A comparison of the effectiveness of pentaerythritol tetranitrate with pentaerythritol tetranitrate and meprobamate in angina pectoris.
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Angina Pectoris↗
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Effects of nonintermittent treatment of rabbits with pentaerythritol tetranitrate on vascular reactivity and superoxide production.
Pentaerythritol tetranitrate is an organic nitrate ester that undergoes metabolization to pentaerythritol, pentaerythritol trinitrate, pentaerythritol dinitrate and pentaerythritol mononitrate. Recent data suggested that pentaerythritol tetranitrate is endowed with vasoprotective activities in experimental atherosclerosis. This study was undertaken to gain insight into the underlying mechanism. The basic mechanism of action of all pentaerythritol nitrates was evaluated by measuring liberation of nitric oxide (NO), stimulation of human soluble guanylate cyclase and vasorelaxation in rabbit aorta. A subsequent in vivo study in New Zealand White rabbits was performed to investigate the effects of a 4 months lasting nonintermittent oral treatment with 6 mg pentaerythritol tetranitrate kg(-1) day(-1) on vascular superoxide production, endothelium dependent vasorelaxation and vasorelaxation to pentaerythritol tetranitrate itself. The formation rates of NO from the pentaerythritol nitrates (100 microM, n = 5) in presence of 5 mM cystein were (in nM min(-1)): 62.1 +/- 3.2 (pentaerythritol tetranitrate), 21.3 +/- 0.9 (pentaerythritol trinitrate), 6.4 +/- 0.6 (pentaerythritol dinitrate) and 3.2 +/- 0.4 (pentaerythritol mononitrate). Similarly, the pD2 values (-log M) for half-maximal activation of soluble guanylate cyclase decreased from pentaerythritol tetranitrate (3.391 +/- 0.09, n = 4) to pentaerythritol mononitrate (2.655 +/- 0.04, n = 3) as did the pD2 values (in -log M) for half-maximal relaxation of rabbit aortic rings (n = 7) from pentaerythritol tetranitrate (8.3 +/- 0.17) to pentaerythritol mononitrate (5.0 +/- 0.11). Significant correlations were found between the NO formation rates and the pD2 values for enzyme stimulation (r = 0.98, P = 0.002) and vasorelaxation (r = 0.90, P = 0.049) suggesting that these effects of the pentaerythritol nitrates were mediated by NO. The results of the in vivo study showed that aging induces a significant increase of aortic superoxide production (median values, n = 10) from 2.45 nM mg(-1) min(-1) (age 7 months) to 3.39 nM mg(-1) min(-1) (age 11 months, P < 0.01) that was prevented by concurrent treatment with pentaerythritol tetranitrate (2.76 nM mg(-1) min(-1)). In vitro vasorelaxation to pentaerythritol tetranitrate was identical in all groups indicating absence of nitrate tolerance. Endothelium-dependent vasorelaxation was also identical in all groups. These data suggest that oral treatment with pentaerythritol tetranitrate reduces vascular oxidant stress by an NO-dependent pathway, which may contribute to the vasoprotective activity of pentaerythritol tetranitrate in experimental atherosclerosis.
Administration, Oral↗
Sequence and properties of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2.
Pentaerythritol tetranitrate reductase, which reductively liberates nitrite from nitrate esters, is related to old yellow enzyme. Pentaerythritol tetranitrate reductase follows a ping-pong mechanism with competitive substrate inhibition by NADPH, is strongly inhibited by steroids, and is capable of reducing the unsaturated bond of 2-cyclohexen-1-one.
Amino Acid Sequence↗
Blood levels of the metabolites of glyceryl trinitrate and pentaerythritol tetranitrate after administration of a two-step preparation.
Blood levels and urinary excretion rates of glyceryl trinitrate- pentaerythritol tetranitrate, and their less nitrate containing metabolites have been determined in ten human volunteers after a single dose of a two- step preparation containing glyceryl trinitrate and pentaerythritol tetranitrate. Blood levels accounted for peak levels of about 40% of the glyceryl trinitrate and 0.4% of the pentaerythritol tetranitrate metabolites, respectively. Within the first 24 h post administration 22% of the glyceryl trinitrate and 19% of the pentaerythritol tetranitrate were excreted as nitrate metabolites, chiefly in form of conjugates. The determinations were obtained by gas chromatography on extremely inactive columns and electron capture detection by means of derivatives.
Adult↗
NEW and nonofficial remedies: pentaerythritol tetranitrate.
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Nitrites↗
Spectrophotometric determination of pentaerythritol tetranitrate in tablets.
A sensitive spectrophotometric method is reported for the quantitative determination of pentaerythritol tetranitrate in tablets. The method is based on reduction of pentaerythritol tetranitrate with zinc and calcium chloride, and reaction of the nitroso compound thus formed with 1-naphthylamine in acidic medium. The reaction gives a purple product having an absorbance maximum at 545 nm. Beer's law is obeyed in the concentration range of 1-10 micrograms/mL of reaction mixture. The presence of meprobamate in tablets does not interfere with the proposed analytical determination.
Calcium Chloride↗
Validation of high-performance liquid chromatographic methods for analysis of sustained-release preparations containing nitroglycerin, isosorbide dinitrate, or pentaerythritol tetranitrate.
The assay of sustained-release tablets or capsules containing nitroglycerin, isosorbide dinitrate, or pentaerythritol tetranitrate by high-performance liquid chromatography is described. Acetonitrile was found to be the sample preparation solvent with the most general applicability to these products. Anisole was used as an internal standard for nitroglycerin and pentaerythritol tetranitrate, while 4-chloroacetanilide was used for isosorbide dinitrate. The method, which uses a C18 bonded-phase column, a methanol-water mobile phase, and 214-nm detection, was shown to be accurate, linear, and reproducible.
Acetonitriles↗
Effects of oral pentaerythritol tetranitrate in cardiac failure and angina pectoris. Assessment by hemodynamic measurement and exercise capacity.
Oral pentaerythritol tetranitrate produces sustained beneficial hemodynamic effects in patients with cardiac failure of varied etiology. The principle action is a reduction of elevated left ventricular filling pressure. In a small group of angina patients, the oral nitrate in high dosage resulted in considerable increase in angina-limited exercise capacity compared to placebo for four hours following drug administration. No side effects were associated with ingestion of pentaerythritol tetranitrate in these investigations.
Administration, Oral↗
Atoms-in-molecules study of intra- and intermolecular bonding in the pentaerythritol tetranitrate crystal.
Chemical bonding in the pentaerythritol tetranitrate crystal based on the experimental electron density obtained from X-ray diffraction data at 100 K and theoretical calculations at the experimental molecular geometry have been analyzed in terms of the Quantum Theory of Atoms in Molecules. Features of the intra- and intermolecular bond critical points and the oxygen atom lone-pair locations are discussed. Numerous intermolecular bonding interactions, including O...H and O...O, have been found and characterized. Atomic charges and atomic energies were integrated and compared with those for similar compounds. The N-O topological bond orders have been calculated for the first time, and the PETN atomic valences have been estimated.
Journal Article↗
Crystallization and preliminary diffraction studies of pentaerythritol tetranitrate reductase from Enterobacter cloacae PB2.
Pentaerythritol tetranitrate (PETN) reductase of Enterobacter cloacae PB2, a flavoprotein involved in the biodegradation of the explosive PETN, ethylene glycol dinitrate (EGDN) and glycerol trinitrate (GTN), was purified from an overexpressing strain of E. coli and crystallized at 293 K using the sitting-drop vapour-diffusion method. Diffraction data can be seen at 1.8 A. The primitive orthorhombic cell has a monomer in the asymmetric unit. Preliminary molecular-replacement calculations have been performed using a search model based on Old Yellow enzyme.
Bacterial Proteins↗
Kinetic and structural basis of reactivity of pentaerythritol tetranitrate reductase with NADPH, 2-cyclohexenone, nitroesters, and nitroaromatic explosives.
The reaction of pentaerythritol tetranitrate reductase with reducing and oxidizing substrates has been studied by stopped-flow spectrophotometry, redox potentiometry, and X-ray crystallography. We show in the reductive half-reaction of pentaerythritol tetranitrate (PETN) reductase that NADPH binds to form an enzyme-NADPH charge transfer intermediate prior to hydride transfer from the nicotinamide coenzyme to FMN. In the oxidative half-reaction, the two-electron-reduced enzyme reacts with several substrates including nitroester explosives (glycerol trinitrate and PETN), nitroaromatic explosives (trinitrotoluene (TNT) and picric acid), and alpha,beta-unsaturated carbonyl compounds (2-cyclohexenone). Oxidation of the flavin by the nitroaromatic substrate TNT is kinetically indistinguishable from formation of its hydride-Meisenheimer complex, consistent with a mechanism involving direct nucleophilic attack by hydride from the flavin N5 atom at the electron-deficient aromatic nucleus of the substrate. The crystal structures of complexes of the oxidized enzyme bound to picric acid and TNT are consistent with direct hydride transfer from the reduced flavin to nitroaromatic substrates. The mode of binding the inhibitor 2,4-dinitrophenol (2,4-DNP) is similar to that observed with picric acid and TNT. In this position, however, the aromatic nucleus is not activated for hydride transfer from the flavin N5 atom, thus accounting for the lack of reactivity with 2,4-DNP. Our work with PETN reductase establishes further a close relationship to the Old Yellow Enzyme family of proteins but at the same time highlights important differences compared with the reactivity of Old Yellow Enzyme. Our studies provide a structural and mechanistic rationale for the ability of PETN reductase to react with the nitroaromatic explosive compounds TNT and picric acid and for the inhibition of enzyme activity with 2,4-DNP.
Carbon↗
Sustained beneficial effects of oral pentaerythritol tetranitrate on ventricular function in chronic congestive heart failure.
The hemodynamic effects of a single oral dose of 80 mg of pentaerythritol tetranitrate (PETN) were determined in 16 patients with chronic congestive heart failure over a 5-hour period. PETN produced significant (p < 0.05) decreases in pulmonary capillary wedge pressure (27 to 18 mmHg), right atrial pressure (15 to 9 mmHg), mean systemic arterial pressure (89 to 80 mmHg) and systemic vascular resistance (1812 to 1466 dynes . sec . cm-5). There were significant increases (p < 0.01) in cardiac index (2.0 to 2.3 l/m2/min) stroke volume index (24 to 38 ml/m2) and stroke work index (25 to 31 gm-m/m2). The peak reduction in pulmonary capillary wedge pressure occured two hours after PETN administration and the hemodynamic effects were still apparent at fivae hours following drug ingestion. In nine patients in whom left and right ventricular ejection fractions were determined by radionuclide ventriculography before and after administration of PETN, no significant changes were found in left ventricular ejection fraction (0.22 to 0.24, p. = NS) although a modest increase was noted in right ventricular ejection fraction (0.29 to 0.34 p < 0.05). The data indicates that orally-administered pentaerythritol tetranitrate may produce beneficial effects on preload and afterload in congestive cardiac failure, the duration of which may be five hours or longer.
Administration, Oral↗
Modified NF method for quantitative determination of pentaerythritol tetranitrate.
A modified NF method for the quantitative determination of pentaerythritol tetranitrate is reported. A solution of powder is made directly from the dosage form in glacial acetic acid and is then reacted with phenoldisulfonic acid TS. The proposed method saves approximately 75% of the time required with the NF method. The results on six differnet commercial dosage forms with four different colors and three other active ingredients are reported.
Methods↗
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.
Chromatography, High Pressure Liquid↗
[Clinical evaluation of pentaerythritol tetranitrate in two doses in patients with stable angina pectoris].
Pentaerythritol tetranitrate (PETN) has raised a great deal of interest in recent years, because it is probably the only organic "tolerance-sparing" nitrate. However, some clinicians doubt whether this drug is really effective in reducing angina and ischemia. The aim of this study, therefore, was to evaluate the clinical efficacy and adverse effects (AEs) of PETN in two doses: 50 mg (PETN-50) and 100 mg (PETN-100), after single ingestion. Twenty-five male patients (pts) with stable angina were enrolled in a randomized, double-blind and placebo (P) controlled study. Ten of them received PETN-50 or P and fifteen of them PETN-100 or P. Antianginal efficacy of the drugs was evaluated by analyzing the parameters of tolerance of effort and coronary reserve taken from serial exercise stress tests on the treadmill performed before single oral ingestion, then after 2h and 6h. Simple hemodynamic parameters were also evaluated at rest and during exercise. In comparison to P, PETN-50 did not change any parameter of tolerance of effort and coronary reserve, nor any simple hemodynamic parameter (all values statistically not significant - n.s.). However, in comparison to P, PETN-100 significantly improved the mean total walking time after 2h by 20.8% (p < 0.01) and also after 6h by 11.3% (p < 0.05). Similarly, PETN-100 improved walking time to angina after 2h by 18.8% (p < 0.05) and after 6h by 10.5% (p < 0.05). The drug also improved walking time to ischemia after 2h by 32.5% (p < 0.01) and after 6h by 13.8% (p < 0.05). PETN-100 did not significantly change the resting heart rate, but it decreased resting systolic blood pressure in both positions 6h after ingestion: in supine by 6.1% (p < 0.05) and in standing by 5.9% (p < 0.05). No postural hypotension in any pt occurred. Diastolic blood pressure significantly decreased only in standing position by 6.8% (p < 0.05) after 6h. During maximal exercise no significant reduction of systolic blood pressure occurred, but there was a significant reduction in diastolic blood pressure 6h after ingestion only. This study shows the good clinical tolerance and safety of PETN in both doses. There were no AEs after single ingestion of PETN-50 and AEs after ingestion of PETN-100 included headaches in 3 pts only (in 1 pt after P) in the group of 15 pts. Thus no clinical activity of PETN-50 was shown. However, our investigations suggest that PETN-100 is an active coronary drug, effective not less than 6 h after ingestion, and well tolerated by pts. Further studies are needed to evaluate the efficacy of PETN in long-term therapy.
Adult↗
Differential effects of pentaerythritol tetranitrate and nitroglycerin on the development of tolerance and evidence of lipid peroxidation: a human in vivo study.
OBJECTIVES: We investigated the development of nitrate tolerance after continuous exposure to nitroglycerin (GTN) as compared with pentaerythritol tetranitrate (PETN) in humans. BACKGROUND: Sustained therapy with GTN causes tolerance and has been associated with increased production of free oxygen radicals by the endothelium. Pentaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the development of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical production or hemodynamic tolerance. METHODS: We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (control group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The levels of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation. RESULTS: Tolerance, as demonstrated by blood pressure and forearm plethysmography, developed in the GTN group and was absent in the PETN group (p < 0.05). Therapy with GTN was associated with a significant increase in plasma markers of lipid peroxidation. This response was not observed in those treated with PETN (isoprostanes: control: 38 +/- 5; GTN: 59 +/- 6; PETN: 38 +/- 3 microg/ml; p < 0.005). CONCLUSIONS: Treatment with PETN does not cause tolerance and is not associated with evidence of increased free radical production.
Administration, Cutaneous↗
Electrochemiluminescence enzyme immunoassays for TNT and pentaerythritol tetranitrate.
Electrochemiluminescence enzyme immunoassays for 2,4,6-trinitrotoluene (TNT) and pentaerythritol tetranitrate (PETN) are described. The latter is, to the best of our knowledge, the first report of an immunoassay for PETN. Haptens corresponding to these explosives were covalently attached to high-affinity dextran-coated paramagnetic beads. The beads were mixed with the corresponding Fab fragments and the sample. After adding a second HRP-labeled antispecies-specific antibody, the mixture was pumped into an electrochemiluminometer where beads were concentrated on the working electrode magnetically. The amount of analyte in the sample was determined by measuring light emission when H2O2 was generated electrochemically in the presence of luminol and an enhancer. The detection limits for TNT and PETN were 0.11 and 19.8 ppb, respectively. Details of bead preparation and performance are given. The increase in sensitivity obtained when Fab fragments are used instead of whole antibodies is explained, and the implications of this observation for nanoparticle-based assays are discussed.
Animals↗
Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates.
Mitochondrial aldehyde dehydrogenase (ALDH-2) was recently identified to be essential for the bioactivation of glyceryl trinitrate (GTN). Here we assessed whether other organic nitrates are bioactivated by a similar mechanism. The ALDH-2 inhibitor benomyl reduced the vasodilator potency, but not the efficacy, of GTN, pentaerythritol tetranitrate (PETN), and pentaerythritol trinitrate in phenylephrine-constricted rat aorta, whereas vasodilator responses to isosorbide dinitrate, isosorbide-5-mononitrate, pentaerythritol dinitrate, pentaerythritol mononitrate, and the endothelium-dependent vasodilator acetylcholine were not affected. Likewise, benomyl decreased GTN- and PETN-elicited phosphorylation of the cGMP-activated protein kinase substrate vasodilator-stimulated phosphoprotein (VASP) but not that elicited by other nitrates. The vasodilator potency of organic nitrates correlated with their potency to inhibit ALDH-2 dehydrogenase activity in mitochondria from rat heart and increase mitochondrial superoxide formation, as detected by chemiluminescence. In contrast, mitochondrial ALDH-2 esterase activity was not affected by PETN and its metabolites, whereas it was inhibited by benomyl, GTN applied in vitro and in vivo, and some sulfhydryl oxidants. The bioactivation-related metabolism of GTN to glyceryl-1,2-dinitrate by isolated RAW macrophages was reduced by the ALDH-2 inhibitors benomyl and daidzin, as well as by GTN at concentrations >1 microM. We conclude that mitochondrial ALDH-2, specifically its esterase activity, is required for the bioactivation of the organic nitrates with high vasodilator potency, such as GTN and PETN, but not for the less potent nitrates. It is interesting that ALDH-2 esterase activity was inhibited by GTN only, not by the other nitrates tested. This difference might explain why GTN elicits mitochondrial superoxide formation and nitrate tolerance with the highest potency.
Aldehyde Dehydrogenase↗