Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Fetal programming effects of pentaerythritol tetranitrate in a rat model of superimposed preeclampsia.

Preeclampsia is a common medical condition during pregnancy and a major cause of maternal and prenatal mortality. The present study was conducted to investigate the effects of maternal treatment with pentaerythritol tetranitrate (PETN) in Dahl salt-sensitive rats (DSSR), a model of superimposed preeclampsia. F0 parental DSSR were treated with PETN (50 mg/kg) from the time point of mating to the end of lactation. Maternal PETN treatment improved fetal growth and had no effect on blood pressure in DSSR offspring fed with normal chow or high-salt diet. Upon high-fat diet (HFD) feeding, offspring from PETN-treated mother showed improved glucose tolerance despite similar weight gain. Unexpectedly, maternal PETN treatment significantly potentiated the HFD-induced blood pressure elevation in male DSSR offspring. Endothelium-derived hyperpolarization factor (EDHF)-mediated vasodilation was similar between NCD-fed and HFD-fed control offspring but was markedly reduced in HFD-fed PETN offspring. EDHF genes were downregulated in the vasculature of HFD-fed PETN offspring, which was associated with epigenetic changes in histone modifications. In conclusion, maternal PETN treatment in DSSR shows both beneficial and unfavorable effects. It improves fetal growth and ameliorates glucose tolerance in the offspring. Although maternal PETN treatment has no effect on blood pressure in offspring fed with normal chow or high-salt diet, the offspring is at higher risk to develop HFD-induced hypertension. PETN may potentiate the blood pressure response to HFD by epigenetic modifications of EDHF genes. KEY MESSAGES: The core findings of this article suggest that maternal PETN treatment of DSSR, a rat model of a spontaneous superimposed preeclampsia, leads to • Improvement of fetal growth; • No changes of maternal blood pressure or markers of preeclampsia; • Amelioration of HFD-induced glucose intolerance in adult offspring; • No changes in blood pressure development of the offspring on normal chow or high salt-diet; • Potentiation of blood pressure elevation of the offspring on HFD.

Does Pentaerytrithyltetranitrate reduce fetal growth restriction in pregnancies complicated by uterine mal-perfusion? Study protocol of the PETN-study: a randomized controlled multicenter-trial.

BACKGROUND: Affecting approximately 10% of pregnancies, fetal growth restriction (FGR), is the most important cause of perinatal mortality and morbidity. Impaired placental function and consequent mal-perfusion of the placenta is the leading cause of FGR. Although, screening for placental insufficiency based on uterine artery Doppler measurement is well established, there is no treatment option for pregnancies threatened by FGR. The organic nitrate pentaerithrityl tetranitrate (PETN) is widely used for the treatment of cardiovascular disease and has been shown to have protective effects on human endothelial cells. In a randomized placebo controlled pilot-study our group could demonstrate a risk reduction of 39% for the development of FGR, and FGR or death, by administering PETN to patients with impaired uterine artery Doppler at mid gestation. To confirm these results a prospective randomized placebo controlled double-blinded multicentre trial was now initiated. METHOD: The trial has been initiated in 14 centres in Germany. Inclusion criteria are abnormal uterine artery Doppler, defined by mean PI > 1.6, at 190 to 226 weeks of gestation in singleton pregnancies. Included patients will be monitored in 4-week intervals. Primary outcome measures are development of FGR (birth weight < 10th percentile), severe FGR (birth weight < 3rd centile) and perinatal death. Placental abruption, birth weight below the 3rd, 5th and 10th centile, development of FGR requiring delivery before 34 weeks` gestation, neonatal intensive care unit admission, and spontaneous preterm delivery < 34 weeks` and 37 weeks` gestation will be assessed as secondary endpoints. Patient enrolment was started in August 2017. Results are expected in 2020. DISCUSSION: During the past decade therapeutic agents with possible perfusion optimizing potential have been evaluated in clinical trials to treat FGR. Meta-analysis and sub-analysis of trials targeting preeclampsia revealed ASS to have a potential in reducing FGR. Phosphodiesterase-type-5 inhibitors have recently been tested in a worldwide RCT for therapy of established FGR, failing to show an effect on neonatal outcome. The ongoing multicenter trial will, by confirming our previous results, finally provide a therapeutic option in cases at risk for FGR. TRIAL REGISTRATION: DRKS00011374 registered at September 29th, 2017 and NCT03669185 , registered September 13th, 2018.

Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary analysis of the PETN-pilot trial.

AIM: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. METHODS: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. RESULTS: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [-0.20, 95% confidence interval (CI): -0.34 to -0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181-0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. CONCLUSION: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN-pilot trial.

Impact of the nitric oxide-donor pentaerythrityl-tetranitrate on perinatal outcome in risk pregnancies: a prospective, randomized, double-blinded trial.

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are associated with impaired placentation. Patients who are at risk of developing both these disorders can be identified by abnormal uterine artery Doppler at mid-trimester pregnancy. Nitric oxide (NO)-donors like pentaerithrityl-tetranitrate (PETN) reduce the impedance in the uteroplacental vessels and possess protecting effects on the endothelium. We tested the effectiveness of the NO-donor PETN for secondary prevention of IUGR, PE, and preterm birth in pregnancies at risk. Some 111 women who presented with abnormal placental perfusion at 19-24 weeks of gestation (w.o.g.) were included into a prospective, randomized, placebo-controlled, double-blinded study. The primary endpoint was IUGR and/or perinatal death. Secondary endpoints were preterm birth, PE, and placental abruption. Pentaerithrityl-tetranitrate significantly decreased the risk for IUGR and/or perinatal death [adjusted odds ratio (OR) 0.410; 95% confidence interval, CI, 0.184-0.914] and for IUGR (adjusted OR 0.436; 95% CI 0.196-0.970). Preterm birth before 32 w.o.g. (adjusted OR 0.204; 95% CI 0.052-0.801) was reduced, but not the risk for PE. No placental abruption occurred in the PETN, but five occurred in the placebo group [corrected]. These results suggest that secondary prophylaxis of adverse pregnancy outcome might be feasible in pregnancies exhibiting abnormal placentation using PETN.

Efficacy of the long-acting nitro vasodilator pentaerithrityl tetranitrate in patients with chronic stable angina pectoris receiving anti-anginal background therapy with beta-blockers: a 12-week, randomized, double-blind, placebo-controlled trial.

BACKGROUND: The organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study ('CLEOPATRA' study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris. METHODS AND RESULTS: A total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo (n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline ≤9 min, n = 257), PETN appeared more effective than placebo treatment (P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels (n = 120; P = 0.017). Pentaerithrityl tetranitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo. CONCLUSION: Although providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity.

Chronic protection against ischemia and reperfusion-induced endothelial dysfunction during therapy with different organic nitrates.

INTRODUCTION: Ischemic and pharmacologic preconditioning have great clinical potential, but it remains unclear whether their effects can be maintained over time during repeated exposure.We have previously demonstrated that the acute protective effect of nitroglycerin (GTN) is attenuated during repeated daily administration. Pentaerythrityl tetranitrate (PETN) is an organic nitrate with different hemodynamic and biochemical properties. The purpose of the current experiment was to study the preconditioning-like effects of PETN and GTN during repeated daily exposure. METHODS AND RESULTS: In a randomized, investigator-blind parallel trial, 30 healthy (age 25-32) volunteers were randomized to receive (1) transdermal GTN (0.6 mg/h) administered for 2 h a day for 6 days; (2) oral PETN (80 mg) once a day for 6 days; or (3) no therapy. One week later, endothelium-dependent flow-mediated dilation was assessed before and after exposure to ischemia and reperfusion (IR). IR caused a significant blunting of the endothelium-dependent relaxation in the control group (FMD before IR: 5.8 ± 2.1%; after IR 1.0 ± 2.1%; P < 0.01). Daily, 2-h exposure to GTN partially prevented IR-induced endothelial dysfunction (FMD before IR: 7.7 ± 2.4%; after IR 4.3 ± 3.0%; P < 0.01 compared to before IR). In contrast, daily PETN administration afforded greater protection from IR-induced endothelial injury (FMD before IR: 7.9 ± 1.7%; after IR 6.4 ± 5.3%, P = ns; P < 0.05 ANOVA across groups). In vitro, incubation of human endothelial cells with GTN (but not PETN) was associated with inhibition (P < 0.01) of aldehyde dehydrogenase, an enzyme that is important for both nitrate biotransformation and ischemic preconditioning. DISCUSSION: We previously showed that upon repeated administration, the preconditioning-like effects of GTN are attenuated. The present data demonstrate a gradient in the extent of protection afforded by the two nitrates, suggesting that PETN-induced preconditioning is maintained after prolonged administration in a human in vivo model of endothelial dysfunction induced by ischemia. Using isolated human endothelial cells, we propose a mechanistic explanation for this observation based on differential effects of GTN versus PETN on the activity of mitochondrial aldehyde dehydrogenase.

Characterization of the antioxidant properties of pentaerithrityl tetranitrate (PETN)-induction of the intrinsic antioxidative system heme oxygenase-1 (HO-1).

Organic nitrates are among the oldest and yet most commonly employed drugs in the chronic therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practise, our understanding of their mechanism of action and of their side effects remains incomplete. To date, the most commonly employed nitrates are isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), and nitroglycerin (GTN). Another nitrate, pentaerithrityl tetranitrate (PETN), has long been employed in eastern European countries and is currently being reintroduced also in western countries. So far, PETN is the only organic nitrate in clinical use, which is devoid of induction of oxidative stress and related side-effects such as endothelial dysfunction and nitrate tolerance. Some of these effects are related to special pharmacokinetics of PETN, but upon chronic administration, PETN also induces antioxidative pathways at the genomic level, resulting in increased expression of heme oxygenase-1 (HO-1) and ferritin, both possessing highly protective properties. There is good experimental evidence that at least part of the beneficial profile of long-term PETN treatment is based on activation of the heme oxygenase-1/ferritin system.

Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study.

BACKGROUND: Pentaerythritol tetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. The purpose of this study was to determine the effect of PETN on endothelial function in patients with coronary artery disease (CAD). We hypothesized that the treatment with PETN improves endothelial function in patients with CAD. METHODS: In a prospective, double-blind study, we randomly assigned 80 patients to treatment for 8 weeks with oral PETN 80 mg t.i.d. (PETN) or placebo (C). The primary endpoint was the absolute change in brachial artery flow-mediated dilation (FMD) from baseline to follow-up. Furthermore, changes in nitroglycerin-mediated dilation (NMD), digital peripheral arterial tonometry (PAT) index, vascular shear stress, mean flow velocity, plasma bilirubin, C-reactive protein (CRP) and thiobarbituric acid reactive substances (TBARS), serum ferritin, and the activity of the PETN bioactivating enzyme aldehyde dehydrogenase-2 (ALDH-2) in peripheral blood mononuclear cells were analyzed. Raw data entry, data monitoring and statistical analysis were performed independently. RESULTS: The treatment groups were comparable regarding demographics, cardiovascular risk and concomitant medication. There was no difference in the change in FMD between the two treatment groups (mean +/- SD: PETN: +1.6 +/- 3.3% vs. C: +1.4 +/- 4.1%; P = 0.7). NMD increased after treatment with PETN and was higher compared with C (PETN: +3.8 +/- 5.5% vs. C: +0.6 +/- 4.2%; P = 0.004). Mean PAT index and ALDH-2 activity remained unchanged. Relative changes in mean flow volume (P = 0.04) and mean flow velocity (P = 0.01) upon ischemia increased in the PETN group versus C. Changes in bilirubin, ferritin, TBARS and CRP did not differ between the groups. CONCLUSIONS: We conclude that chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function and with beneficial effects on the microcirculation.

Long-term use of short- and long-acting nitrates in stable angina pectoris.

Long-acting nitrates are effective antianginal drugs during initial treatment. However, their therapeutic value is compromised by the rapid development of tolerance during sustained therapy, which means that their clinical efficacy is decreased during long-term use. Sublingual nitroglycerin (NTG), a short-acting nitrate, is suitable for the immediate relief of angina. In patients with stable angina treated with oral long-acting nitrates, NTG maintains its full anti-ischemic effect both after initial oral ingestion and after intermittent long-term oral administration. However, NTG attenuates this effect during continuous treatment, when tolerance to oral nitrates occurs, and this is called cross-tolerance. In stable angina long-acting nitrates are considered third-line therapy because a nitrate-free interval is required to avoid the development of tolerance. Nitrates vary in their potential to induce the development of tolerance. During long-lasting nitrate therapy, except pentaerythritol tetranitrate (PETN), one can observe the development of reactive oxygen species (ROS) inside the muscular cell of a vessel wall, and these bind with nitric oxide (NO). This leads to decreased NO activity, thus, nitrate tolerance. PETN has no tendency to form ROS, and therefore during long-term PETN therapy, there is probably no tolerance or cross-tolerance, as during treatment with other nitrates.

Non-hemodynamic effects of organic nitrates and the distinctive characteristics of pentaerithrityl tetranitrate.

Organic nitrates are among the oldest and yet most commonly employed drugs in the long-term therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practice, our understanding of their mechanism of action and side effects remains incomplete. For instance, recent findings provide evidence of previously unanticipated, non-hemodynamic properties that include potentially beneficial mechanisms (such as the induction of a protective phenotype that mimics ischemic preconditioning), but also toxic effects (such as endothelial and autonomic dysfunction, rebound angina, tolerance). To date, the most commonly employed organic nitrates are isosorbide mononitrate, isosorbide dinitrate, and nitroglycerin (glyceryl trinitrate). Another organic nitrate, pentaerithrityl tetranitrate (PETN), has long been employed in eastern European countries and is currently being reintroduced in Western countries. In light of their wide use, and of the (re)introduction of PETN in Western markets, the present review focuses on the novel effects of organic nitrates, describing their potential clinical implications and discussing differences among different compounds. We believe that these recent findings have important clinical implications. Since the side effects of organic nitrates such as nitroglycerin and isosorbides appear to be mediated by reactive oxygen species, care should be taken that drugs with antioxidant properties are co-administered. On the other hand, efforts should be made to clinically exploit the preconditioning effects of these drugs.

Effect of oral organic nitrates on expression and activity of vascular soluble guanylyl cyclase.

BACKGROUND AND PURPOSE: The regulation of vascular soluble guanylyl cyclase (sGC) expression by nitric oxide (NO) is still under discussion. In vitro, NO has been shown to downregulate the expression of sGC but it is unclear if this mechanism is operative in vivo and occurs during nitrate treatment. EXPERIMENTAL APPROACH: We investigated whether high dose isosorbide mononitrate (ISMN) or pentaerythrityl tetranitrate (PETN) treatment changes vascular sGC expression and activity in vivo. New Zealand White rabbits received a standard diet, 2 or 200 mg ISMN kg(-1) d(-1) for 16 weeks, and C57BL/6 mice received a standard diet, 6, 60 or 300 mg PETN kg(-1) d(-1) for four weeks. Absorption was checked by measuring the plasma levels of the drug/metabolite. KEY RESULTS: Western blots of rabbit aortic rings showed similar protein levels of sGC alpha1- (P=0.2790) and beta1-subunits (P=0.6900) in all groups. Likewise, ANOVA showed that there was no difference in the expression of sGC in lungs of PETN-treated mice (P=0.0961 for alpha1 and P=0.3709 for beta1). The activities of isolated sGC in response to SNAP (1 microM-1 mM) were identical in aortae of ISMN-treated rabbits (P=0.0775) and lungs of PETN-treated mice (P=0.6348). The aortic relaxation response to SNAP slightly decreased at high ISMN but not at high PETN. CONCLUSIONS AND IMPLICATIONS: These data refute the hypothesis that therapeutic treatment with long acting NO donors has a significant impact on the regulation of vascular sGC expression and activity in vivo.

New insights into bioactivation of organic nitrates, nitrate tolerance and cross-tolerance.

Organic nitrates still represent a group of very effective anti-ischemic drugs used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. Long-term therapy with organic nitrates, however, results in a rapid development of nitrate tolerance blunting their hemodynamic and antiischemic efficacy. Recent studies revealed that mitochondrial reactive oxygen species (ROS) formation and a subsequent oxidative inactivation of nitrate reductase, the mitochondrial aldehyde dehydrogenase (ALDH-2), play an important role for the development of nitrate and crosstolerance. The present review focuses firstly on the role of ALDH-2 for organic nitrate bioactivation and secondly on the role of oxidative stress in the development of tolerance and cross-tolerance (endothelial dysfunction) in response to various organic nitrates. Finally, we would like to draw the reader's attention to the protective properties of the organic nitrate pentaerithrityl tetranitrate (PETN), which, in contrast to all other organic nitrates, is able to upregulate enzymes with a strong antioxidative capacity thereby preventing tolerance and the development of endothelial dysfunction.

Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate.

Neither therapeutic dosage of nitrovasodilators nor the development of tolerance correlates with nitrate groups in these molecules. Clinically, low dosages of glyceryl trinitrate (GTN) develop tolerance, but 100-fold higher dosages of pentaerythrityl tetranitrate (PETN) do not. Vasorelaxation was studied on prostaglandian F2alpha (PGF2alpha)-precontracted porcine pulmonary arteries in organ bath procedure. In vitro tolerance was induced by incubating the arteries with different nitrate concentrations and thereafter concentration-response curves were repeated. Furthermore, 14 mg/kg PETN were daily administered to rats by gavage; PETN and metabolites were measured in feces and blood. In vitro, the vasodilator potencies increased from mononitrates to tetranitrates (pD2: 4.14 to 8.18); PETN was the most potent vasodilator. In vitro tolerance was found with PETN and trinitrates but not with dinitrates and mononitrates. Thus, in vitro tolerance correlated with the in vitro potency of nitrates but not with the vasodilator potency of NO donors in general, because S-nitroso-N-aectyl-D-penicillamine and N-phenylpiperazin-NONOate were more potent than GTN but did not induce tolerance. After feeding of rats with PETN, pentaerythrityl dinitrate (PEdiN) and mononitrate (PEmonoN) but neither PETN nor PEtriN (both detected in feces) were found in the blood. The missing systemic bioavailability of PETN and PEtriN may explain the discrepancy between in vitro and in vivo findings. We conclude that the partially denitrated metabolites PEdiN and PEmonoN contribute to the moderate and tolerance-devoid clinical activity of PETN.

Long-term effects of early administered sildenafil and NO donor on the cardiovascular system of SHR.

We evaluated the long-term effect of NO-donor, pentaerythrityl tetranitrate (Petn), and sildenafil citrate (sildenafil) on the cardiovascular system of the spontaneously hypertensive rat (SHR). Petn (100 mg/kg/day) and sildenafil (10 mg/kg/day) were administered to SHR individually or together from week 4 (pre-hypertensive period) to week 9 of age. Blood pressure (BP) was measured using a plethysmographic method. The animals were perfused with a glutaraldehyde fixative (120 mmHg). Carotid (AC) and coronary artery (RS) were processed according to electron microscopy procedure. Geometry of the arteries was measured on semi-thin sections using light microscopy. Administration of Petn and sildenafil to SHR individually or together did not prevent an increase of BP, but evoked a decrease of cardiac hypertrophy. Petn and sildenafil affected the geometry of RS and AC differently. In the RS, an increase of inner diameter (ID) without an increase of wall thickness (WT) resulted in increased WT/ID and circumferential stress. In the AC, changes in ID were accompanied by changes in WT and, thereby, WT/ID and circumferential stress remained unchanged. The arterial wall mass of both arteries was increased. The data suggest that administration of the NO donor, Petn, and/or sildenafil does not result in a beneficial effect on the myocardium or on the geometry of the carotid and coronary arteries.

[Clinical evaluation of pentaerythritol tetranitrate in two doses in patients with stable angina pectoris]. / Badania kliniczne czteroazotanu pentaerytrytylu w dwóch dawkach u pacjentów ze stabilna choroba wiencowa.

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.

Nitroester drug's effects and their antagonistic effects against morphine on human sphincter of Oddi motility.

AIM: To evaluate the effects of nitroester drugs on human sphincter of Oddi (SO) motility and their antagonistic effects against morphine which shows excitatory effect on Oddi's sphincter motility. METHODS: The effects of these drugs on SO were evaluated by means of choledochofiberoscopy manometry. A total of 67 patients having T-tubes after cholecystectomy and choledochotomy were involved in the study, they were randomly divided into glyceryl trinitrate (GTN) group, isosorbide dinitrate (ISDN) group, pentaerythritol tetranitrate (PTN) group, morphine associated with GTN group, morphine associated with ISDN group and morphine associated with PTN group. Basal pressure of Oddi's sphincter (BPOS), amplitude of phasic contractions (SOCA), frequency of phasic contractions (SOF), duration of phasic contractions (SOD), duodenal pressure (DP) and common bile duct pressure (CBDP) were scored and analyzed. Morphine was given intramuscularly while nitroester drugs were applied sublingually. RESULTS: BPOS and SOCA decreased significantly after administration of ISDN and GTN, BPOS reduced from 10.95+/-7.49 mmHg to 5.92+/-4.04 mmHg (P<0.05) evidently after application of PTN. BPOS increased from 7.37+/-5.58 mmHg to 16.60+/-13.87 mmHg, SOCA increased from 54.09+/-38.37 mmHg to 100.70+/-43.51 mmHg, SOF increased from 7.15+/-3.20 mmHg to 10.38+/-2.93 mmHg and CBDP increased 3.75+/-1.95 mmHg to 10.49+/-8.21 mmHg (P<0.01) evidently after injection of morphine. After associated application of ISDN and GTN, the four indications above decreased obviously. As for application associated with PTN, SOCA and SOF decreased separately from 100.64+/-44.99 mmHg to 66.17+/-35.88 mmHg and from 10.70+/-2.76 mmHg to 9.04+/-1.71 mmHg (P<0.05) markedly. CONCLUSION: The regular dose of GTN, ISDN and PTN showed inhibitory effect on SO motility, morphine showed excitatory effect on SO while GTN, ISDN and PTN could antagonize the effect of morphine. Among the three nitroester drugs, the effect of ISDN on SO was most significant.