial plasticity may manifest in the liberation of signals mediating either oncotic or necrotic cell death, further perpetuating the cardiac failure associated with adriamycin-induced mitochondrial cardiomyopathy.
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PMID:Adriamycin-induced interference with cardiac mitochondrial calcium homeostasis. 1765 13


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