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PubMed1983

Analysis of oral molsidomine effects on ventricular function and dimensions in the conscious dog.

The effects of oral administration of molsidomine (50, 100 and 250 micrograms/kg) on left ventricular function, dimensions and hemodynamics were studied in chronically equipped, resting conscious dogs and compared to those of orally administered nitroglycerin (5, 10 and 20 micrograms/kg), as well as isosorbide dinitrate (50, 100 and 250 micrograms/kg). Enteral absorption of molsidomine was similar to that following intravenous administration of the compound, but was delayed in the case of both nitrates, so that restraint hemodynamic effects were noted. Molsidomine significantly decreased ventricular preload and internal heart dimensions. These effects were longer-lasting and more pronounced than those induced by either nitrate compound. Heart rate and LV dP/dtmax remained unaffected by molsidomine but increased in a dose-dependent fashion after administration of the nitrates. Left ventricular ejection phase contractility decreased with all three compounds. This effect was probably due to the reduced ventricular volumes and dimensions caused by molsidomine and isosorbide dinitrate, and to the additional tachycardia with concomitant reduction in ejection phase induced by nitroglycerin. Ejection time and stroke volume fell with all three agents but the effect occurred with a greater delay of onset and was more persistent after molsidomine. Nitroglycerin was found to increase cardiac output, initially, as a sequel of positive inotropy and chronotropy, with a subsequent decrease of cardiac output. In contrast, cardiac output fell by 28% and 30% (p less than 0.02) after administration of 250 micrograms/kg molsidomine or isosorbide dinitrate, respectively. These results suggest that molsidomine has no direct effects on myocardial hemodynamics and function in the resting, awake dog. The drug exerts its beneficial effects on heart performance by a long-lasting diminution of cardiac preload caused preferentially by dilatation of postcapillary venous vessels.

Administration, Oral↗
PubMed1983

Newer aspects of the pharmacokinetics of organic nitrates.

Plasma drug and metabolite concentrations were measured after single oral doses of 40 mg sustained-release 14C-isosorbide dinitrate to humans. The bioavailability of isosorbide dinitrate from this sustained-release formulation was about 90% of that from a standard formulation. The pharmacokinetics of isosorbide-5-mononitrate were studied in humans after intravenous infusion (8 mg/h) and oral doses of 20 mg. The systemic availability of the drug after oral doses was 93%, its systemic clearance was 127 ml/min, its volume of distribution was 48.5 liters and its half-life was 4.4 h.

Biological Availability↗
PubMed1995

Comparison of gastric mucosal blood flow in normal subjects and in patients with portal hypertension using endoscopic laser-Doppler velocimetry.

OBJECTIVE: To compare gastric mucosal blood flow (GMBF) in normal subjects with that in patients with portal hypertension with or without portal hypertensive gastropathy (PHG). METHODS: GMBF was measured by endoscopic laser-Doppler velocimetry in 20 gastroscopically normal subjects and 30 patients with portal hypertension with or without PHG. The effects of breath-holding (vasomotor reflex), submucosal epinephrine and sublingual isosorbide dinitrate were also studied. RESULTS: In normal subjects, GMBF on the greater curvature was (mean +/- SD) 9.5 +/- 1.3 V and on the lesser curvature, 9.1 +/- 1.9 V. Breath-holding caused a reduction in GMBF by 57.1 +/- 13.7%, submucosal epinephrine reduced it by 41.5 +/- 21.5% and sublingual isosorbide caused a rise of 25.8 +/- 15.2%. The GMBF on the greater and lesser curvature respectively in patients with mild PHG (7.7 +/- 1.2 V and 7.7 +/- 0.8 V) and those with severe PHG (6.5 +/- 3.5 V and 6.3 +/- 2.2 V), was significantly less than that in normal subjects (p < 0.05 and p < 0.001 respectively). Vasomotor reflex was blunted in patients with mild and severe PHG (23.3% +/- 20.3 and 23.1% +/- 17.7 respectively, p < 0.001). Responses to submucosal epinephrine and sublingual isosorbide were similar to those recorded in normal subjects. CONCLUSIONS: Patients with portal hypertension have significantly reduced GMBF and significantly attenuated vasomotor reflex in the gastric vascular bed as compared to normal subjects.

Adult↗
PubMed1976

[Hemodynamic and electrocardiographic prolonged nitrate effect during frequency load in coronary disease].

Hemodynamic and electrocardiographic analysis during rapid right atrial stimulation was performed before and one, two, and four hours after oral application of longacting nitroglycerin (5 mg) and isosorbide dinitrate (20 mg) in 11 and 9 patients, respectively with coronary heart disease. Atrial stimulation without nitrate induced significant ischemic ST segment depression. Cardiac output showed a small decrease and the mean arterial, pulmonary artery, and pulmonary wedge pressure increased. Isosorbide dinitrate reduced the ischemic reaction by 40% from the first to the fourth hour after application. Cardiac output, stroke volume, aterial, pulmonary artery, and pulmonary wedge pressure also decreased continuously. Nitroglycerin caused a similar reduction of ischemic ST segment depression for two hours. Systolic, diastolic, and mean arterial pressure decreased significantly. Cardiac output, stroke volume, and pulmonary artery pressure remained unchanged. It was concluded that the applied dose of isosorbide dinitrate showed a more extensive longacting effect.

Blood Pressure↗
PubMed1996

[Are beta-blockers generally contraindicated in patients with peripheral arterial occlusive disease?].

Ninety patients with chronic ischemic heart disease and stage IIb peripheral arterial occlusive disease were investigated to determine the effect of celiprolol, atenolol and isosorbide dinitrate on peripheral arterial blood flow. Walking distance and the resistance index in the femoral artery were measured before and after 3 months medication and compared with the findings in controls (30 patients with chronic ischemic heart disease and stage IIb peripheral arterial occlusive disease) who received placebo. Patients with peripheral arterial occlusive disease who were treated with atenolol 50 mg/day demonstrated significant decreases in both pain-free and maximal walking distance. In contrast, the walking distances in those given celiprolol 200 mg/day and those who received isosorbide dinitrate 80 mg/day did not differ from the distances in control subjects. The Doppler flow through the femoral artery, as measured by color duplex sonography, showed a significant decrease in resistance index, both in patients given celiprolol and in those given isosorbide dinitrate. In patients treated with atenolol the resistance index rose significantly. The results of this study confirm that the beta-adrenoceptor blocker celiprolol exerts a supplementary vasodilatory action resembling that of nitrates and hence can be used in patients with chronic ischemic heart disease and impaired peripheral arterial perfusion.

Adrenergic beta-Antagonists↗
PubMed1997

Beta-blockers and nitrates in patients with peripheral arterial occlusive disease: long-term findings.

METHODS: The effect of 6 months' administration of celiprolol, atenolol and isosorbide dinitrate on peripheral arterial occlusive disease (PAOD), double-blind and placebo-controlled, was investigated in 56 patients with chronic ischaemic heart disease and stage IIb PAOD, using as criteria the walking distance and the change in resistance index in the femoral artery. The placebo group consisted of 14 patients with chronic ischaemic heart disease and the same stage of PAOD. RESULTS: Patients on 50 mg/day atenolol showed a significant reduction in both pain-free and maximal walking range compared with the controls. In contrast, those taking 200 mg/day celiprolol and those on 80 mg/day isosorbide dinitrate demonstrated significant increases in pain-free and maximal, walking distance compared with the control group. The colour duplex sonographically measured Doppler flow through the femoral artery showed a significant decrease both in the patients taking celiprolol and in those on isosorbide dinitrate, while in those receiving atenolol the resistance index increased significantly. CONCLUSIONS: The study shows that the beta-adrenoceptor blocker celiprolol also possesses a nitrate-like vasodilatory property and can be used in patients with chronic ischaemic heart disease and impaired peripheral arterial blood flow.

Adrenergic beta-Antagonists↗
PubMed1997

Nitrate tolerance, rebound, and their clinical relevance in stable angina pectoris, unstable angina, and heart failure.

Vascular tolerance develops rapidly in isolated vascular strips exposed to millimolar concentrations of nitroglycerin. Several mechanisms, including depletion of sulfhydryl groups, reduced biotransformation of nitrates to NO or nitrosothiols, oxygen free radical injury, and downregulation of a membrane-bound enzyme or a nitrate receptor, have been proposed, but the exact mechanism responsible for in-vitro tolerance remains unknown. In-vivo tolerance of the beneficial effects of nitrates on hemodynamics, myocardial ischemia, and exercise performance develops rapidly. It has been suggested, but remains to be proven, that development of venous tolerance and not arterial tolerance is responsible for the attenuation of nitrate effects during long-term nitrate therapy. Several mechanisms, including neurohormonal activation, depletion of sulfhdryl groups, and the shift of fluid from the extravascular to intravascular compartment have been implicated. However, the use of agents to counteract these mechanisms (ACE inhibitors, sulfhydryl donors, diuretics) has produced conflicting results. Thus, at present the mechanism responsible for in vivo tolerance to nitrates remains unknown. Both in vitro and in vivo vascular tolerance to nitrates can be prevented or minimized by providing nitrate-free or low-nitrate intervals. However, during nitrate-free periods, rebound phenomena (rest angina in patients with ischemic heart disease or a deterioration in exercise performance prior to the renewal of the morning dose in patients with stable angina) remain a clinical concern. When treating patients with stable angina pectoris, it must be recognized that none of the nitrate preparations or formulations can provide round-the-clock antianginal or antiischemic prophylaxis. In these patients, beneficial antianginal and antiischemic effects of nitrates for 10-14 hours during the daytime can be maintained by using formulations and dosing regimens that avoid or minimize the development of tolerance (standard formulation of isosorbide-5-mononitrate, 20 mg in the morning and 7 hours later; slow-release formulation of isosorbide-5-mononitrate, 120-240 mg once a day; or nitroglycerin patch delivering 0.6 nitroglycerin per hour for 10-12 hours each day). Only the patch on and off treatment is associated with nitrate rebound. Although intermittent nitrate therapy is not associated with the development of tolerance, this strategy cannot be recommended for treating unstable angina because rebound angina during nitrate-free periods complicates clinical decision making. In the acute phase of unstable angina, continuous treatment with intravenous nitroglycerin is recommended because it permits rapid up- or down-titration. Tolerance towards antianginal and antiischemic effects does develop in a substantial number of patients with 24 hours, but this can be overridden by dose escalation and restoration of the therapeutic effectiveness of nitroglycerin. Tolerance towards the beneficial effects of nitrates on hemodynamics and on exercise performance also develops rapidly during continuous or long-term nitrate therapy, and for these reasons nitrates are not used as first-line therapy to treat chronic heart failure. In combination with hydralazine, high-dose isosorbide dinitrate (30-40 mg four times a day) improves survival, but this combination therapy is inferior to ACE inhibitors.

Angina Pectoris↗
PubMed1992

Role of nitrates in angina pectoris.

Nitrates are used extensively for the treatment of angina pectoris. However, continuous therapy with either oral nitrates or nitroglycerin patches leads to rapid development of tolerance, with loss or diminution of antianginal and anti-ischemic effects. The only practical way to avoid the development of tolerance is to use intermittent daily therapy with nitrates. Nitroglycerin patches applied for 10-12 hours during the day increase exercise duration for 8-12 hours, but a rebound increase in anginal attacks during the nitrate-free interval may occur. Oral isosorbide-5-mononitrate, 20 mg twice a day, with the first dose administered in the morning and the second dose 7 hours later, increases exercise duration for at least 12 hours without the development of tolerance to either the morning or afternoon dose. This dosing regimen has been shown not to produce a rebound phenomenon during the periods of low nitrate levels at night and early hours of the morning. Isosorbide dinitrate (30 mg) prescribed at 7 AM and 1 PM does not produce tolerance to the 7 AM dose, but effects of the afternoon dose have not been evaluated. Recent data suggest that isosorbide dinitrate given 3 or 4 times daily produces tolerance and this dosing schedule is inadequate for antianginal prophylaxis. It should be recognized that intermittent oral or patch therapy with nitrates during the day leaves the patient unprotected at night and early hours of the morning. If this is of concern, additional therapy with another class of antianginal agent, preferably a long-acting beta blocker or a long-acting calcium antagonist should be instituted.

Angina Pectoris↗
PubMed1983

Metabolism and disposition of 2',3'-di-O-nitro-adenosine-5'-(N-ethyl-carboxamide) in dogs.

2',3'-Di-O-nitro-[8-3H]-adenosine-5'-(N-ethyl-carboxamide) (20 micrograms/kg) was denitrated completely within 1-3 hr in perorally and intravenously dosed dogs. Extremely rapid disappearance of the unchanged drug in serum was parallelled by the instantaneous appearance of mononitrates with 3'-mononitrate levels exceeding those of 2'-mononitrate three-fold. The mononitrates were eliminated with a half-life of 30-70 min, giving rise to the completely denitrated product, adenosine-5'-(N-ethyl-carboxamide) (NECA). The latter product was not further metabolized and was eliminated with a half-life of about 4 hr. Urinary excretion averaged 50% of the administered dose within 4 days and was represented essentially by the completely denitrated drug. Volatile 3H-label of the drug was found in serum and urine during in vivo experiments. Oral bioavailability of the drug was about 90%. In vitro studies indicated that thiols are involved in denitration and reactions are catalysed by glutathione S-transferases, which were partially purified from dog liver. Nitrate ester cleavage was more easily accomplished at the 2'-position than at the 3'-position of the drug and resulted in the liberation of inorganic nitrite. Comparison of in vitro denitration rates gave the following ranking order; 2',3'-di-O-nitro-NECA greater than isosorbide-2,5-dinitrate greater than 2'-nitro-NECA greater than 3'-nitro-NECA greater than isosorbide-2-mononitrate, while nitrate ester cleavage of isosorbide-5-mononitrate was not detectable.

Adenosine↗
PubMed1993

Direct inhibition of platelet function by organic nitrates via nitric oxide formation.

This study investigates the mechanisms of platelet inhibition by the nitrate esters isosorbide dinitrate, isoidide dinitrate, isomannide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate as compared to the spontaneous nitric oxide (NO)-donor linsidomine, the active metabolite of molsidomine. Nitrates and linsidomine dose-dependently inhibited aggregation, ATP secretion and thromboxane formation of washed human platelets at a rank order of potency, identical with that for stimulation of cyclic GMP in cultured rat lung fibroblasts. While linsidomine (0.1 mM) caused a 3-fold platelet cGMP elevation, there was a weak (< or = 30%) but significant cGMP stimulation by organic nitroesters, which was tightly correlated with inhibition of platelet aggregation (r = 0.926, P = 0.008). Zaprinast (2 microM) potentiated, while methylene blue (1 microM) and oxyhemoglobin (10 microM) reversed the antiaggregatory effects. Linsidomine (0.5 microM-0.1 mM) dose-dependently released NO in a cell-free system. No spontaneous NO release was detected with organic nitroesters (0.1 mM). These data suggest that, to some extent, bioactivation of organic nitroesters occurs in platelets, resulting in platelet inhibition via the NO/cGMP system.

Adenosine Triphosphate↗
PubMed2004

The effect of nitric oxide on the resting tone and the contractile behaviour of the external urethral sphincter: a functional urodynamic study in healthy humans.

AIMS: This functional urodynamic study assessed the effect of the nitric oxide donor isosorbide dinitrate on the external urethral sphincter and hypothesised first that nitric oxide could lower the resting sphincter pressure, second that nitric oxide could influence the sphincter contractility during magnetic stimulation, and third that nitric oxide could induce a faster external urethral sphincter fatigue during continuous magnetic stimulation. METHODS: Eight healthy males gave their written informed consent and were included. A 2-channel microtip pressure transducer catheter was inserted into the urethra measuring the bladder and the external urethral sphincter pressure. Magnetic stimulation of the sacral roots was performed to evoke reproducible contractions of the external urethral sphincter. The baseline protocol included six single pulse stimulations and three stimulations 10sec in duration each for two frequencies 5Hz and 50Hz with intensities at the motor threshold of the pelvic floor. Then the subjects received 10 mg of isosorbide nitrate sublingually and the protocol was repeated 5min, 20min, 40min and 60min after drug administration. RESULTS: The sublingual administration of isosorbide dinitrate could significantly reduce the resting pressure of the external urethral sphincter for at least one hour. The maximal contractile strength measured as the maximal urethral pressure during single pulse and continuous magnetic stimulation of the sacral roots also decreased significantly. Nitric oxide did not induce a significantly faster fatigue of the external urethral sphincter during continuous magnetic stimulation of the sacral roots. CONCLUSIONS: This study shows a functionally relevant effect of nitric oxide on the resting tone and the contractile behaviour of the human external urethral sphincter in vivo while the fatigue properties did not changed significantly. Nitric oxide donors could offer a new pharmacological approach to treat urinary retention due to overactive or non-relaxing external urethral sphincter.

Adult↗
PubMed1993

New approaches in the pharmacologic treatment of portal hypertension.

To alleviate the risk of variceal bleeding, the portal pressure gradient--usually evaluated as the hepatic venous pressure gradient (HVPG)--must be reduced to < or = 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to < or = 12 mmHg in only 12% of patients, while only 24% of patients have a > or = 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1997

Medial elastic structure alterations in atherosclerotic arteries in minipigs: plaque proximity and arterial site specificity.

Using a model of atherosclerosis in minipigs, we analyzed changes in elastic structure within the medial sections of the abdominal aorta and left interventricular coronary artery both in the vicinity of and distal to atheromatous plaques. Twenty-four animals, divided into three groups, were fed either a control diet or a hypercholesterolemic and hyperhomocysteinic atherogenic diet, alone or in association with an antihypertensor, namely isosorbide dinitrate (Risordan). The atherogenic diet, administered for a period of four months, induced in the minipig advanced noncalcified atherosclerotic lesions that were histologically similar to those found in humans. A morphodensitometric analysis of the medial elastic structures was carried out on images obtained from specifically stained transverse arterial sections examined under a light microscope. The volume density of the elastic structures was diminished in the arterial media of the atherosclerotic animals due to opening and widening of the fenestrae in the elastic laminate and increased communication between the interlamellar spaces. Whereas this elastolytic process was uniform and independent of the proximity of atheromatous plaques in the left interventricular coronary artery, it was intensified in the vicinity of the plaques in the abdominal aorta. Overall elastolytic activity was increased in the walls of atheromatous artery in both arterial sites, and metalloproteinases were implied in this increase of activity. We previously reported that treatment with isosorbide dinitrate significantly reduced the moderate systolic hypertension and the increase in transparietal stress observed in the abdominal aorta of atheromatous animals. We report here that isosorbide dinitrate prevented the atherogenic-diet-induced deterioration of the elastic structure in these arteries; complete inhibition of changes to the elastic laminae was evident in areas remote from plaque formation, but only partial inhibition in the vicinity of such plaques. It did not, however, prevent structural damage in the left interventricular coronary artery or modify the increase in parietal elastolytic activity in either of the two arteries. This suggests that damage to the elastic structure in atheromatous arteries is dependent not only on overall elastolytic activity but also on localized factors, possibly related to parietal stresses, affected by the presence of atheromatous plaques.

Amino Acids↗
PubMed1993

Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms.

BACKGROUND: A group of patients has been described who have chest pain resembling angina and positive exercise tests, but normal coronary angiograms and no coronary-artery spasm. This constellation of features has sometimes been called syndrome X or microvascular angina. We attempted to determine whether endothelium-dependent vasodilatation of the coronary vasculature was impaired in patients with this syndrome. METHODS: We infused the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilators papaverine and isosorbide dinitrate into the left coronary artery of 9 patients and 10 control subjects. The diameter of the left anterior descending coronary artery was assessed by quantitative angiography, and changes in coronary blood flow were estimated with the use of an intracoronary Doppler catheter. RESULTS: Acetylcholine, given in doses of 1, 3, 10, and 30 micrograms per minute, increased coronary blood flow in a dose-dependent manner in both groups. However, the mean (+/- SD) acetylcholine-induced increases in coronary blood flow were significantly less (P < 0.001) in the patient (8 +/- 14, 37 +/- 37, 59 +/- 67, and 103 +/- 77 percent, respectively) than in the controls (62 +/- 52, 186 +/- 93, 341 +/- 128, and 345 +/- 78 percent, respectively). The changes in coronary blood flow in response to 2 mg of isosorbide dinitrate (236 +/- 66 percent vs. 280 +/- 56 percent) and 10 mg of papaverine (366 +/- 168 percent vs. 411 +/- 92 percent) did not differ significantly between the patients and controls. The administration of papaverine resulted in myocardial lactate production in the patients but not in the controls. The three lower doses of acetylcholine caused a similar degree of dilatation of the left anterior descending coronary artery in the two groups, and the highest dose caused a similar degree of constriction in the two groups. Isosorbide dinitrate and papaverine caused a similar degree of dilatation in both groups. CONCLUSIONS: These findings suggest that endothelium-dependent dilatation of the resistance coronary arteries is defective in patients with anginal chest pain and normal coronary arteries, which may contribute to the altered regulation of myocardial perfusion in these patients.

Acetylcholine↗
PubMedDate not supplied

Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement.

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.

Administration, Cutaneous↗
PubMed1992

Active and passive effects of antihypertensive drugs on large artery diameter and elasticity in human essential hypertension.

The effects of antihypertensive drugs on the large arteries consist of two parts: the passive effect due to the change in pressure and the active effect, the drug action per se. This study proposes a method of dissociating the passive effect from the active effect. The diameter of the arterial artery was determined by the pulsed Doppler method and the pulse wave velocity of the brachioradial artery by mecanography. Arterial compliance was calculated by the Bramwell-Hill formula. Active and passive effects were determined by a logarithmic pressure-diameter model. This model was supported by in situ direct measurements of blood pressure and diameter in a segment of the femoral artery in dogs. Six drugs, cadralazine, ketanserin, medroxalol, nitrendipine, captopril, and isosorbide dinitrate, administered orally, were tested in 70 essential hypertensive patients. For all drugs, the pressure reduction induced a passive decrease in arterial diameter (p less than 0.02 to p less than 0.01). Cadralazine actively decreased arterial diameter (p less than 0.01), ketanserin had no active effect on diameter, and medroxalol, nitrendipine, captopril, and isosorbide dinitrate actively increased arterial diameter (p less than 0.05, p less than 0.01, p less than 0.01, and p less than 0.01, respectively). For all drugs, the pressure reduction also induced a passive increase in arterial compliance (p less than 0.05 to p less than 0.01). However, only nitrendipine, captopril, and isosorbide dinitrate actively increased arterial compliance (p less than 0.01, p less than 0.05, and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

The effects of organic nitrates on osteoporosis: a randomized controlled trial [ISRCTN94484747].

BACKGROUND: Osteoporotic fractures are common and are associated with increased morbidity, mortality and health care costs. The most effective way to moderate increases in health care costs and the sickness and premature death associated with osteoporotic fractures, is to prevent osteoporosis. Several lines of evidence suggest that nitrates, drugs typically prescribed for the treatment of angina, may be effective in preventing postmenopausal osteoporosis. METHODS: We have designed a multicentre randomized controlled trial to determine the effects of nitrates on bone. The trial consists of two studies. The objective of the first study is to determine whether isosorbide mononitrate at 20 mg/day or nitroglycerin ointment at 15 mg/day leads to fewer headaches. The nitrate that is best tolerated will be used in a second study with one main objective: To determine if postmenopausal women with a T-score at the lumbar spine (L1 to L4) between 0 and -2.0 randomized to two years of treatment with intermittent nitrates have a greater increase in spine bone mineral density as compared to women randomized to placebo. We hypothesize that: 1. Women will report fewer headaches when they are randomized to intermittent nitroglycerin ointment at 15 mg/day compared to intermittent oral isosorbide mononitrate at 20 mg/day, and, 2. After two years, women randomized to intermittent nitrates will have a greater percent increase in lumbar spine bone mineral density compared with women randomized to placebo. DISCUSSION: We have completed our pilot study and found that transdermal nitroglycerin was associated with fewer headaches than oral isosorbide mononitrate. We are currently recruiting patients for our second main study.

Journal Article↗
PubMed1987

Use of nitrates in acute and chronic congestive heart failure.

The literature available on the use of nitrates (glyceryl trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate) as various formulations (oral, buccal, sublingual, transdermal and intravenous) in the treatment of acute and chronic congestive heart failure is reviewed. There are adequate data on the acute haemodynamic effects of these preparations, but little information is available on the long term use of nitrates in chronic congestive heart failure. The exception is isosorbide dinitrate, which, in combination with hydralazine, has been shown to reduce mortality.

Acute Disease↗