Preparation Of Nitrate Research Articles

Prevention of tolerance to hemodynamic effects of nitrates with concomitant use of hydralazine in patients with chronic heart failure

This study was designed to determine the effect of oral hydralazine on the development of nitrate tolerance in patients with chronic congestive heart failure. Early development of nitrate tolerance with either continuous administration of intravenous or topical nitrate preparations or frequent dosing of oral nitrates leads to significant attenuation of nitrate-mediated hemodynamic and anti-ischemic effects. In recent animal experiments, prevention of nitroglycerin-induced hemodynamic tolerance with a concomitant use of hydralazine was demonstrated. This finding may have important clinical relevance. Twenty-eight patients with chronic heart failure due to left ventricular systolic dysfunction were randomized to receive either a continuous infusion (24 h) of nitroglycerin alone (group I, 14 patients) or concomitantly with oral hydralazine (75 mg four times a day [group II, 14 patients]). The effect of nitroglycerin in each group was evaluated by analysis of variance for repeated measures. The power of the analysis to detect a 5.4-mm Hg (20%) change in mean pulmonary artery wedge pressure was 90%. Baseline hemodynamic variables as well as the initial hemodynamic response to nitroglycerin were comparable in both groups. Compared with the initial response to nitroglycerin, a significant attenuation of effect was found in group I at 24 h in mean (+/- SE) pulmonary artery pressure (27 +/- 4% vs. 10 +/- 3%, p < 0.05) and mean pulmonary artery wedge pressure (40 +/- 4% vs. 16 +/- 4%, p < 0.05). In group II, conversely, oral hydralazine prevented nitroglycerin-induced hemodynamic tolerance and resulted in a persistent effect on mean pulmonary artery and wedge pressures throughout the study period (31 +/- 3% vs. 27 +/- 4%, p = 0.13 and 37 +/- 4% vs. 34 +/- 6%, p = 0.40, respectively). In addition, the initial effect on blood pressure was attenuated at 24 h in group I (5 +/- 2% vs. 12 +/- 3%, p < 0.05) but not in group II (15 +/- 3% vs. 17 +/- 2%, p = 0.46). In patients with chronic heart failure due to left ventricular systolic dysfunction, the concomitant use of oral hydralazine prevents early development of nitrate tolerance and results in a persistent nitrate-mediated hemodynamic effect on systemic and pulmonary artery and left ventricular filling pressures. These data may support the concurrent use of hydralazine in patients with heart failure treated with organic nitrates.

Preparation and spectral characterization of copper(I) halide, nitrate and perchlorate complexes of pyrazinic acid and X-ray crystal structure of polymeric [Cu 2(pyrazinic acid) 2I 2] · 3H 2O

Copper(l) salts formed with pyrazinic acid (pyz-H) complexes of the types Cu(pyz-H) 2X · 2H 2O for X  Cl or Br, Cu(pyz-H)X · H 2O for X  Br, NO 3 or ClO 4 and Cu 2(pyz-H) n X 2 · 3H 2O where n = 3 for X  Cl and n = 2 for X  I. The complexes were characterized by elemental analysis, IR and electronic spectra. The overall physical measurements suggest that pyz-H acts as a monodentate ligand in the Cu(pyz-H) 2X · 2H 2O complexes and as a N,O-bidentate neutral ligand in the hydrated 1 : 1 complexes, whereas Cu 2(pyz-H) 3Cl 2 · 3H 2O contains both types of acid molecules. The structure of the trihydrated copper(I) iodide complex of pyrazinic acid, as determined by X-ray crystallography, contains the asymmetric Cu 2(pyz-H) 2I 2 · 3H 2O units which are linked together forming a stair or ribbon polymeric structure with tetrahedral copper(I) environments. The two pyrazinic acid molecules in the asymmetric unit behave differently; one acid molecule acts as a neutral ligand whereas the other functions as a zwitterion. Both molecules, however, act as monodentate ligands. The neutral pyrazinic acid molecule forms hydrogen bonds with two water molecules and the zwitterion binds the third water molecule through a hydrogen bond of the type N H … O. The CuN distances are 2.053(4) and 2.064(5) Å the CuI bond lengths vary from 2.618(1) to 2.645(1) Å, and the CuCu distance within the cyclic Cu 2I 2 unit is 2.771(1) Å.

The Role of Nitrates in Coronary Heart Disease

The organic nitrates are a safe and effective choice for the management of ischemic syndromes related to coronary heart disease. Although the anti-ischemic effects of these compounds have been recognized for more than a century, the mechanisms by which they exert their beneficial effects are still being delineated. In addition to their well-established venodilative activity, nitrates are now known to cause vasorelaxation of coronary arteries, coronary stenoses, and coronary collateral vessels and to prevent episodic coronary constriction. An antiplatelet effect has also been hypothesized. The three nitrate compounds currently available in the United States--nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate--are provided in a variety of dosage forms, including sublingual, transmucosal, oral, and transdermal preparations. The rapid- but short-acting nitrate preparations are useful in arresting and preventing acute attacks of angina pectoris, whereas longer-acting oral and transdermal formulations are indicated for the relief of chronic symptomatic and asymptomatic ischemia. The intermittent nitrate dosing regimens introduced in recent years have reduced the likelihood of tolerance, which greatly limited the usefulness of long-acting nitrates in the past. Intravenous infusion of nitroglycerin is particularly appropriate for the management of unstable angina and the early complications of acute myocardial infarction. Preliminary evidence suggests that intravenous nitroglycerin may also be beneficial in preventing postinfarction ventricular remodeling, although it cannot yet be recommended for this purpose.

Phenomenon of nitrate tolerance

The phenomenon of nitrate tolerance has now been appreciated for almost a century, and our understanding of this process has greatly improved during the past 20 years. Therapeutic nitrates are now recognized as exogenous sources of nitric oxide (or nitrosothiols), which appears to be a primary mediator of natural vasodilatation. Nitrates have been clearly shown to have vasodilatory and antiplatelet effects, both of which diminish during continuous exposure. Nitrate tolerance has been documented with most nitrate preparations when the patient is given continuous nitrate therapy. Tolerance to nitrates may occur in any patient, regardless of underlying illness, medication dose, or serum concentration of NTG. The cause of this phenomenon is multifactorial; there appear to be both cellular and systemic processes involved. To date, no adjuvant pharmacologic intervention has conclusively demonstrated benefit in preventing, abating, or reversing nitrate tolerance. Interruption of nitrate exposure for as little as 8 to 12 hours does appear to be the best means of preventing or reversing tolerance. Nevertheless, some patients with objective tolerance continue to experience relief of symptoms. In addition, despite laboratory-documented cross-tolerance, patients receiving continuous nitrate therapy at usual clinical doses may continue to benefit from the hemodynamic and antianginal effects of SL NTG. Hence, nitrate tolerance is a real entity, but the clinical importance of this phenomenon remains controversial. Finally, further investigation will need to address quality-of-life issues and perhaps assess relief of ischemia by other means.

The Effect of Different Nitrate Preparations on Plasma Heparin Concentrations and the Activated Partial Thromboplastin Time

The Effect of Different Nitrate Preparations on Plasma Heparin Concentrations and the Activated Partial Thromboplastin Time

Preparation, analysis, and atmospheric production of multifunctional organic nitrates

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPreparation, analysis, and atmospheric production of multifunctional organic nitratesKayambu Muthuramu, Paul B. Shepson, and Jason M. O'BrienCite this: Environ. Sci. Technol. 1993, 27, 6, 1117–1124Publication Date (Print):June 1, 1993Publication History Published online1 May 2002Published inissue 1 June 1993https://doi.org/10.1021/es00043a010RIGHTS & PERMISSIONSArticle Views318Altmetric-Citations73LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (982 KB) Get e-Alerts Get e-Alerts

Preparation of organic nitrates from alcohols and N2O5 for species identification in atmospheric samples

Several mono- and bifunctional organic nitrates of atmospheric interest were prepared in a one-step synthesis, based on the reaction of alcohols with N2O5 (dinitrogen pentoxide) at low temperatures. The method is well suitable for micro-scale preparations. The compounds were characterized by GC/ECD, GC/NO y -specific detection, and GC/CI (chemical ionization) mass spectrometry.

Convenient Preparation of Alkyl Nitrates Free of Nitrites with Potassium Nitrate and Boron Trifluoride Hydrate

Primary and secondary alkyl nitrates free of nitrites were conveniently prepared by treating the corresponding alcohols with potassium nitrate and boron trifluoride 1.25 hydrate. This procedure was also successful for the preparation of 1-adamantyl nitrate

Rationale for intermittent nitrate therapy

Tolerance to the pharmacologic and therapeutic effects of nitrate therapy is now well established. This phenomenon may be defined as either a decreased response to a given amount of nitrate or the need for an increased amount of nitrate to maintain a constant effect. Tolerance has been demonstrated with all forms of nitrate therapy that maintain continuous blood levels of the drug, including frequent oral dosing, constant intravenous infusion, and continuous transdermal delivery. It can develop rapidly after only a few doses of a nitrate preparation and tends to be partial rather than absolute. Strategies for the prevention of nitrate tolerance include the avoidance of maximum nitrate doses and the use of intermittent nitrate dosing regimens. Providing a relatively brief nitrate-free interval restores vascular responsiveness to nitrates, most likely due to a recovery of the metabolic mechanisms responsible for the therapeutic effect of these drugs. The duration of this period of nitrate abstinence varies, depending on the nitrate preparation used but is generally in the range of 8–12 hours. Such intermittent therapy not only reduces the risk of nitrate tolerance, but also provides a convenient approach to outpatient management.

Placebo effect of nitrate monotherapy for myocardial ischemia

Nitrate monotherapy was assessed by treadmill exercise stress testing in 18 patients with significant but relatively asymptomatic myocardial ischemia who were receiving no other antianginal therapy. In addition, prolonged ambulatory electrocardiographic monitoring was performed in 7 patients with demonstrable ischemia during baseline monitoring. After baseline assessment, 5 treatment periods were used in a random order (each of 1 week duration), incorporating 2 dose levels of transdermal nitrate (10 and 20 mg/24 hours) and isosorbide dinitrate (ISDN) (30 and 60 mg/day in divided doses) with a 10-hour nitrate-free interval every 24 hours, as well as a placebo period using a double-blind technique. All treatment periods (including placebo) showed a significant (p < 0.01) 45 to 69% prolongation in the time to 1 mm ST depression during exercise. Paired baseline times of 231 ± 28 and 233 ± 30 seconds increased to 367 ± 37 seconds with 30 mg/day of ISDN, 393 ± 37 seconds with 60 mg/day of ISDN, 381 ± 31 seconds with 10 mg/day of transdermal nitrate, and 372 ± 33 seconds with 20 mg/day of transdermal nitrate. The value for placebo was 342 ± 29 seconds, which was not significantly different from active treatment (p >0.1). Some patients appeared to individually respond to ≥ 1 nitrate preparation significantly more than to placebo, but this appeared to be unpredictable and largely independent of dosage level and route of administration. There was a qualitatively similar but statistically insignificant reduction in total ischemic time during ambulatory monitoring. No significant effects on total exercise duration or heart rate/systolic pressure product at 1 mm ST depression or end exercise were observed. It is concluded that nitrate monotherapy produces a clinically important effect in delaying the onset of myocardial ischemia during exercise, but there was also a large placebo response in this particular patient group, and thus, no drug-specific effects of nitrate monotherapy on myocardial ischemia could be reliably demonstrated.

Current Medical therapy for esophageal motility disorders

Treatment of patients with an esophageal source of chest pain remains a challenging problem. Although a variety of measures--including nitrates, anticholinergics, sedatives, calcium channel antagonists, esophageal dilation, and psychological reassurance--are available for the management of esophageal chest pain, none has emerged as the treatment of choice. Studies of nitrate preparations for the treatment of painful motility disorders are limited by a small number of patients and the lack of randomized, placebo-controlled investigations. The efficacy of anticholinergic drugs in hypercontractile esophageal motility disorders has not been reported. In the only prospective placebo-controlled trial using an anti-depressant, trazodone was superior to placebo in relieving symptoms in patients with a variety of esophageal motility disorders. Conflicting results have been described in placebo-controlled trials of the calcium channel antagonists nifedipine and diltiazem in patients with "nutcracker esophagus" or diffuse spasm. Information about the efficacy of verapamil and hydralazine is limited. Esophageal dilation has been useful in selected patients. For many patients, esophageal chest pain may be associated with gastroesophageal reflux. Treatment of these patients with nitrates, calcium channel antagonists, or anticholinergics may aggravate their reflux. The mechanisms of esophageal chest pain remain unknown. Recent studies have suggested that abnormal motility may not be the only factor associated with chest pain. An important number of patients have behavioral abnormalities, increased nociception, impaired coronary vasodilatory reserve, or a diffuse abnormality of smooth muscle. Research into rational therapy for chest pain patients should take into account the contribution of these other factors.

Antianginal and Anti-Ischemic Efficacy of Nicorandil in Comparison with Isosorbide-5-Mononitrate and Isosorbide Dinitrate

The purpose of the two double-blind studies summarized in this article was to compare the antianginal and anti-ischemic effects of nicorandil with those of two different nitrate preparations. A total of 129 patients with stable New York Heart Association functional class II or III coronary heart disease were enrolled in the studies. Ninety-five patients received nicorandil, 34 received isosorbide dinitrate (ISDN), and 63 received isosorbide-5-mononitrate (MN). In study 1, nicorandil was compared with MN in a crossover design with 54 protocols eligible for efficacy assessment of MN and 52 eligible for nicorandil, respectively. Twenty milligrams of nicorandil and 20 mg MN administered b.i.d. for 4 weeks were equally effective in the treatment of stress-induced angina. Both drugs prolonged bicycle exercise tolerance and reduced weekly anginal attack rates. In study 2, nicorandil and ISDN were administered to two parallel groups of patients at a dose of 10 mg t.i.d. for 2 weeks and then 20 mg t.i.d. for 4 weeks. Under the assumption that the repetitive administration of nitrates with short dosing intervals might induce the development of tolerance to the nitrate mechanism of action, the t.i.d.-dosing regimen had been chosen in this study. Thirty-two protocols from those receiving nicorandil and 34 protocols from those receiving ISDN were eligible for efficacy assessment. Both drugs increased exercise capacity and reduced ST-segment depression at identical work loads with no significant difference between groups (p > 0.05). For both drugs, the higher doses were more effective than the lower doses. tolerance to the nitrate mechanism of action did not develop with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

HPLC preparation of nitrate from ice cores for mass spectrometric 15N/14N measurements

A method for the analysis of δ15N-data of nitrate at ultratrace levels in ice cores is described. Samples are pre-concentrated using a HPLC-system. Nitrate is then reduced using the Dumas method to molecular nitrogen, which is analysed by mass spectrometry. The overall analytical precision of the method is ±0.4‰δ15N at a sample size of 35 bar μl N2. First results of deep ice-core analyses from Dome Summit, Greenland, are given.

Randomized study to evaluate the relation between oral isosorbide dinitrate dosing interval and the development of early tolerance to its effect on left ventricular filling pressure in patients with chronic heart failure.

Early development of nitrate tolerance has been shown in patients with chronic congestive heart failure (CHF) receiving continuous nitroglycerin therapy. The influence of dosing interval of oral isosorbide dinitrate (ISDN), the nitrate preparation most widely used for the treatment of CHF, has not been investigated. We performed a prospective, randomized study to evaluate the effect of various regimens of oral ISDN on the development of early tolerance to its effect on left ventricular filling pressure in patients with moderate to severe CHF. Forty-four responders (20% or greater reduction in mean pulmonary artery wedge pressure lasting 1 hour or longer) were divided into four groups of 11 patients each, and randomized to receive their effective ISDN dose (40-120 mg) Q 4 hours, Q 6 hours, Q 8 hours, or t.i.d. (drug given at 0, 6, 12, and 24 hours allowing 12 hours of ISDN washout interval between the third and fourth doses). All groups demonstrated a significant and comparable reduction in LV filling pressure following administration of the first ISDN dose. Early attenuation of hemodynamic response was demonstrated with frequent dosing (Q 4 hours and Q 6 hours) ISDN. Tolerance was with a Q 8-hour regimen as demonstrated by preserved hemodynamic response to each dose. The effect of each dose, however, was short-term, with return of pulmonary artery wedge pressure to baseline level at 2 to 4 hours, resulting in an intermittent effect totaling no longer than 12 hours of the 30-hour study period. The use of a t.i.d. regimen resulted in marked attenuation of response after the third dose with complete restoration of nitrate effect following a 12-hour washout period between the third and fourth doses. ISDN plasma concentration was measured in five patients in each of the Q 4- and Q 8-hour groups. In the Q 4-hour group, plasma levels were significantly higher after administration of the last dose than after the first dose (area under the curve, 242 +/- 216 versus 123 +/- 130 ng/ml, p less than 0.05), and trough levels before administration of the second and the fifth dose (15 +/- 17 and 27 +/- 27 ng/ml, respectively) were both markedly higher than the baseline value of 2 +/- 4 ng/ml. Our data demonstrate the development of tolerance and early attenuation of effect on left ventricular filling pressure with frequent oral dosing (Q 4 and Q 6 hours) with ISDN in patients with chronic CHF, which may be related to persistently elevated trough blood levels of ISDN. The development of tolerance can be reversed after a washout period of 12 hours and can be prevented with a Q 8-hour administration. These regimens, however, are limited by an inconsistent effect. Although long-term implications of these findings need further evaluation, the present study demonstrates the difficulty of maintaining a persistent ISDN-mediated reduction in left ventricular filling pressure in patients with chronic, moderate to severe CHF. These results suggest the need to use intermittent ISDN therapy allowing a daily nitrate washout interval and the rationale for combined vasodilator therapy in patients with CHF.

Hemodynamic resistance to intravenous nitroglycerin in severe congestive heart failure and restored response after diuresis

A wide variety of organic nitrate preparations are often used in the management of congestive heart failure (CHF). This class of drugs exerts a vasodilatory action, predominantly on the venous capacitance vessels, that leads to a reduced ventricular filling pressure and usually without an increase in cardiac output. 1,2 Two major problems exist that deter its widespread acceptance as an effective drug in CHF: the development of tolerance and hemodynamic resistance or primary drug failure. Tolerance is responsible for the loss of hemodynamic and clinical benefits after nitrate therapy has been initiated. 3–5 An absent or feeble hemodynamic response to nitrates, a relatively common occurrence, has been reported to occur in approximately ≥50% of treated patients. 6,7 However, nitrate resistance is not always apparent when intravenous nitroglycerin is used without hemodynamic monitoring. This study was designed for 2 purposes: (1) to substantiate previously described hemodynamic and clinical correlates of CHF predictive of resistance to intravenous nitroglycerin, 6,7 and (2) to determine whether hemodynamic modification using alternate drug therapy might restore responsiveness to nitroglycerin.

Nitrato Amine Nitrates: Nitrate ester explosives with reduced impact sensitivity

AbstractThe preparation and properties of several nitrato amine nitrates are given along with calculated detonation velocities and measured impact sensitivities. Comparison of these compounds with the high performance explosive PETN is also given.

A practical guide to nitrate use

Nitrate preparations are useful in the treatment of acute and chronic angina, acute and chronic congestive heart failure, and acute myocardial infarction. Development of tolerance is best managed by providing a nitrate-free interval, thus avoiding continuous drug levels. This interval probably should be 10 to 12 hours with use of a transdermal patch. Nitrate treatment of the elderly may require lower doses to avoid hypotension.

Nitrosonium nitrate: A simple cryogenic preparation and phase transitions

A simple method is suggested for the preparation of pure nitrosonium nitrate (NO+ NO3−) thin films, by deposition of nitrogen dioxide from the gas phase onto a cold tip under specified conditions and subsequent warming up of the layer. Fourier-transform infrared spectra were used for its characterization and to determine its purity. The NO+ NO3− solid thus formed was found to be stable up to 230 K. Raman examination of temperature cycling effects on thev(NO+) band and on the phonon region of the thin films indicates one amorphous and two crystalline phases. Amorphous-crystalline and crystalline-crystalline transition temperatures are reported.

Preparation and x-ray diffraction structural analysis of rubidium neodymium nitrate, Rb3[Nd2(NO3)9

Preparation and x-ray diffraction structural analysis of rubidium neodymium nitrate, Rb3[Nd2(NO3)9

Sustained effect of and lack of development of tolerance to controlled-release isosorbide-5-mononitrate in chronic stable angina

Tolerance has been shown to develop when nitrate preparations are used in such a manner as to produce plasma levels within the therapeutic range continuously over a 24-hour period. However, a period of reduced or low nitrate plasma levels of a few hours per day may limit or completely prevent tolerance development. In 18 patients with chronic stable angina pectoris, a single 60-mg daily dose of a controlled-release preparation of isosorbide-5-mononitrate (ISMN) was compared with the administration of 30 mg, 4 times daily, of immediate-release isosorbide dinitrate (ISDN) in a double-blind, randomized, placebo-controlled, crossover study. The comparisons were carried out on the first day of therapy and after 11 to 14 days of continuous therapy to assess the duration of effectiveness and the development of tolerance. On short-term therapy, both drugs produced a significant improvement in treadmill walking times to moderate angina in comparison with placebo. The values for ISMN were 87 ± 99 seconds (23%) at 12:30 P.M., 72 ± 91 seconds (19%) at 5 p.m. and 51 ± 81 seconds (13%) at 8:30 P.M. For ISDN, the respective values were 71 ± 83 seconds (19%), 89 ± 98 seconds (24%) and 79 ± 87 seconds (21%). There were no significant differences between drugs. Plasma nitrate levels for each drug paralleled the improvements in exercise performance. After 11 to 14 days of sustained therapy, only ISMN retained any significant beneficial effects (61 ± 71 seconds [21%] at 12:30 p.m. and 42 ± 60 seconds [14%] at 5 P.M.), but no significant effect at 8:30 p.m., with plasma levels slightly higher than those achieved on short-term therapy. ISDN produced no effect at any time point. This loss of effectiveness for ISDN occurred despite a slight increase in serum nitrate levels in comparison with short-term dosing, at all time points. Thus, the use of controlled-release ISMN minimized the development of tolerance, presumably because the nitrate plasma levels decreased into the subtherapeutic range during the inactive hours of the late evening and night. ISMN provided significant antianginal effects both with short-term and sustained therapy for at least 8.5 hours after a single morning dose.