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PubMed1996

Investigation on the chemical stability of erythromycin in solutions using an optimization system.

Erythromycin, an antibiotic commonly used topically in the treatment of acne, is unstable in solution. The stability is influenced by the pH and by the presence of water. The influence of the pH on the stability of erythromycin was investigated even with the use of dimethyl isosorbide as co-solvent instead of water. The addition of zinc was attempted to ameliorate erythromycin stability as suggested in the literature. To investigate these three factors and their interactions, an optimization technique was carried out consisting of a 2(3) factorial analysis and a rotative central composite design. The erythromycin solutions were analysed with an HPLC method. The pH and the concentration of dimethyl isosorbide had a significant influence on the stability of erythromycin but the addition of zinc was not a significant factor. Moreover, there was a significant interaction between the pH and dimethyl isosorbide.

Anti-Bacterial Agents↗
PubMed1980

Effect of osmotic diuresis on gentamicin-induced nephrotoxicity in rats.

The effect of isosorbide diuresis on gentamicin excretion and tissue accumulation as well as gentamicin-induced histopathologic changes in renal tissue were examine in rats. Gentamicin (30, 60, 120, 160 mg/kg) was administered s.c. for 10 consecutive days with or without isosorbide pretreatment. Osmotic diuresis with isosorbide did not significantly reduce the dose-dependent extent of gentamicin accumulation in renal tissues in comparison to nondiuresed rats. Although the urinary concentration of gentamicin was reduced in the diuresed animals, total gentamicin excretion remained unaffected. In addition, diuresis altered neither the renal excretion of the proximal tubular cell marker enzyme, N-acetyl-B-glucosaminidase, nor the severity of pathologic damage as determined by light microscopic examination of renal tissues. It appears that osmotically-induced diuresis alone is insufficient to prevent or significantly reduce gentamicin nephrotoxicity in rats. This is in contrast to other forms of diuretic therapy, such as furosemide, which have been shown to effectively reduce renal accumulation and resultant renal toxicity of aminoglycoside administration.

Acetylglucosaminidase↗
PubMed1987

Pharmacokinetics and pharmacodynamics of organic nitrates.

The pharmacokinetic and pharmacodynamic aspects of organic nitrates are discussed, with particular emphasis on the 3 major organic nitrates currently in use, nitroglycerin (NTG), isosorbide dinitrate and isosorbide-5-mononitrate. After intravenous administration, both NTG and isosorbide dinitrate exhibit large systemic clearances and both nitrates appear to be extensively distributed in vascular and other peripheral tissues. Two pharmacokinetic features appear particularly notable for NTG: there is a significant arteriovenous extraction of the drug, and its systemic clearance is related to cardiac output. Both of these features, plus other evidence, suggest that organic nitrates may be substantially removed from the systemic circulation by the vasculature itself. During nitrate tolerance, plasma drug concentrations remain elevated, but vascular activity is diminished. This apparent paradox might be explainable by a unifying hypothesis of reduced nitrate metabolism during vascular tolerance; thus, in the tolerant state, reduced systemic clearance of the intact drug brought about elevated plasma concentrations, whereas reduced cellular metabolism at the smooth muscle brought about a decrease in vascular activity. The complex relations among plasma kinetics, vascular metabolism and pharmacologic action of organic nitrates are still poorly understood.

Animals↗
PubMed1983

Pharmacokinetics of nitroglycerin and long-acting nitrate esters.

The current literature on the human pharmacokinetics of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrates is briefly reviewed and evaluated. The pharmacokinetics of nitroglycerin are unusual in that its systemic clearance is extremely large and that there is a distinct arterial-venous gradient in plasma concentration. These features had created substantial difficulties in the documentation and interpretation of nitroglycerin plasma concentrations and pharmacokinetics. Studies with isosorbide dinitrate showed that this nitrate is absorbed as intact drug at about 20 percent of a comparable intravenous dose, firmly disproving a previous belief that orally administered nitrate is completely degraded by presystemic metabolism. The current data suggest that plasma nitrate concentration may relate to some of its pharmacologic effects after short-term dosing, but the concentration-response relationship is complex after long-term dosing. Studies of nitrate pharmacokinetics in their presumed sites of action, namely, the vasculature, appear to be useful for the further understanding of the mechanism of action for these vasodilators.

Absorption↗
PubMed1996

Epicardial coronary arteries are not adequately sized in hypertensive patients.

OBJECTIVES: This study sought to compare coronary artery dimensions in hypertensive patients and normal subjects. BACKGROUND: Myocardial oxygen demand at rest and corresponding coronary blood flow are the main determinants of large coronary artery dimensions in humans. Coronary diameters are increased in aortic valve disease. METHODS: Left main, proximal and distal left anterior descending and proximal circumflex coronary artery diameters were measured by quantitative angiography in 10 control subjects (group 1) and 26 untreated hypertensive patients, 12 without (group 2a) and 14 with (group 2b) left ventricular hypertrophy. All patients had normal cholesterol levels and angiographically normal coronary arteries. Measurements were made at baseline and after 2 mg of intracoronary isosorbide dinitrate to obtain maximal dimensions of vessels. Coronary flow velocity was measured in the distal left anterior descending coronary artery by Doppler ultrasound. RESULTS: Despite a higher rate-pressure product in hypertensive patients, all segment diameters were slightly but not significantly higher at baseline in group 2b than in groups 1 and 2a. Diameters were similar in the three groups after isosorbide dinitrate. Conversely, coronary flow velocity was significantly higher in hypertensive patients than in group 1 either at baseline (10.4 +/- 2.2 [mean +/- SD] cm/s [group 2a] and 12.8 +/- 2.4 cm/s [group 2b] vs. 6.5 +/- 2.0 cm/s [group 1], all p < 0.001) or after isosorbide dinitrate (6.8 +/- 2.8 cm/s [group 2a] and 7.8 +/- 2.1 cm/s [group 2b] vs. 3.7 +/- 0.8 cm/s [group 1], p < 0.01 and p < 0.001, respectively). CONCLUSIONS: Despite an elevated myocardial oxygen demand, maximal dimensions of large coronary arteries are not increased in hypertensive patients, resulting in an elevated coronary flow velocity that may increase longitudinal shear stress at the endothelial surface. This elevated flow velocity might be an important determinant in the pathogenesis of atherosclerosis in hypertensive patients.

Blood Flow Velocity↗
PubMed1996

Impaired endothelial function with essential hypertension assessed by ultrasonography.

The objective of this investigation was to evaluate the role of hypertension in endothelial function, changes in which are known to be an early event of atherosclerosis. We assessed endothelial function in 13 subjects with normal blood pressure and 13 subjects with essential hypertension who had never been treated for hypertension or hyperlipidemia and who had no history of smoking or coronary or cerebrovascular disease. B-mode ultrasonography was used to measure the diameter of the brachial artery. Endothelium-dependent dilatation was assessed as the change in diameter of the artery during reactive hyperemia. Endothelium-independent dilatation was evoked, as a control, by sublingual administration of isosorbide dinitrate. Despite similar ages and lipid and glucose levels in the study groups, endothelium-dependent dilatation was less in patients with hypertension (13.1% +/- 1.6%) than in subjects with normal blood pressure (18.5% +/- 1.9%) (p < 0.05), whereas isosorbide dinitrate-induced changes were similar. Systolic and diastolic blood pressure were significantly correlated with endothelium-dependent vasodilatation (r = -0.57 and r = -0.53, respectively) but not with the change by isosorbide dinitrate. These results suggest that endothelial dysfunction exists in patients with hypertension and precedes overt atherosclerotic disease.

Adult↗
PubMed1999

Vasomotor responses of coronary stenoses to acetylcholine and their relation to serum lipid levels in stable angina pectoris.

The effects of acetylcholine administration on coronary stenoses in relation to serum lipids level were evaluated in 18 patients (15 men, 3 women) with coronary artery disease and stable angina. Intracoronary acetylcholine was infused in concentrations 10(-7), 10(-6), 10(-5) M, followed by intracoronary bolus administration of isosorbide dinitrate. Computerized angiography was used to assess the changes in the diameter of stenoses and of proximal and distal segments. During acetylcholine infusion, at concentrations between 10(-7) to 10(-5) M, there was a significant (p <0.01) dose-dependent constriction of proximal and distal segments and of stenoses reversed by isosorbide dinitrate. There was no correlation between the serum total cholesterol level and the responses of proximal and distal segments to acetylcholine or nitrate. A correlation (p <0.05) was found between the serum total cholesterol level and the response of stenoses to acetylcholine, but there was no correlation with the response to isosorbide dinitrate. In conclusion, in patients with stable angina current serum total cholesterol level correlates with the vasomotor response of coronary stenoses to intracoronary acetylcholine. These findings are consistent with a direct effect of cholesterol, increasing basal coronary vasomotor tone and increasing the stimulated vasoconstrictor response of stenoses.

Acetylcholine↗
PubMed1999

Isoforms of cytochrome P450 on organic nitrate-derived nitric oxide release in human heart vessels.

Glutathione S-transferases and the cytochrome P450 system have been proposed for the vascular biotransformation systems in the metabolic activation of organic nitrates. The present study was designed to elucidate the role of human cytochrome P450 isoforms on nitric oxide formation from organic nitrates using lymphoblast microsomes transfected with human CYP isoforms cDNA. CYP3A4-transfected microsomes had the most effective potential of nitric oxide formation from isosorbide dinitrate. Anti-CYP3A2 antibody (which cross-reacts with CYP3A4) or ketoconazole (an inhibitor of the CYP3A superfamily) inhibited nitric oxide formation from isosorbide dinitrate in rat heart microsomes. Immunohistochemistry of human heart also showed intense bindings of CYP3A4 antibody in the endothelium of the endocardium and coronary vessels. These results suggest that the CYP3A4-NADPH-cytochrome P450 reductase system specifically participates in nitric oxide formation from isosorbide dinitrate.

Animals↗
PubMed2001

Pharmacological modulation of human gastric volumes demonstrated noninvasively using SPECT imaging.

Three-dimensional single-photon emission computed tomography (SPECT) imaging allows noninvasive measurement of human postprandial gastric accommodation. The aim of this study was to determine whether 99mTCO4-SPECT demonstrates effects on pre- and postprandial gastric volumes of intravenous (i.v.) erythromycin lactobionate and sublingual isosorbide dinitrate, as predicted from previous literature. Twenty volunteers received no medication (controls), while 12 were randomized to either i.v. erythromycin 2 mg kg-1 over 20 min, or 10 mg sublingual isosorbide. After a 10-min preprandial SPECT measurement, a standard 300-mL, 300-kcal liquid meal was ingested, followed by a 20-min postprandial measurement. Gastric images were reconstructed from transaxial images and total volume was measured using the Analyseeth software system. Fasting gastric volume was greater with isosorbide [223 +/- 14 (SE) mL vs. 174 +/- 9 mL, control; P < 0.05], and postprandial volume was lower with erythromycin [393 +/- 27 mL vs. 582 +/- 17 mL, control; P < 0.05]. The ratio of postprandial over fasting volume and mean difference between pre- and postprandial volumes were significantly lower in both drug groups compared to controls. We conclude that 99mTCO4-SPECT imaging is able to semiquantitatively demonstrate pharmacological modulation of fasting gastric volume and postprandial accommodation in humans.

Administration, Sublingual↗
PubMed1998

The effect of a nitric oxide donor on Doppler flow velocity waveforms in the uterine artery during the first trimester of pregnancy.

Our objectives were to study the effect of a nitric oxide donor on uterine blood flow velocity waveforms and maternal heart rate and blood pressure during the first trimester of pregnancy. Eleven women were examined at 8-12 weeks' gestation, prior to elective termination of pregnancy. Each woman was randomly given a sublingual tablet containing 5 mg of isosorbide dinitrate or placebo, on two consecutive days. Measurements of maternal blood pressure, heart rate and Doppler flow velocity waveforms of the ascending branch of the main uterine artery were obtained before, and every 2 min (for 20 min) after taking the drug or placebo. Following administration of isosorbide dinitrate, the mean arterial blood pressure fell from a control value of 82.5 +/- 5.6 mmHg to a nadir of 73 +/- 4.1 mmHg at 16 min (p < 0.0001). The mean maternal heart rate increased from a control value of 80.9 +/- 2.8 beats/min to a peak of 90.4 +/- 4.6 beats/min at 10 min (p < 0.001). The mean resistance index in the uterine artery fell from a control value of 0.80 +/- 0.02 to a nadir of 0.73 +/- 0.03 at 10 min (p < 0.0001). Analysis of covariance was employed to compensate for the effect of heart rate on the resistance index. The drug had a significant effect on the resistance index in the uterine artery, independent of maternal heart rate. These results suggest that drugs such as isosorbide dinitrate may have a potential benefit under such conditions where the production of nitric oxide (i.e. endothelium-derived relaxing factor) is decreased.

Adult↗
PubMed1975

[Long-term action of nitrites in coronary heart disease (author's transl)].

Haemodynamic investigations were performed before and after oral ingestion of nitroglycerine and isosorbide dinitrate, both in depot form, in eleven and nine patients, respectively, with coronary heart disease. Nitroglycerine (5 mg) led to a significant decrease in arterial and pulmonary artery mid-pressure over one to two hours. Heart rate and mean pulmonary capillary pressure as well as cardiac output and stroke volume hardly changed. After ingestion of isosorbide dinitrate (20 mg) there was a continuous and significant fall in mean arterial, pulmonary artery, and pulmonary capillary pressure already demonstrable during the first hour. Cardiac output and left ventricular work decreased accordingly for up to four hours. At the same time the cardiac output remained constantly lowered over four hours despite the significant increase in frequency. Isosorbide dinitrate has thus a more complete and longer lasting protective haemodynamic effect than nitroglycerine.

Blood Pressure↗
PubMed1986

[Dose-dependent serum concentration of ISDN and its metabolites following administration of ISDN-retard. Studies under steady-state conditions].

In a randomized cross-over trial of four groups of patients (total 49 patients) the serum concentrations of isosorbide dinitrate (ISDN), isosorbide-2-mononitrate (IS-2-MN) and isosorbide-5-mononitrate (IS-5-MN) were measured under steady-state conditions after administration of 20, 40, 60 and 80 mg, respectively, of two ISDN preparations, the two being bioequivalent. At the studied dosage there was a linear relationship between dose and serum concentration of ISDN and its two metabolites in the proportion of 1:6:70. Because the serum concentration of IS-5-MN is so high under steady-state conditions, there is the potential problem of tolerance developing. The drug should therefore be administered at a lower dose twice daily.

Aged↗
PubMed1987

Intermittent coronary occlusion in acute myocardial infarction. Value of combined thrombolytic and vasodilator therapy.

We performed continuous electrocardiographic ST-segment monitoring and serial coronary arteriography in 45 consecutive patients presenting in the early stages of acute myocardial infarction. During cardiac catheterization, 28 episodes of arteriographically confirmed coronary reopening and subsequent reocclusion were observed in 16 patients before (3 episodes) and during (25 episodes) continuous intracoronary infusion of streptokinase. In addition, ST-segment monitoring demonstrated 12 episodes of spontaneous transient return of the ST segment to the base line in eight patients between the time of admission and the performance of coronary arteriography. During arteriographically documented reocclusion, intracoronary isosorbide dinitrate (2 mg) reestablished the patency of the coronary artery within one to two minutes in 14 of 28 episodes that occurred in 11 of 16 patients. After streptokinase infusion, intracoronary administration of isosorbide dinitrate was followed by dilatation of the infarct-related stenosis from a mean value (+/- SD) of 1.12 +/- 0.3 mm (58.1 +/- 12.1 percent) to 1.33 +/- 0.4 mm (51.6 +/- 12.9 percent; P = 0.004). Spontaneous intermittent coronary recanalization and reocclusion resulting from a variable combination of thrombosis and vasoconstriction are frequent during the early phase of acute myocardial infarction. We propose that the combination of intracoronary streptokinase and isosorbide dinitrate may increase the rate of stable coronary recanalization.

Adult↗
PubMed2002

Nitric oxide induced cervical ripening in the human: Involvement of cyclic guanosine monophosphate, prostaglandin F(2 alpha), and prostaglandin E(2).

OBJECTIVE: The purpose of the study was to investigate possible mechanisms and morphologic changes involved in nitric oxide-induced cervical ripening. STUDY DESIGN: Women scheduled for surgical termination of first trimester pregnancy were randomized to 1 of 3 groups: isosorbide 5-mononitrate 40 mg 4 hours or 10 hours before the operation or no preoperative treatment. Cervical specimens were obtained for the analysis of tissue levels of cyclic guanosine monophosphate, cyclic adenosine monophosphate, cyclo-oxygenase 1, cyclo-oxygenase 2, prostaglandin F(2 alpha), and prostaglandin E(2) or were fixed in glutaraldehyde for microscopy. RESULTS: Increased levels of cyclic guanosine monophosphate, cyclo-oxygenase 2, prostaglandin F(2 alpha), and prostaglandin E(2) were found in samples that were exposed to isosorbide 5-mononitrate compared with control samples. Electron microscopy revealed stromal edema and collagen disorganization after isosorbide 5-mononitrate treatment. CONCLUSION: Cyclic guanosine monophosphate, prostaglandin F(2 alpha), and prostaglandin E(2) are involved in nitric oxide-induced cervical ripening. Nitric oxide causes morphologic changes similar to those changes seen during spontaneous cervical ripening.

Cervical Ripening↗
PubMed1992

Nitrate tolerance. How to prevent it or minimize its effect.

Continuous therapy with nitrates rapidly produces tolerance along with loss or diminution of circulatory, antianginal, and anti-ischemic effects. Development of tolerance can be avoided by various approaches. In patients with stable angina, intermittent use of nitrates with long nitrate-free intervals, use of transdermal nitroglycerin during the day or oral isosorbide dinitrate or isosorbide-5-mononitrate twice daily in the morning and early afternoon, and intermittent use of nitrates in combination with another class of antianginal agent are appropriate. In patients with unstable angina, continuous therapy with intravenous nitroglycerin is recommended during the acute phase of angina. Despite development of partial tolerance, oral isosorbide dinitrate, 30 to 60 mg four times a day, plus hydralazine may be useful for patients with congestive heart failure who cannot tolerate angiotensin-converting enzyme inhibitors. Concomitant use of sulfhydryl donors or angiotensin-converting enzyme inhibitors, agents that might theoretically prevent nitrate tolerance, is not recommended. Data on these agents are conflicting, and added costs and adverse effects are likely to preclude their use in the future.

Angina Pectoris↗
PubMed1986

An indirect approach for the study of the elastic modulus of the brachial artery in patients with essential hypertension.

An indirect approach for the study of the changes in the incremental circumferential modulus (E) of the brachial artery after arteriolar vasodilatation was undertaken in patients with sustained essential hypertension. The product of E and the thickness (h) of the arterial wall was evaluated by means of the Moens-Korteweg equation using determinations of brachioradial pulse wave velocity and brachial artery diameter with pulsed Doppler methods. In three homogeneous groups of patients with hypertension the Eh product was studied after vasodilatation caused either by nitrendipine, a calcium entry blocking agent, or by medroxalol, an alpha and beta blocking agent, or by isosorbid dinitrate. The three drugs caused similar reductions in blood pressure and increases in arterial diameter and hence decreases in wall thickness. Variance analysis for multigroups indicated that the decrease in Eh after vasodilatation was significant for nitrendipine but not for medroxalol and isosorbid dinitrate. Covariance analysis showed that for any level in Eh product the decrease in Eh was higher for nitrendipine than for isosorbid dinitrate and medroxalol. Since the three drugs had comparable mechanical and geometrical effects, the study provided evidence that, in men with essential hypertension, the smooth muscle tone of the brachial artery was significantly more sensitive to calcium inhibition than to autonomic blockade, causing a more important decrease in elastic modulus.

Adult↗
PubMed1988

Coronary constriction in acute myocardial infarction: role of nitrates.

We have investigated the coronary vasodilator responses to nitrates in the early stages of acute myocardial infarction before, during and after the administration of thrombolytic therapy. Before thrombolysis, intracoronary doses (2-4 mg) of isosorbide dinitrate failed to induce recanalisation of the totally occluded infarct related artery. Episodes of coronary reopening and reocclusion associated with ST-segment resolution and re-elevation were frequently observed both spontaneously before and during thrombolytic therapy. In 50-86% of patients, intracoronary isosorbide dinitrate promptly re-established full coronary patency immediately after acute reocclusion or whenever coronary occlusion was incomplete, both before and during thrombolysis. After thrombolysis further intracoronary isosorbide dinitrate dilated the infarct related stenoses but not uninvolved adjacent normal coronary branches. Coronary thrombosis and constriction frequently interact during the early phases of acute myocardial infarction. The combination of high local concentrations of nitrates with thrombolytic agents promotes stable coronary recanalization and may be beneficial in patients with acute myocardial infarction.

Coronary Vessels↗
PubMed1988

Pharmacokinetics of organic nitrates in man: an overview.

The pharmacokinetics of glyceryl trinitrate are still not completely understood. The substance disappears rapidly from plasma largely by extrahepatic mechanisms. It is converted in glyceryl dinitrates and glyceryl mononitrates. After transdermal application of a controlled delivery system, plasma concentrations of glyceryl trinitrate can be maintained over the time period of application but, as for other routes, there are important intra- and inter-individual variations and fluctuations. Isosorbide dinitrate disappears less rapidly from the body; it is converted to the isosorbide mononitrates. Plasma concentrations of isosorbide dinitrate and mononitrates are quite predictable in different circumstances, e.g. on application of oral sustained release formulations. Measurement of the plasma concentrations of nitrates has been used to characterize different preparations and routes of administration. However, these plasma concentrations cannot be used to predict the effect, probably because of the important counter-regulation and tolerance which develop rapidly after administration of the drugs.

Absorption↗