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PubMed1998

Treatment of Older Patients With CHF Associated With Normal LVEF.

CHF with a normal LVEF should be treated with a low salt diet, cautious use of loop diuretics, and Ã -blockers. If CHF persists despite the use of diuretics and Ã -blockers, ACE inhibitors should be administered. If the patient cannot tolerate ACE inhibitors because of cough, rash, or altered taste sensation, angiotensin II type 1 receptor antagonists should be given. If CHF persists despite treatment with diuretics, Ã -blockers, and ACE inhibitors, isosorbide dinitrate plus hydralazine should be given. If the patient cannot tolerate Ã -blockers, ACE inhibitors, and angiotensin II type 1 receptor antagonists, isosorbide dinitrate plus hydralazine should be administered. If CHF persists despite the use of diuretics and the patient is unable to tolerate Ã -blockers, ACE inhibitors, and isosorbide dinitrate plus hydralazine, calcium channel blockers are preferred. Digoxin should be avoided if sinus rhythm is present.

Journal Article↗

PubMed1990

[Changes in left-ventricular function in chronic congestive heart failure treated with digoxin, furosemide and vasodilators].

48 patients (62.8 +/- 9.1 yrs) with III or IV NYHa class congestive heart failure after 2-week therapy with digoxin (D) and furosemide (F) underwent two-dimensional echocardiographic examination to assess left ventricular function. Then in 25 patients (group I) DF and nifedipine (N) were given within 2 weeks, D, F, N and captopril (C) within 4 weeks and again D, F, N within 2 weeks. In 23 patients (group II) isosorbide dinitrate (S) was administered instead of nifedipine. 2-DE examination had been performed at the end of the each study stage. Optimal daily drug dose were: D-0.34 +/- 0.07 mg, F-40.7 +/- 12.5 mg, S-44.3 +/- 10.4 mg and 75.8 +/- 26.4 mg. Nifedipine and isosorbide dinitrate administrated with digoxin and furosemide did not improve left ventricular function in comparison with a standard therapy (DF). The best positive changes were observed in both groups during treatment with captopril. Ejection fraction by Teichholz increased from 42.9 +/- 15.0% during DF stage to 45.2 +/- 11.5% (DFNK stage) in group I (p less than 0.001) and from 35.3 +/- 10.5% to 36.4 +/- 10.4% in group II respectively (p greater than 0.01). Left ventricular systolic and diastolic internal diameters significantly decreased (p less than 0.05) whereas stroke volume and cardiac indices nonsignificantly increased (p greater than 0.05). Captopril with digoxine, furosemide and nifedipine caused significant hemodynamic improvement. Effect of captopril with nifedipine was greater that of captopril with isosorbide dinitrate.

Adult↗

PubMed1990

[Results of treatment for severe congestive heart failure with digoxin, furosemide and vasodilating agents].

In 61 patients with class IV (NYHA) of chronic congestive cardiac failure treated for 2 weeks with digoxin (0.290 +/- 0.108 mg/d) and furosemide (13.0 +/- 4.1 mg/d), for 2 weeks with digoxin, furosemide and isosorbide dinitrate (44.5 +/- 9.8 mg/d) or nifedipine (42.0 +/- 12.2 mg/d), for 4 weeks with digoxin, furosemide, isosorbide or nifedipine and captopril (angiotensin converting enzyme inhibitor) (75.1 +/- 24.4 mg/d), and for the last 2 weeks with digoxin, furosemide, isosorbide or nifedipine without captopril, after each stage the clinical state, exercise tolerance and haemodynamic parameters determined echocardiographically were assessed. Ten weeks of treatment by this method caused regression of pulmonary congestion in 80%, oedema in 63.3% and hepatomegaly in 33.3% of the patients. Moreover, 60.7% of the patients returned to class III, 13.1% to class II, and 26.2% remained in class IV (NYHA). In the group treated with digoxin, furosemide, nifedipine with captopril (n = 30) a significant rise was observed of the value of the ejection fraction and cardiac index in relation to the treatment with digoxin and furosemide and the treatment with digoxin, furosemide, nifedipine (p less than 0.05). No drug improved significantly the tolerance of submaximal exercise. During the treatment with captopril no clinical improvement was achieved in 4 cases, and worsening occurred in 3 cases of severe cardiac failure (7 of 61 patients, 11.5%). The obtained results showed that vasodilating drugs are safe in congestive cardiac failure and in many cases of severe failure captopril contributed to rapid clinical and haemodynamic improvement.

Adult↗

PubMed1987

[Use of peripheral vasodilators with different mechanisms of action in treating heart failure patients].

The efficacy of peripheral vasodilators with various mechanisms of action was studied in 26 patents with congestive heart failure, left ventricular dilatation and valvular regurgitation. An acute pharmacological test using prazosin was used in all the patients, 20 of them were given a 15-day course of prazosin therapy, 19 patients received a prolonged course of prazosin therapy (over 3 mos.), 15 patients were given a 15-day course with a combination of isosorbide dinitrate and hydralazine. ECG monitoring, catheterization of the right cardiac chambers, thermodilution, and tetrapolar impedance plethysmography were employed. Heart rate, arterial pressure, parameters of cardiac pre- and afterload and pulmonary hemodynamics were studied. Prazosin and isosorbide dinitrate in combination with hydralazine showed a high clinical efficacy in the treatment of patients with congestive heart failure. The improvement of clinical symptomatology was accompanied by considerable positive shifts of the central and peripheral hemodynamics. No considerable differences in the efficacy of prazosin and the combination of isosorbide dinitrate with hydralazine were revealed.

Adolescent↗

PubMed1983

Importance of venodilation during long-term vasodilator therapy of chronic left ventricular failure.

Vasodilators with different sites of action are used for long-term therapy of congestive heart failure, and selection of agents based on acute hemodynamic effects has been recommended. We compared the acute hemodynamic effects (by Swan-Ganz catheterization) and long-term responses (maximal oxygen uptake during exercise) associated with isosorbide dinitrate, a predominant venodilator, captopril, an arterial and venous dilator, and minoxidil, an arterial dilator, in 22 patients with congestive heart failure. In eight patients isosorbide dinitrate reduced pulmonary wedge pressure by 29% +/- 8% acutely (p less than .001) without significantly changing cardiac index or systemic vascular resistance. In eight patients captopril acutely reduced pulmonary wedge pressure by 42% +/- 22% (p less than .001) and systemic vascular resistance by 27% +/- 12% (p less than .01), while raising cardiac index by 19% +/- 18% (p less than .02). In six patients minoxidil raised cardiac index acutely by 38% +/- 30% (p less than .05) and reduced systemic vascular resistance by 35% +/- 12% (p less than .05) without changing pulmonary wedge pressure. After 2-5 months vasodilator administration maximal exercise oxygen uptake was increased by 7 +/- 3 ml/min/kg on isosorbide dinitrate (p less than .01), by 3 +/- 2 ml/min/kg on captopril (p less than .01), and by only 1 +/- 2 ml/min/kg on minoxidil (ns). Thus exercise capacity improved only during administration of drugs with venodilating action, failing to change during treatment with the arterial dilator despite a reduction in systemic vascular resistance. Predominantly arterial dilators alone may not be suitable for long-term vasodilator therapy for heart failure, and the regimens used should include venodilating agents.

Aged↗

PubMed1994

Generation of nitric oxide from nitrovasodilators modulates the release of histamine from mast cells.

The effect of organic and inorganic nitrovasodilators (sodium nitroprusside; 3-morpholinosydnonimine; glyceryl trinitrate; isosorbide dinitrate; sodium nitrite, was studied on the release of histamine evoked by compound 48/80 and calcium ionophore A 23187 in isolated purified rat serosal mast cells. All the compounds tested were capable of significantly reducing the release of histamine in a concentration-dependent fashion, at different levels of potency. This effect was reverted by oxyhaemoglobin. The inhibitory effect of glyceryl trinitrate on the release of histamine was potentiated in cells taken from animals pretreated with Escherichia coli lipopolysaccharide, and decreased by NG-nitro-L-arginine methyl ester. Glyceryl trinitrate and isosorbide dinitrate concentration-dependently increase the generation of nitric oxide by rat serosal mast cells. The inhibitory effect of glyceryl trinitrate and isosorbide dinitrate on the release of histamine from mast cells was potentiated by N-acetylcysteine, which significantly increases the generation of nitric oxide by mast cells. It is concluded that nitrovasodilators inhibit the release of mast cell histamine through the generation of nitric oxide. The effect may be relevant in considering the perivascular location of mast cells and the role played by these cells in cardiovascular pathophysiology.

Acetylcysteine↗

PubMed1993

[The tourniquet test in evaluating the analgesic action of antianginal preparations].

Twenty-two patients with coronary heart disease (CHD) were examined for pain threshold and pain tolerance by a tourniquet test. The relationships between pain and ST segment depression were studied simultaneously during bicycle exercise. Pain sensitivity was measured in response to action of various antianginal drugs (isosorbide dinitrate, verapamil, nifedipine, diltiazem, propranolol, atenolol) and placebo. Reproducibility of the tourniquet test proved satisfactory. There were significant correlations between tourniquet test evidence and clinical patterns of ischemic myocardial episodes: significant differences in the values of pain threshold and pain tolerance in patients with painful myocardial ischemia, in combination of angina of effort with painless myocardial ischemia (p < 0.0001). Significant were also correlations between tourniquet test findings at bicycle exercise and value describing the proportion of ST depression to pain. As for the drugs, verapamil appeared most active in the tourniquet test (p < 0.02 and p < 0.05 for pain threshold and pain tolerance, respectively). Pain tolerance changes due to isosorbide dinitrate were somewhat greater than for placebo (p = 0.06). The study provided evidence in support of the adequacy of the tourniquet test for assessment of general pain sensitivity and pain sensitivity to myocardial ischemia as well as of analgetic effects of the drugs. Verapamil and isosorbide dinitrate are suggested to have analgetic activity.

Aged↗

PubMed1993

[The problem of tolerance to nitrates and the means to resolve it in patients with exertional stenocardia].

The problem of nitrates tolerance and resistance has been studied for 10 years in a number of clinical pharmacological cross-over studies in patients with stable angina of effort by specially devised pharmacodynamic and pharmacokinetic methods. Both single doses in different medicinal forms and long-term course intake of nitrates were investigated. The results led the authors to the following conclusions: 1) tolerance to isosorbide dinitrate arises in 58% of the patients for 6-12 weeks under regular administration of the drug; 2) transdermal nitroglycerin (nitroderm) and in a less degree oral sustak under long-term treatment regimens become tolerable, whereas a buccal form (trinitrolong) secures a prolonged stable effect; 3) tolerance develops in 2-month administration of oral isosorbide-5-mononitrate; 4) donors of SH-group (methionine) and inhibitors of angiotensin-converting enzyme with SH-group and without it (captopril and perindopril, respectively) in single doses potentiate an antianginal effect of isosorbide dinitrate (even in initial resistance to nitrate), being ineffective in its absence; 5) molsidomine is promising in long-term regimens as an antianginal drug alternative to nitrates.

Angina Pectoris↗

PubMed1993

[Coronary vasoconstriction induced by digoxin in normal subjects and in patients with coronary atherosclerosis].

This study evaluated the effects of digoxin infusion (0.014 mg/kg in 10 min i.v.) on large coronary arteries measured by quantitative digital angiography. Twenty-two patients (aged 47 +/- 12), divided in 3 groups were studied. The effects of digoxin infusion (after 10 and 20 min) and sublingual administration of isosorbide dinitrate were investigated in Group I (patients with angiographically normal coronary arteries, n = 9) and in Group II (patients with atherosclerotic coronary arteries, n = 8). In Group III (n = 5) to determine whether or not the effects of digoxin were mediated by activation of alpha-adrenergic receptors, coronary angiographies were performed after alpha-adrenoceptor blockade (phentolamine 0.11 mg/kg, i.v.). In Group I, 10 min after the end of digoxin infusion, cross-sectional area decreased from 7.7 +/- 4.1 mm2 to 6.0 +/- 2.2 mm2, and after 20 min to 5.6 +/- 2.6 mm2 (p < 0.05). Isosorbide dinitrate reverted digoxin-induced vasoconstriction as cross-sectional area increased to 8.5 +/- 3.4 mm2 (NS versus baseline). By 20 min after digoxin infusion heart rate was significantly reduced from 79 +/- 16 to 74 +/- 13 b/min (p < 0.01). Peripheral vascular resistances increased significantly 10 min after digoxin infusion (from 1396 +/- 693 to 1693 +/- 984 dyne*s*cm-5, p < 0.05), whereas cardiac output did not change. In Group II, minimal stenosis diameter decreased significantly 20 min after digoxin infusion from 1.6 +/- 0.5 mm to 1.4 +/- 0.5 mm (p < 0.05). Again, isosorbide dinitrate reverted digoxin-induced vasoconstriction as minimal stenosis diameter increased (NS versus control).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1979

Gallium nitrate (NSC-15200) induced toxicity in the rat: a pharmacologic, histopathologic and microanalytical investigation.

Administration of gallium nitrate to rats resulted in the formation of renal precipitates which occluded tubular lumina. When analyzed with a combination of scanning electron microscopy and x-ray energy spectrometry, these precipitates were found to contain gallium complexed with calcium and phosphate. Injection of gallium nitrate also resulted in hypercalciuria, although serum calcium levels remained unaltered. Administration of an osmotic diuretic, isosorbide, prior to gallium treatment resulted in the formation of fewer renal precipitates and histopathologic changes than in the nondiuresed animals. Diuresis did not alter gallium serum pharmacokinetics, the 24 hour cumulative renal excretion of gallium or the extent of the drug-induced hypercalciuria. However, isosorbide pretreatment significantly reduced the urinary concentrations of both gallium and calcium. The data presented indicate that diuresis reduces the severity of gallium-induced renal lithiasis and subsequent renal accumulation of gallium by diluting the urinary concentration of gallium and calcium thereby lowering the incidence of interaction of these two elements within the kidney tubule.

Animals↗

PubMed1990

Reproducible uniform coronary vasomotor tone with nitrocompounds: prerequisite of quantitative coronary angiographic trials.

In quantitative analysis of repeated coronary angiograms, a variable vasomotor tone of the epicardial coronary arteries may influence the accuracy of the results. Therefore, we evaluated the extent and reproducibility of coronary artery dilation with nitrocompounds. In 32 patients with coronary artery disease, the vasodilatory response of angiographically normal coronary segments to different nitrocompounds was analyzed with the computer-assisted contour detection system CAAS. Twenty patients received 5 mg or 10 mg of isosorbide dinitrate sublingually. After 10 to 15 min, a maximal diameter increase was measured with an average of 16 +/- 11% (5 mg: P less than 0.01) and 28 +/- 13% (10 mg: P less than 0.001) from control. Another 12 patients received 0.025 mg per kg body weight of SIN-1, the active metabolite of molsidomine, as an intravenous infusion over 5 min. A comparable maximal dilation (29 +/- 5%; P less than 0.001) occurred after 10 to 15 min and could not be enhanced further with 0.8 mg nitroglycerin administered sublingually (28 +/- 7%; n.s.). One hour after square root of Sin-1, coronary dilation was still 24 +/- 8% (P less than 0.001 compared with control), and 0.8 mg of nitroglycerin sublingually reestablished the previous maximal dilation of 28 +/- 8%. We conclude that high doses of nitrocompounds induce a reproducible maximal coronary dilation that eliminates a substantial source of error in quantitative analysis of repeated coronary angiograms. At present, sublingual administrations of either 10 mg isosorbide dinitrate once or 0.8 mg nitroglycerin repeatedly seem to represent the easiest practicable modes to achieve maximal coronary vasodilation for an adequate period.

Angiography↗

PubMed1978

A comparison of four potential agents for reducing necrosis after prolonged coronary occlusion.

In anesthetized closed-chest dogs, four vasodilators were compared after prolonged coronary occlusion induced by catheter wedging in a coronary branch. With treatment given between 1 hour and 2 hours of occlusion, five groups were studied: no treatment, isosorbide dinitrate, nitroprusside, dipyridamole, and methylprednisolone. Measured were heart rate, cardiac pressures and blood flow (with 85Kr); and cardiac index, left ventricular ejection fraction with vascular resistance, left ventricular minute work index, and an oxygen consumption index were calculated. At sacrifice, ischemic inner/outer wall isotope distribution and myocardial K+, Na+, and H2O were determined. With no treatment, left ventricular end-diastolic pressure and vascular resistances rose while cardiac index, ejection fraction, minute work index, and index of myocardial oxygen consumption fell, with no further change between 1 and 2 hours. Vasodilators did not affect coronary hemodynamics or isotope distribution. Hemodynamic effects of isosorbide dinitrate and nitroprusside differed qualitatively from dipyridamole and methylprednisolone. The latter drugs caused increases in ejection fraction, and dipyridamole also significantly increased cardiac index and minute work index. Only nitroprusside decreased minute work index and O2 consumption index. Only nitroprusside and dipyridamole, despite differing hemodynamics, tended to reduce K+ loss and Na+ and H2O gain in ischemic tissue. Further extended studies with these agents are warranted.

Animals↗

PubMed1981

Effect of caffeine on ergotamine absorption from rat small intestine.

The effect of caffeine on the absorption of ergotamine from the rat small intestine was studied. The results of a series of experiments showed that caffeine significantly enhanced absorption of ergotamine from solutions of pH 5.0 when both substances were in solution and when an intact blood supply was either absent (in vitro everted sac experiments) or present (in situ experiments). Caffeine did not appear to influence the absorption rate of ergotamine in situ experiments when the solution pH was 3.0. Isosorbide dinitrate, a vasodilator, enhanced ergotamine absorption when both substances were administered simultaneously into intestinal loops in situ. Isosorbide dinitrate probably exerts its effect by increasing blood flow to the intestine. The results are consistent with an hypothesis that the rate-determining step in ergotamine absorption is the transport of the drug from a lipid phase (GI membrane) into an aqueous phase (blood). Caffeine is thought to exert its rate-accelerating effect by increasing the water solubility of ergotamine neutral molecules.

Animals↗

PubMed2006

Generalized gamma frailty model.

In this article, we present a frailty model using the generalized gamma distribution as the frailty distribution. It is a power generalization of the popular gamma frailty model. It also includes other frailty models such as the lognormal and Weibull frailty models as special cases. The flexibility of this frailty distribution makes it possible to detect a complex frailty distribution structure which may otherwise be missed. Due to the intractable integrals in the likelihood function and its derivatives, we propose to approximate the integrals either by Monte Carlo simulation or by a quadrature method and then determine the maximum likelihood estimates of the parameters in the model. We explore the properties of the proposed frailty model and the computation method through a simulation study. The study shows that the proposed model can potentially reduce errors in the estimation, and that it provides a viable alternative for correlated data. The merits of proposed model are demonstrated in analysing the effects of sublingual nitroglycerin and oral isosorbide dinitrate on angina pectoris of coronary heart disease patients based on the data set in Danahy et al. (sustained hemodynamic and antianginal effect of high dose oral isosorbide dinitrate. Circulation 1977; 55:381-387).

Angina Pectoris↗

PubMed1999

The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells.

The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In porcine aortic endothelial cells, a 24 h incubation with PETN (1-100 microM) or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the antioxidant protein ferritin up to three-fold over basal, whereas isosorbide dinitrate and isosorbide-5-mononitrate were without significant effect under these conditions. PETriN-induced ferritin expression was blocked by the NO scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not influence basal ferritin synthesis. The iron chelator desferrioxamine abolished ferritin induction by PETriN. Our results show that PETN or its active metabolite PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP-independent pathways. Increased activity of ferritin may contribute to, and at least in part explain, the specific antiatherogenic and antioxidant action of PETN.

Animals↗

PubMed1994

Mechanisms of action of nitrates.

Glyceryl trinitrate, isosorbide dinitrate, and isosorbide-5-mononitrate are organic nitrate esters commonly used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Organic nitrate esters have a direct relaxant effect on vascular smooth muscles, and the dilation of coronary vessels improves oxygen supply to the myocardium. The dilation of peripheral veins, and in higher doses peripheral arteries, reduces preload and afterload, and thereby lowers myocardial oxygen consumption. Inhibition of platelet aggregation is another effect that is probably of therapeutic value. Effects on the central nervous system and the myocardium have been shown but not scrutinized for therapeutic importance. Both the relaxing effect on vascular smooth muscle and the effect on platelets are considered to be due to a stimulation of soluble guanylate cyclase by nitric oxide derived from the organic nitrate ester molecule through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases. The cyclic GMP produced by the guanylate cyclase acts via cGMP-dependent protein kinase. Ultimately, through various processes, the protein kinase lowers intracellular calcium; an increased uptake to and a decreased release from intracellular stores seem to be particularly important.

Angina Pectoris↗

PubMed1994

Short and long-acting oral nitrates for stable angina pectoris.

Nitroglycerin (NTG) spray and sublingual tablets rapidly relieve an established attack of angina, and their infrequent use is not associated with the development of tolerance. Although, following a suitable nitrate-free interval, the first dose of oral, long-acting nitrates produces significant hemodynamic effects, increases angina free walking, and decreases exercise-induced ischemia, during continued long-term therapy tolerance limits their usefulness. Appropriate dosing regimens of controlled-release formulations of isosorbide dinitrate (ISDN) and controlled-release NTG during long-term therapy have not been established. Use of immediate-release formulation of 15-120 mg of ISDN in a qid regimen lead to a marked reduction in the size and duration of antianginal effects compared to the initial dose. Asymmetric tid therapy with 30 mg of ISDN (7 a.m., 1 p.m., and 6 p.m.) is also associated with the development of partial tolerance and appears to provide antianginal prophylaxis for only a period of 6 hours each day. Asymmetric bid therapy with ISDN at 7 a.m. and noon may give sustained effect but is supported by only a single, small study that did not examine effectiveness after the noon dose in long-term use. Isosorbide-5-mononitrate (IS-5-MN) has been the subject of more recent studies than other nitrates because of attempts to bring a number of products into the U.S. market. IS-5-MN in qid, tid, and standard bid (8 a.m. and 8 p.m.) dosing regimens produce tolerance. Asymmetric regimens of immediate-release IS-5-MN (10 and 20 mg) given bid (once in the morning and again 7 hours later) decrease the development of tolerance compared to symmetric regimens and produce an increased exercise duration after each dose of the day; the 20 mg bid dosing is more effective. Similarly, once-daily 120 and 240 mg controlled-release IS-5-MN does not produce tolerance and gives a sustained increase in daytime exercise duration. Both asymmetric bid immediate-release and once-daily controlled-release IS-5-MN preparations do not produce deterioration in exercise performance prior to the administration of the medication in the morning (i.e., no zero-hour effect). Further studies are needed to establish useful dosing regimens for ISDN, for controlled-release ISDN, and for controlled-release nitroglycerin. None of the dosing regimens of any oral, long-acting nitrate (including IS-5-MN) provide 24 hour antianginal and antiischemic effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1987

Changes in distal esophageal function in response to cooling.

The effects upon esophageal motility of water at room temperature and 0 degrees C, taken as repeated small boluses and as 200-ml volumes swallowed as rapidly as possible, were compared before and after pretreatment with isosorbide denitrate 5 mg sublingually, in nine young healthy subjects and two patients with esophageal spasm. Iced water caused reduced strength, increased duration, and reduced velocity of distal esophageal contractions. It also reduced the force of lower esophageal sphincteric contraction, an effect that was more transient than that seen in the esophageal body, but it did not alter the magnitude of sphincteric relaxation. Esophageal responses in normal subjects with water at the two temperatures were not affected by isosorbide denitrate. The responses to iced water in the two patients with esophageal spasm were qualitatively similar to those in normal subjects. These findings indicate that cooling brings about a transient state of relative paralysis in the distal esophagus and lower esophageal sphincter. Taken in conjunction with other observations, they are consistent with the notion that cold-induced chest pain, whether in normal subjects or in patients with esophageal motor disorders, is related to esophageal distension.

Adult↗