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PubMed1995

Pharmacokinetics and bioavailability of pentaerithrityl tetranitrate and two of its metabolites.

Two preparations containing 100 mg pentaerithyrityl tetranitrate (PETN, CAS 78-11-5) each were administered to 24 healthy male volunteers in an open randomised two-way cross-over design. The test preparation was a commercially available 50 mg tablet (Pentalong 50 mg Tabletten, 2 tablets per dose), the reference preparation was an aqueous suspension prepared immediately before application from the same 25% PETN/lactose trituration as was used for manufacturing the tablets. Blood samples were withdrawn pre-dose and at 14 time points within 24 h after dosing. The resulting plasma was analysed by a GC/MS method developed on purpose. Since in a pilot study not a single one of 120 plasma samples contained concentrations of unchanged PETN or of its metabolite pentaerithrityl trinitrate (PE-tri-N, CAS 1607-17-6) above the quantification limit of 50 pg/ml, the samples of this study were assayed for the metabolites pentaerithrityl dinitrate (PE-di-N, CAS 1607-01-8) and pentaerithrityl mononitrate (PE-mono-N, CAS 1607-00-7) only. -Mean peak levels of 17 ng/ml and 7.5 ng/ml PE-di-N were reached ca. 3 h after application of tablets or trituration. The plasma elimination half-life was 4-5 h. Average maximum PE-mono-N levels of 79 ng/ml (tablets) and 35 ng/ml (trituration) were observed at 7 h p. appl. They declined with a half-life of 10-11 h. The relative bioavailability of the tablets as determined by means of the AUC of PE-di-N is 280-290%. This high value is explained by the specific properties of drug liberation and dissolution from the preparations used.

Adult↗
PubMed1995

Exercise increases endothelin-1 plasma concentrations in patients with coronary artery disease: modulatory role of LDL cholesterol and of pentaerithrityltetranitrate.

Previous studies suggest that ET-1 plays a role in induction of coronary artery disease (CAD). It was shown that secretion of endothelin-1 (ET-1) by the vascular endothelium is enhanced in atherosclerotic alterations and may be antagonized by EDRF. The objective of the present study was to investigate the effects of ergometric exercise on plasma ET-1 concentrations, and the potential modulatory role of LDL cholesterol, and the effects of an orally administered nitrate, PETN, in patients with CAD. Ten men with CAD and 10 healthy men underwent bicycle ergometry according to the WHO-standards. Venous blood samples for determination of ET-1 concentrations were drawn directly before and 5 min after ergometric exercise. Patients were randomized and treated for 72 h in a crossover design either with placebo or pentaerithrityltetranitrate (PETN). After 72 h the identical ergometric protocol was repeated. Basal plasma levels of ET-1 were 6.1 +/- 0.7 pg/ml (patients) and 5.5 +/- 0.6 pg/ml (controls) (n.s.). After ergometric exercise ET-1 plasma concentrations rose significantly (7.3 +/- 0.9 pg/ml; p < 0.05) in the patient group under placebo treatment, whereas they remained constant (5.5 +/- 0.7 pg/ml) with PETN treatment. ET-1 levels remained unaffected by ergometric exercise in healthy controls. Mean LDL cholesterol plasma levels in patients with CAD were 156 +/- 8 mg% and 152 +/- 7 mg% in healthy controls. In the patient group there was a significant (p < 0.002) positive correlation between the exercise-induced increase in ET-1 and the LDL cholesterol plasma concentrations (r = 0.85). Blood pressure and heart rate were not modified by PETN treatment. In patients with CAD bicycle ergometry induced an increase in ET-1 plasma concentrations. The positive correlation with the LDL cholesterol plasma levels indicates that LDL cholesterol is involved in regulation of ET-1 secretion in vivo. PETN therapy completely abolished the exercise-induced increase in ET-1 plasma levels. This may result from local hemodynamic effects of the nitrate; hypothetically a nitrate-induced rise in the local NO concentrations can be considered. The clinical implications of these findings remain elusive. However, the findings of the present study are in accordance with the beneficial clinical effects of nitrates in patients with CAD.

Cholesterol, LDL↗
PubMed1997

Quantitative determination of pentaerythrityl tetranitrate and its metabolites in human plasma by gas chromatography/mass spectrometry.

Up to now, there has been no data available on the pharmacokinetics of pentaerythrityl tetranitrate (PETN, CAS 78-11-5) and its metabolites, pentaerythrityl-trinitrate (PE-tri-N), pentaerythrityl-dinitrate (PE-di-N), pentaerythrityl-mononitrate (PE-mono-N) in human plasma. Therefore, in order to determine PETN and its metabolites in plasma sensitive and highly selective GC/MS methods had to be developed and validated. PETN and its metabolite PE-tri-N were validated in the concentration range 50 pg/ml to 10 ng/ml. Isosorbide dinitrate (ISDN) was used as the internal standard and the analytes were extracted with dichloromethane from the plasma. The mass spectrometric tests were carried out using chemical ionization in the negative mode (NlCl) with the application of ammonia as a reagent gas. The nitrate ion m/z 62 was determined in the analytes and internal standard. The accuracy of the mean of the quality control samples during the three days (between days) was between 100 and 110% (PETN), as well as 90 and 106% (PE-tri-N). After an oral application of 100 mg PETN in a pilot study, unchanged PETN and PE-tri-N was measured in plasma. Both metabolites PE-di-N and PE-mono-N were validated at the concentration range of 0.25 ng/ml to 25 ng/ml plasma. After extraction, these analytes were derivatized with BSTFA (N,O-bis[trimethylsilyl]trifluoro-acetamide). The applied internal standard was isosorbide-5-mononitrate (IS-5-MN). The mass spectrometric tests were carried out in the same manner as for PETN and PE-tri-N with chemical ionization in the NlCl mode. The detected masses were m/z 324 for PE-di-N, m/z 351 for PE-mono-N and m/z 217 for IS-5-MN. The accuracy of the mean of the quality control samples during 5 days were between 104 and 107% (PE-di-N) and 102 and 106% (PE-mono-N). The maximum concentration of these analytes in the subject samples were on the average all over 5 ng/ml plasma after the oral administration of 100 mg PETN.

Calibration↗
PubMed1998

Application of solid-phase microextraction to the recovery of organic explosives.

The application of solid-phase microextraction to the recovery of residues of organic explosives by headspace sampling is discussed. It was found that the technique was rapid and simple. Polydimethylsiloxane and polyacrylate resin were examined as adsorption phases and the latter was found to be more effective. It was found that non-volatile explosives (PETN, RDX, and TNT) should be extracted at about 100 degrees. Acceptable limits of detection were achieved using bench top quadrupole mass spectrometry and short extraction times (about 30 min). Increasing the extraction times to many hours resulted in significantly enhanced detection. Desorption of PETN from the solid phase was found to induce some decomposition of the explosive, but the technique was still valuable for the analysis of this compound.

Acrylic Resins↗
PubMed1998

[Actions of pentaerithritol tetranitrate, isosorbide mononitrate and placebo on headache and ability to work of healthy subjects].

In a randomised, double-blind, four-way crossover study, 24 healthy volunteers received 240 mg/d pentaerithritol tetranitrate (PETN, CAS 78-11-5), 150 mg/d PETN, 60 mg/d isosorbide mononitrate slow release (ISMN, CAS 16051-77-7) or placebo in each study period for two days. Headache and disability to work were self-rated six times per day; individual measurements were combined to total scores. ISMN caused headaches more frequently (in approx. 90% of volunteers) and more severe (average total score 15.2) and a greater disability (average total score 6.0) than the high or low PETN-dosage (both in approx. 50%, headache score 4.9 or 6.4, disability score 1.1 or 2.1, resp.) and placebo (in approx. 10%, headache 0.8, disability 0), all these differences were statistically significant (p < 0.01, Wilcoxon). The high PETN-dosage showed a non-significant trend to produce fewer systemic side effects than the low PETN-dosage (not vice versa). With ISMN six volunteers prematurely terminated the study period and one volunteer who was replaced withdrew from the entire study due to side effects; all volunteers completed the study periods with the other medications.

Adult↗
PubMed1998

Formation of reactive oxygen species by pentaerithrityltetranitrate and glyceryl trinitrate in vitro and development of nitrate tolerance.

Anti-ischemic therapy with organic nitrates is complicated by tolerance. Induction of tolerance is incompletely understood and likely multifactorial. Recently, increased production of reactive oxygen species (ROS) has been investigated, but it has not been clear if this is a direct consequence of the organic nitrate on the vessel or an in vivo adaptation to the drugs. To examine the possibility that nitrates could directly stimulate vascular ROS production, we compared the development of nitrate tolerance with the formation of ROS induced by pentaerithrityltetranitrate (PETN) or nitroglycerin (GTN) in vitro in porcine smooth muscle cells, endothelial cells, washed ex vivo platelets and whole blood. By examining cGMP formation, it was found that 24-hr treatment with GTN but not PETN induced significant nitrate tolerance, which was prevented by parallel treatment with Vit C. Incubation of vascular cells acutely with 0.5 mM GTN doubled the rate of ROS generation, whereas PETN had no such effect. The rate of ROS (peroxynitrite and O2) formation detected by specific spin traps in tolerant smooth muscle cells, treated for 24 hr with 0.01 mM GTN, was substantially higher (30.5 nM/min) than in control cells acutely treated with 0.5 mM GTN (25 nM/min). In contrast to PETN, GTN induces nitrate tolerance and also increases the formation of ROS both in vascular cells and in whole blood. ROS formation is minimally stimulated by PETN comparable to data obtained in Vit C-suppressed GTN tolerance. ROS formation induced by organic nitrates seems to be a key factor in the development of nitrate tolerance.

Animals↗
PubMed1998

The effect of pentaerithrityl-tetranitrate on parameters of the microcirculation.

AIM OF THE STUDY: The effect of organic nitrates on microcirculation was first studied in 1964 and with regard to glyceroltrinitrate (GTN) an "internal hemodilution" (i.e. a fluid shift from the extravascular fluid to the intravascular compartment) was observed. Therefore, we found it of interest to study the effects of the long-acting PETN on parameters of hemorrheology. METHODS: The effects of single doses of 25, 50, and 80 mg PETN, 0.4 mg GTN, and of placebo were investigated on the capillary erythrocyte velocity (CEV; Capiflow), the tissue oxygen tension (tcpO2), the deformability of red blood cells, the plasma viscosity and of the fibrin content of the plasma in a single-blind, randomized study over 12 h in 12 healthy female and male volunteers. The CEV and the tcpO2 were measured in the nailfold of the fourth finger and on the skin of its end phalanx, respectively. Statistical analysis was performed by analysis of variance, the calculation of epsilon (Greenhouse-Geisser), and the multiple t test. RESULTS: After administration of 50 or 80 mg PETN the CEV decreased by 30% over a period of 2 or 4 h (p = 0.02 or 0.002). A decrease by 11% was measured 1 and 2 h after administration of GTN (p = 0.034). Under the same PETN doses tcpO2 increased from 1.41 to 1.78 mm mercury (p = 0.002). The deformability of red blood cells was slightly increased after 50 and 80 mg PETN under share rates of 60 Pa from 55.5 to 58.0% 8 and 12 h after intake. The plasma viscosity was decreased after intake of 50 mg PETN 4 to 8 h (1.36 vs. 1.34 Pa x s, p = 0.023) and after intake of 80 mg 2 to 12 h post dose (1.36 vs. 1.33 Pa x s, p = 0.015). The systolic or diastolic blood pressure decreased, but was not significant. CONCLUSIONS: The PETN-induced decrease in CEV can be explained with the pre- and afterload decreasing properties of the nitrates. The increase in tcpO2 and erythrocyte deformability and the decrease in viscosity are additional advantageous effects on the microcirculation. If the results are transferred from the nailfold of the finger to the myocardium, the benefit of nitrates could not only be seen in the decrease in preload due to their vasodilating properties, but also in improving the parameters of microcirculation. The internal hemodilution and the slightly enhanced deformability might provide an additional supply of myocardial capillaries in case of myocardial ischemia.

Administration, Oral↗