Identifying Raman and Infrared Vibrational Motions of Erythritol Tetranitrate.

The vibrational bands of erythritol tetranitrate (ETN) were measured experimentally with both Raman spectroscopy and attenuated total reflectance Fourier transform infrared (ATR FT-IR) spectroscopy. Seventy-two (3N-6) vibrational modes were predicted for ETN using density functional theory calculations performed using the B3LYP/6-31G* density functional basis set and geometry optimization. Raman spectroscopy and ATR FT-IR were used to measure observable Raman and IR signatures between 140 and 3100 wavenumbers (cm(-1)). Within this spectral range, 32 Raman bands and 21 IR bands were measured and identified by their predicted vibrational motion. The spectroscopic and theoretical analysis of ETN performed will advance the detection and identification capabilities of field measuring instruments for this explosive.

NO donors. Part 18: Bioactive metabolites of GTN and PETN--synthesis and vasorelaxant properties.

The vasodilators glyceryl trinitrate (GTN) and pentaerythrityl tetranitrate (PETN) are supposed to be degraded in vivo to the lower nitrates PETriN, PEDN, PEMN, 1,2-GDN, 1,3-GDN, 1-GMN, and 2-GMN. We synthesized these bioactive metabolites as reference compounds for pharmacokinetic studies. The use of HPLC-methods for monitoring the stepwise reduction of PETN to lower nitrates and the syntheses of the glyceryl dinitrates proved advantageous. Furthermore, we measured the vasorelaxant properties of all metabolites by performing organ bath experiments with porcine pulmonary arteries. In general, the vasodilator potency increases with the number of nitrate moieties in the compound.

Nitric oxide modulation of the growth hormone-releasing activity of Hexarelin in young and old dogs.

The growth hormone (GH)-releasing activity of Hexarelin, a potent GH-releasing peptide (GHRP) analog, was evaluated in eight young (aged 1 to 6 years) and five old (10 to 16 years) beagle dogs pretreated with erythrityl tetranitrate, a liposoluble nitric oxide (NO) donor, and/or indomethacin, an inhibitor of cyclooxygenase enzymes, and N-nitro-L- or N-nitro-D-arginine methylester (L-NAME and D-NAME), active and inactive NO synthase (NOS) inhibitors, respectively. Erythrityl tetranitrate (0.3 mg x kg(-1) oral [p.o.]) strikingly potentiated Hexarelin-stimulated GH secretion (31.25 microg x kg(-1) intravenous [i.v.]) in both young (area under the time-concentration curve at 0 to 90 minutes AUC(0-90)] 878.50 +/- 267.02 v 1,994.04 +/- 434.20 ng x mL(-1) x h, P < .01) and aged animals (314.82 +/- 117.11 v 1,314.12 +/- 484.75 ng x mL(-1) x h, P < .01). The NO donor alone did not modify baseline GH levels in either young dogs (188.68 +/- 85.24 ng x mL(-1) x h) or old dogs (120.49 +/- 22.03 ng x mL(-1) x h). L-NAME (5 mg x kg(-1) x 2 i.v.) suppressed GH release induced by the peptide in young dogs (1,367.68 +/- 251.87 v 411.12 +/- 68.49 ng x mL(-1) x h, P < .01), but potentiated it in old dogs (314.73 +/- 117.10 v 1,103.97 +/- 374.11 ng x mL(-1) x h, P < .01). D-NAME (5 mg x kg(-1) x 2 i.v.) did not affect the GH response to Hexarelin in either young (1,328.68 +/- 433.54 ng x mL(-1) x h) or aged (342.32 +/- 84.82 ng x mL(-1) x h) dogs. Indomethacin (1.5 mg x kg(-1) i.m.) abolished the NO-donor potentiation of the GH response induced by Hexarelin in both young dogs (1,627.25 +/- 260.90 v 1,163.37 +/- 334.84 ng x mL(-1) x h, P < .05) and old dogs (1,061.47 +/- 210.38 v 365.69 +/- 79.27 ng x mL(-1) x h, P < .01) without affecting the plasma GH peak evoked by the peptide alone (young dogs, 786.04 +/- 153.44 v 960.04 +/- 444.44 ng x mL(-1) x h, P = NS; old dogs, 474.55 +/- 47.30 v 490.82 +/- 144.86 ng x mL(-1) x h, P = NS). In conclusion, (1) NO donors are capable to further increase the strong GH-releasing activity of Hexarelin in both young and old dogs, although the site(s) and mechanism(s) of action of NO is still obscure; (2) the different GH response to the peptide after NOS inhibition in young and old dogs signifies in the latter an alteration of the somatotrope function; and (3) prostaglandins are the downstream effectors of the chain of events triggered by activation of the NO-ergic system.

Erythrityl tetranitrate; drug efficacy study implementation; revocation of exemption; opportunity for a hearing--FDA. Notice.

The Food and Drug Administration (FDA) is revoking the temporary exemption that has allowed single-entity coronary vasodilator drug products containing erythrityl tetranitrate to remain on the market beyond the time limits scheduled for implementation of the Drug Efficacy Study. FDA is announcing that the products lack substantial evidence of effectiveness and is offering an opportunity for a hearing on a proposal to withdraw approval of any applicable new drug applications (NDA's) or abbreviated new drug applications (ANDA's).

Pentaerithrityl tetranitrate and its phase I metabolites are potent activators of cellular cyclic GMP accumulation.

Using pig kidney epithelial cells (LLC-PK1), the present study assesses the cyclic GMP stimulatory effect of pentaerithrityl tetranitrate and its metabolites in comparison to other therapeutically used nitric oxide donors. Pentaerithrityl tetranitrate was found to be the most potent activator of cyclic GMP synthesis compared to other clinically relevant organic nitrates (glyceryl trinitrate, isosorbide dinitrate, isosorbide-5-mononitrate). The phase I metabolite pentaerithrityl trinitrate was equipotent with its parent compound in stimulating cyclic GMP. The concentration-response curves of pentaerithrityl dinitrate and isosorbide dinitrate for cyclic GMP accumulation were virtually identical. In contrast, pentaerithrityl mononitrate and the phase II metabolite pentaerithrityl trinitrate glucuronide did not alter basal cyclic GMP levels. It is concluded that the long-term vasodilatory and antiischemic effects of pentaerithrityl tetranitrate are caused to a substantial extent by cyclic GMP-mediated actions of its pharmacologically active phase I metabolites.

High-performance liquid chromatographic determination of the nitrate esters isosorbide dinitrate, pentaerythritol tetranitrate, and erythrityl tetranitrate in various tablet forms.

A reliable, sensitive, and specific assay for isosorbide dinitrate pentaerythritol tetranitrate, and erythrityl tetranitrate in sublingual, uncoated, sustained-release, and chewable dosage forms, using high-performance liquid chromatography, is described. The nitrate ester dosage forms were dissolved in methanol, filtered, and injected directly into the liquid chromatograph. A variable-wavelength UV detector, operated at 220 nm, and a reverse-phase C18 microporous silica column were employed. The mobile phase was methanol-water (40:60). The proposed method is quantitative and reproducible.

Erythrityl tetranitrate compared with isosorbide dinitrate. Effects on systolic time intervals and nitrate modification of effects of food.

The pharmacologic effects of erythrityl tetranitrate (ETN) and isosorbide dinitrate (ISDN) were compared to placebo using systolic time intervals (STI) in a randomized, double-blind study in 15 fasted male volunteers. Sublingual doses of ETN 5 mg, ISDN 5 mg, and placebo were administered to each volunteer at weekly intervals, and measurements of heart rate and STI [pre-ejection period (PEP), left ventricular ejection time (LVET), and PEP/LVET ratio] were made serially for up to 6 hours after each dose. STI were determined using ear densitography. Evaluation of the pharmacologic effects of ETN and ISDN were based on placebo-corrected changes from baseline values. Ejection time index (ETI) [LVET corrected for heart rate] was shortened, but the changes were not statistically significant for either drug. However, after ETN and ISDN, statistically significant (p less than 0.05) changes in PEP and PEP/LVET ratio were demonstrated for up to 240 minutes after dosing. Unexpected marked changes in the baseline corrected PEP/LVET ratio were observed following food at 4 hours after dosing. This suggests increased inotropy during the postprandial period.

[Clinical and statistical study of 121 cases of acute myocardial infarct from 1976 to 1981 (month of April). Critical review]. / Studio clinico-statistico su 121 casi di infarto miocardico acuto (IMA) dal 1976 al 1981 (mese di aprile). Revisione critica.

The authors realized a retrospective clinical-statistical study about 121 cases of acute myocardial infarction (AMI), treated in the Department of general medicine with a pharmacological association of Lysine acetylsalicylate--Erythrityl tetranitrate--Papaverine hydrochloride, with the purpose of obtaining a vasodilatation on coronary arteries and a platelet antiaggregation, in the light of the new etiopathogenetic views about the prolonged coronary spasm and the platelet aggregation, in some cases of myocardial infarction with or without thrombosis. Obtained data are very optimistic about incidence of left ventricular insufficiency and (of) thromboembolisms, to they augur the sistematic adoption of this treatment of AMI, especially as to the early antiaggregation therapy.

Bioavailability of organic nitrates: a comparison of methods for evaluating plethysmographic responses.

Erythrityl tetranitrate, a long-acting organic nitrate, was compared with isosorbide dinitrate in a double-blind, placebo-controlled complete crossover study in 15 healthy male volunteers. A digital plethysmogram and ear densitogram were used to assess the physiologic response to these two sublingual nitrates, with the intensity and duration of drug effect calculated by differences in diastolic amplitude intensity before and after drug administration. Both 5 mg sublingual erythrityl tetranitrate and 5 mg isosorbide dinitrate produced significant increases in diastolic amplitude intensity for up to 3 hours. The erythrityl tetranitrate peak effect was less than that of the isosorbide dinitrate, but the incidence of headaches was also less. The ear densitogram was found to be an effective means of assessing the diastolic amplitude intensity changes.

[Treatment of chronic congestive failure with vasodilators (acute trial with prazosin and erythrityl tetranitrate)]. / Lechenie na khronichnata zastoina nedostatuchnost s vazodilatatori (ostur opit s prazozin i eritritiltetranitrat).

An acute clinical experiment was carried out with 34 patients with chronic refractory cardiac insufficiency with stasis and idiopathic dilating (stasis) cardiomyopathy so as to follow up the hemodynamic effect of the vasodilators prazosin and erythrityl tetranitrate. The values of the central and peripheral vascular hemodynamics were followed up before and one hour after the peroral intake of 2 mg prazosin and half an hour after the peroral intake of 40 mg erythrityl tetranitrate. The results indicate that a statistically significant decrease of the arterial pressure and the total peripheral vascular resistance developed after prazosin intake. The systolic arterial pressure was decreased from 121,80 +/- 3,52 to 102,40 +/- 3,71 (p less than 0,001) and the diastolic--from 80,20 +/- 2,41 to 68,20 +/- 2,56 (p less than 0,01). The values of the total peripheral vascular resistance were decreased from 2629,65 +/- 174 to 1865,53 +/- 153 (p less than 0,001). The indices of the pump function--Stl and SI were increased (Stl from 22,74 +/- 1,85 to 30,37 +/- 2,14 with p less than 0,025 and Sl--from 1,90 +/- 0,08 to 2,64 +/- 0,19; p less than 0,02). The indices of the pressure in the left ventricular filling had no statistically significant change. After the administration of erythrityl tetranitrate, a statistically significant improvement of the indices of the cardiac output was also observed as well as of the total peripheral vascular resistance. The systolic index grew from 1,74 +/- 0,20 to 2,70 +/- 0,16 (p less than 0,01); stroke index--from 18,35 +/- 2,82 to 32,99 +/- 2,88 (p less than 0,01), and the total peripheral vascular resistance was decreased from 2897,0 +/- 186,0 to 1556,0 +/- 154,0 (p less than 0,001). Prazosin and erythrityl tetranitrate led to a considerable decrease of the counter load of the heart and improvement of the pump function of left ventricle in an acute experiment in case of chronic cardiac insufficiency with stasis.

Digital plethysmography for assessing erythrityl tetranitrate bioavailability.

The bioavailability or oral, sublingual, and chewable tablets or erythrityl tetranitrate (ETN) was evaluated in 15 normal men. In a randomized, complete crossover investigation with nitroglycerin and placebo controls, drug-induced changes in the diastolic amplitude response intensity were measured with a digital plethysmogram. Values for area under the response intensity curve (AUC), maximum response intensity (Imax), and time lapse from dosing to peak response (tmax) were obtained by computer processing and converted to intensity values and AUC segments for specific time intervals. Sublingual nitroglycerin induced a response (p less than 0.05) from placebo within the first hour. Although somewhat slower in reaching peak intensity, all forms of ETN induced significant responses over placebo (p less than 0.05) for 2 hr, with oral (swallowed) ETN different 6 hr. Our results indicate that all the ETN dosage forms were bioavailable, with the longest duration of effect by the oral form.

Treadmill exercise protocols to demonstrate effectiveness of nitrate drugs in relief of angina pectoris; duration of action and degree of functional enhancement.

During constant uninterrupted exercise with mild angina present, either placebo, nitroglycerin, isosorbide dinitrate or erythrityl trinitrate was given by buccal membrane absorption. Placebo produced no relief and exercise had to be stopped. Nitroglycerin produced rapid complete relief and the long-acting drugs effected relief more slowly but of long duration as shown on repetitive walks as long as 3 h after drug administration.

[Vasodilator treatment of chronic heart failure: a chronic double-blind trial with prazosin and erythrityl tetranitrate]. / Lechenie na khronichnata surdechna nedostatuchnsot s vazodilatoatori--khronichen dvoino sliap opit s prazozin i eritritiltetranitrat.

A chronic double-blind experiment was carried out with 32 patients with severe chronic stasis cardiac insufficiency, with concomitant idiopathic congestive cardiomyopathy and ischemic heart disease, in assessing the effect of vasodilators prazosin or erythrityl tetranitrate upon the decompensation symptomatics and hemodynamic indices. The clinical indices of cardiac insufficiency with hemodynamic signs of pre-loading, myocardial contractility and postloading of left ventricle were followed up. Besides vasodilators the patients were administered the ordinary maintenance therapy with digoxin and diuretics. The experiment was a double blind one, controlled by placebo-periods and covered a 6 months follow-up period. The combined venous-arteriolar vasodilator prazosin was reduced pre and post-loading, it increased the cardiac output, without essential changes in functional capacity of the patients with chronic cardiac insufficiency. Erythrityl tetranitrate, however, has no substantial effect on the clinical and hemodynamic indices of statis cardiac insufficiency even in higher doses. That suggests the necessity of the chronic cardiac insufficiency treatment to be carried out with vasodilators with venous and arteriolar effect.

Contact dermatitis due to nitroglycerin ointment.

Topical nitroglycerin ointment is among the most effective long-acting vasodilators currently available. We report two cases of contact dermatitis in which patch testing showed allergy to nitroglycerin-containing compounds. The severity of this dermatitis necessitated the discontinuation of topical nitroglycerin therapy in both patients. A potent corticosteroid cream applied once to previous nitroglycerin application sites prevented or minimized this dermatitis and enabled continuation of topical nitroglycerin therapy. Contact dermatitis due to topical nitroglycerin preparations may be more common than is presently realized.

Erythrityl tetranitrate: sustained effects on systolic time intervals. changes consistent with sustained preload reduction.

The effects of sustained preload reduction have been demonstrated for several nitrates but not for erythrityl titranitrate. In seven patients with coronary heart disease, a randomized double-blind crossover clinical trial showed that chewable erthrityl tetranitrate, 10 mg, produced significant changes in systolic time intervals consistent with preload reduction and lasting for at least four hours. As compared with placebo, ejection time index (ETI) fell and remained significantly low between 6 and 90 minutes after administration, and pre-ejection period (PEP), isovolumic contraction time IVCT), and pre-ejection period/left ventricular ejection time (PEP/LVET) rose and remained significantly increased between 22 minutes and the four-hour endpoint. We conclude that erythrityl tetranitrate is a physiologically effective long-acting agents in patients with coronary heart disease.

Medical therapy of angina pectoris.

The pathophysiology of angina pectoris is best understood as an imbalance between oxygen supply and demand. The primary determinants of myocardial oxygen demand are heart rate, arterial pressure, heart size, myocardial contractility, and myocardial mass. The medical therapy of angina pectoris is directed toward reducing myocardial oxygen demand by reducing the workload of the heart and the specific determinants listed. The most common medications used in the treatment of angina pectoris are nitroglycerin and propranolol. Nitroglycerin reduces myocardial oxygen demand primarily by reducing heart size and arterial pressure. Propranolol reduces oxygen demand primarily by reducing heart rate. Medical therapy is generally effective in controlling the symptoms of angina pectoris in 80% or more of the patients and allows them to lead useful and productive lives.

Contractile state of the left ventricle in man as evaluated from end-systolic pressure-volume relations.

End-systolic pressure (PES), volume (VES), wall tension (TES) and circumference (CES) of the human left ventricle were studied at cardiac catheterization in 24 subjects with varying degrees of left ventricular dysfunction. Acute alterations in systolic load consistently resulted in changes in VES and CES, with a smaller volume and circumference characterizing the lower systolic load in each subject. End systolic pressure-volume lines were constructed by plotting PES against VES at the higher and lower systolic load in each subject. The slope of the resultant lines was considerably steeper for normal than for poorly contractile left ventricles. Vo, the volume axis intercept of the line (i.e., the theoretical VES at PES = O) was significantly smaller for normal than for poorly contractile ventricles. Similar findings were noted for Co, the theoretic end-systolic circumference at zero end-systolic ventricular wall tension. Post-extrasystolic potentiation resulted in decreased VES and CES with no change in PES and only a slight fall in TES. In conclusion, end-systolic pressure-volume and tension-circumference relations reflect the contractile state of left ventricular myocardium. Quantitation of these relationships may provide a useful new approach to the assessment of myocardial function in man.