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PubMed2006

[Favourable results with local injections of botulinum-A toxin in patients with chronic isosorbide dinitrate ointment-resistant anal fissures].

OBJECTIVE: To determine the effectiveness of injection of botulinum-A toxin in the internal anal sphincter as a treatment for chronic therapy-resistant anal fissures. DESIGN: Prospective. METHODS: In the period October 2002-February 2005, 32 consecutive patients (15 men and 17 women), with a median age of 44 years (range: 23-78 years) and suffering from chronic isosorbide dinitrate ointment-resistant anal fissures, were treated with an injection of 40 IU botulinum-A toxin (Dysport, Ipsen, The Netherlands) in the ventral side of the internal anal sphincter. The injection was given as an outpatient procedure under general or spinal anaesthesia. RESULTS: After a median follow-up of 14 months (range: 2-28 months), the chronic anal fissures were cured in 24 ofthe 32 patients (75%). Twenty-two patients were given a second or a third injection. A fissure recurred in one of the cured patients (4%), and one patient suffered from temporary flatus incontinence. CONCLUSION: Botulinum-A toxin injections were effective in 75% of patients with isosorbide dinitrate ointment-resistant chronic anal fissures. This is a simple technique with fewer side effects than local application of NO donors and fewer complications and less morbidity than surgical sphincterotomy.

Adult↗
PubMed1983

Determination of isosorbide dinitrate and its mononitrate metabolites in human plasma by high-performance liquid chromatography-thermal energy analysis.

An accurate and sensitive method for the simultaneous determination of isosorbide dinitrate and its 2- and 5-mononitrates in human plasma has been developed. Following extraction of 3.0 ml of plasma with 12.0 ml of dichloromethane-ethyl acetate (1:1) the extract is subjected to high-performance liquid chromatography employing a Zorbax NH2 column. The eluent stream is introduced into a thermal energy analyser, employing chemiluminescence as a specific means of detection. The minimum quantifiable level of the compound in plasma is 200 pg/ml allowing the quantitation of isosorbide dinitrate in human plasma following single oral administration. Nitroglycerin is employed as internal standard.

Chromatography, High Pressure Liquid↗
PubMed1989

Comparison of nifedipine, propranolol and isosorbide dinitrate on angiographic progression and regression of coronary arterial narrowings in angina pectoris.

Calcium antagonists and beta blockers may retard or inhibit atherogenesis. This study investigated whether nifedipine or propranolol influences coronary atherosclerosis in humans. In selected patients with effort angina and proven coronary artery disease, the cineangiographic pattern after 2-year therapy with nifedipine (group 1, 39 patients), propranolol (group 2, 36 patients) or isosorbide dinitrate (group 3, 38 patients) was compared to that before treatment. The disease evolved to a different extent in the 3 groups. Patients with evidence of progression of old narrowings and appearance of new narrowings were significantly fewer in group 1 (31% and 10%) than in group 2 (53% and 34%) and group 3 (47% and 29%). The number of stenoses with evidence of progression was significantly smaller after nifedipine (14), and larger after propranolol (39) compared with group 3 (24). Thus, nifedipine seemed more protective than the other 2 drugs against coronary atherosclerosis. The coronary risk factors were normal in the nifedipine group and remained so with treatment, suggesting that they were dissociated from influences on atherosclerosis. The evolution, as judged by the number of narrowings with progression, appeared significantly (p less than 0.01) worse with propranolol than with isosorbide dinitrate. Propranolol caused unfavorable modifications of serum lipids; there was a 28% increase in total triglycerides and a 25% decrease in high density lipoprotein cholesterol at 12 months in group 2.

Angina Pectoris↗
PubMed1989

Nitroglycerin and isosorbide dinitrate stimulation of glutathione disulfide efflux from perfused rat liver.

Nitroglycerin (GTN) and isosorbide dinitrate (ISD) are metabolized by glutathione S-transferase to nitrite with production of GSSG from GSH. Infusion of organic nitrates into perfused rat liver led to efflux of GSSG in the bile and nitrite in the perfusate. Biliary GSSG increased more rapidly than did nitrite release as GTN infusion rate was increased, indicating that GSSG reducing capacity was being exceeded. Rapid GTN-induced oxidation of GSH may be the mechanism of tissue GSH depletion by GTN and other alkylnitrates. Such depletion of glutathione may reduce nitrite production from organic nitrates and underlie tolerance to these drugs.

Animals↗
PubMed1991

[The ability of captopril to enhance the anti-anginal effect of isosorbide dinitrate in patients with stable exercise-induced angina pectoris].

The interaction between isosorbide dinitrate (ISDN) and the angiotensin-converting enzyme inhibitor captopril was investigated in 14 patients with coronary heart disease concurrent with stable exercise-induced angina pectoris. The efficacy of placebo, ISDN, 10 mg, captopril, 50-100 mg, and ISDN + captopril was evaluated in each patient by pharmacodynamic treadmill studies. The single-blind, randomized technique was applied. Captopril alone produced a weak antianginal effect. The concomitant use of ISDN and captopril showed significantly more marked and prolonged effects than ISDN alone. The highest effect was exhibited by ISDN supplemented with captopril in 6 patients who had been refractory to ISDN alone. Thus, captopril may potentiate the antianginal effect of ISDN.

Angina Pectoris↗
PubMed1975

[Efficacy of a new slow-release isosorbide dinitrate preparation in myocardial infarction (author's transl)].

A new slow-release isosorbide dinitrate preparation (ISDN retard, Boehringer Mannheim) was investigated in a controlled study (double blind/cross over) in 20 patients with clear symptoms of coronary insufficiency after myocardial infarction, comparing the ECG on effort with that under placebo treatment. A favourable effect on the symptoms of coronary insufficiency could be demonstrated under standardised conditions on a bicylce ergometer 4 hours after oral ingestion of ISDN. The ST interval of the ECG was significantly lowered (p less than or equal to 0.025) under comparable cardiac work. The prolonged action of ISDN retard was also shown by a significant reduction in systolic and diastolic blood pressure at rest, during and after effort. Simultaneously, there was a slight but not-significant rise in heart rate.

Administration, Oral↗
PubMed1986

Isosorbide dinitrate: relationship between pharmacokinetics and brachial artery hemodynamics in essential hypertension.

Pharmacokinetics of isosorbide dinitrate (ISDN) and brachial arterial hemodynamics have been studied in 15 patients with sustained essential hypertension. The hemodynamic study was performed by using a pulsed Doppler device enabling evaluation of the diameter of the brachial artery with an error of less than 10%. After intravenous administration until plateau concentrations were reached, the ISDN infusion was stopped in order to study the disappearance curve of the drug and the pharmacokinetic parameters. ISDN caused a significant decrease in systolic pressure, a significant increase in arterial diameter, and no change in heart rate. Brachial hemodynamics were not correlated with the plasma concentration in the steady state or the area under the disappearance curve. In contrast, the changes in arterial diameter during perfusion were significantly correlated with the apparent distribution volume, a finding that might indirectly reflect the affinity of ISDN for vascular tissues.

Adult↗
PubMedDate not supplied

Nitroglycerin and isosorbide dinitrate in pulmonary hypertension of chronic obstructive pulmonary disease.

The effects of sublingual isosorbide dinitrate (ISDN; 10 mg) or nitroglycerin (NTG; 1 mg) on pulmonary hemodynamics, gas exchange and pulmonary function were studied during right heart catheterization in two series of 27 patients with COPD. An immediate significant decrease of pulmonary arterial pressure, cardiac output and work of the right ventricle was obtained with both drugs, but NTG only was able to reduce the pulmonary vascular resistance. Arterial oxygen tension did not decrease, but venous O2 tension did, with no change in blood lactate. NTG had also a slight bronchodilating effect. After chronic use, no improvement of pulmonary function or gas exchange was observed but NTG lowered pulmonary vascular resistances significantly. The effects observed during the acute study were reproduced after six weeks with the same doses of both drugs. NTG appears effective in reducing pulmonary arterial hypertension mainly by vasodilation while the ISDN effect seems due only to the decreased cardiac output.

Hemodynamics↗
PubMed1985

Combination therapy with isosorbide dinitrate: current status and the future.

The excellent safety and predictable efficacy of isosorbide dinitrate (ISDN) have been demonstrated repeatedly during the past 25 years in a number of studies in which the agent has been used alone or in combination with other antianginal agents. Clinical studies to investigate the additive or synergistic effect of ISDN have been difficult to conduct because of the complexity of protocol design and length of studies required. However, combination therapy is well accepted in the clinical practice of medicine and cardiology and is used to obtain additive therapeutic effects while minimizing the side effects. The addition of ISDN not only to other standard and proven antianginal agents but also to calcium antagonists should prove to be a fruitful area for further clinical research benefiting patients with angina pectoris (caused by either coronary artery spasm or occlusive coronary artery disease), hypertension, and congestive heart failure. Noncardiovascular uses of ISDN may include the treatment of hyperspasticity of other smooth muscle beds, such as esophageal spasm and achalasia.

Angina Pectoris↗
PubMed1981

Kinetics of isosorbide dinitrate and relationships to pharmacological effects.

1 The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), form 0-6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose-response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.

Adult↗
PubMed1983

Tolerance to isosorbide dinitrate: rate of development and reversal.

The circulatory response and plasma concentrations of isosorbide dinitrate (ISDN) were determined in 10 patients with chronic, stable angina after administration of 5 mg of sublingual ISDN during the control stage, after 48 hr of therapy with 15 mg of ISDN orally every 6 hr, and subsequently after a 48 hr period when ISDN was substituted by placebo four times daily. Initially, sublingual ISDN induced major reductions in both supine and standing systolic and diastolic blood pressure, but after 45 hr of therapy with oral ISDN, there was a significantly diminished vasodepressor response in both positions. Subsequently, when placebo was substituted for ISDN, the circulatory response initially seen was restored within 21 hr. Plasma ISDN concentrations after the test sublingual dose were slightly higher after 48 hr of oral ISDN dosing (i.e., the tolerant state) than at the start of the study. This suggests that tolerance is unlikely to be caused by reduced bioavailability or accelerated elimination of ISDN. It is possible that tolerance is related to accumulation of ISDN metabolites. The attenuation of the circulatory response to ISDN may be related to the altered antianginal efficacy commonly seen during sustained therapy with ISDN.

Administration, Oral↗
PubMed1985

Regional differences in the actions of verapamil and isosorbide dinitrate on rabbit and dog vascular smooth muscle.

The effects of verapamil and isosorbide dinitrate (ISDN) alone or together on mechanical responses of the rabbit coronary artery and mesenteric vein, and the dog coronary artery have been investigated. Verapamil, in concentrations exceeding 10 nM consistently inhibited and at 10 microM, blocked the contraction evoked by excess concentrations of K in these tissues, but agonist-induced contraction was not modified by the presence or absence of Ca. In concentrations greater than 1 microM, verapamil depolarized the membrane by inhibiting the K-conductance of the membrane. ISDN had little effect on the rabbit coronary artery in concentrations below 10 microM. In contrast, in the rabbit mesenteric vein and dog coronary artery, ISDN in concentrations over 1 microM inhibited the contraction evoked by excess concentrations of K or by agonists. Species differences were apparent in the actions of ISDN on vascular tissues. When verapamil and ISDN were simultaneously applied to the rabbit mesenteric vein and dog coronary artery, the K-induced contraction was markedly inhibited by an amount exceeding that produced by the sum of the contractions evoked by the individual application of both agents. An enhanced vasodilating action induced by simultaneous applications of both agents indicates a possible clinical benefit for anti-anginal treatment.

Animals↗
PubMed1980

[Pharmacodynamic effects of the sustained-release tablet of isosorbide dinitrate and its bioavailability in conscious dogs (author's transl)].

Oral administration of isosorbide dinitrate (ISDN), 1 approximately 2 mg/kg, resulted in a dose-dependent decrease in the pulse pressure by reducing the systolic pressure and slightly elevating the diastolic pressure in conscious dogs. Therefore, this system was employed to evaluate the effectiveness of the sustained-release ISDN tablet as compared with that of the standard tablet. Four standard tablets (20 mg of ISDN) given in a single dose significantly decreased the pulse pressure, which became lowest at 2 hr after administration and returned to the near original level at 6 hr. On the other hand, with four sustained-release tablets (80 mg of ISDN) 4 hr was required to produce a maximum decrease, and at 10 hr, the pulse pressure was still much lower than the original level. The plasma concentration of ISDN was measured by a gas chromatographic method. The time course of the plasma concentration of ISDN after administration of each preparation was correlated with that of the decrease in the pulse pressure. This suggests that the system employed is useful in evaluating the bioavailability of various preparations of organic nitrates (ISDN). In addition, these data demonstrate that the sustained-release formulation of ISDN possesses a prolonged pharmacological effect.

Animals↗
PubMed1990

Membrane permeation-controlled transdermal delivery system design. Influence of controlling membrane and adhesive on skin permeation of isosorbide dinitrate.

A membrane permeation-controlled transdermal delivery system (MC-TDS) of isosorbide dinitrate (ISDN), a model drug, was prepared from polyvinyl alcohol aqueous gel containing the drug, a membrane consisting of ethylene-vinyl acetate copolymer membrane and acrylic adhesive (EV-a). The permeability of ISDN through the EV-a membrane was 2.5 times higher than that through excised hairless rat skin. The ratio of plasma concentration of ISDN after application of MC-TDS on stripped (damaged) skin relative to intact skin was lower than that after application of Frandol tape-S, a marketed ISDN TDS, which suggests that the EV-a membrane might work as a control membrane for overall delivery rate of ISDN to the body. When MC-TDS stored at 30 degrees C for 13.5-48h was applied to the damaged skin, however, the initial plasma concentration of ISDN was very much higher than the expected therapeutic level and was not controlled by the EV-a membrane. The initial high plasma concentration of ISDN after application of the stored MC-TDS on the damaged skin was due to migration of ISDN from the reservoir to the adhesive during storage at 30 degrees C. The migration of drugs into the adhesive might be an important problem in developing efficient MC-TDS.

Administration, Cutaneous↗
PubMed2000

Isosorbide dinitrate inhibits platelet adhesion and aggregation in nonthrombolyzed patients with acute myocardial infarction.

BACKGROUND: Apart from their vasodilatatory properties, nitrates have been shown to inhibit platelet aggregation. The effects of nitrates on platelet adhesion have not been studied. Nonselected patients with acute myocardial infarction (AMI) have been suggested to gain no benefit from administration of nitrates. However, the importance of nitrates may be greater in a subgroup of nonthrombolyzed patients with AMI. HYPOTHESIS: Isosorbide dinitrate (ISDN) decreases platelet adhesion and aggregation in nonthrombolyzed patients with AMI. METHODS: Consecutive 48 men with AMI, not eligible for thrombolytic therapy because of late presentation (> 12 h), were prospectively randomized 2:1 to double-blind ISDN (mean dose 2.4 +/- 0.9 mg/h) (n = 33) or placebo (0.9% sodium chloride) (n = 15) infusion. All patients received aspirin. Blood samples were taken at baseline (no study medication) and 3 h into ISDN or placebo infusion. Platelet adhesion to collagen was measured in the ethylene diamine tetraacetic acid (EDTA)-platelet rich plasma by recording changes in light transmission with an optical aggregometer. Platelet aggregation was measured using the Born's method. RESULTS: Isosorbide dinitrate significantly decreased both platelet adhesion and aggregation. No effect was seen in the placebo group. CONCLUSIONS: In patients with AMI who do not receive thrombolytic therapy, ISDN effectively inhibits platelet adhesion and aggregation. These effects of nitrates may be of therapeutic and prognostic significance in this group of patients.

Adult↗
PubMed1989

Influence of electric foot shock on pharmacokinetics of isosorbide dinitrate subcutaneously administered to rats.

The influence of emotional stress on the pharmacokinetics of isosorbide dinitrate (ISDN) administered s.c. to rats was studied. The plasma level of ISDN in emotionally stressed (ES) rats was the same as that in non-stressed control rats. However, the levels of its metabolites, 5-isosorbide mononitrate (5-ISMN) and 2-isosorbide mononitrate (2-ISMN), were markedly lower in ES rats than in the control rats. On the other hand, urine ISDN and 2-ISMN excretion rates were lower in ES rats than in the control rats. These observations suggest that the pharmacokinetics of ISDN administered s.c. is influenced by emotional stress such as foot shock.

Animals↗
PubMed1987

[Concentration-time profile of isosorbide dinitrate and its metabolites in plasma following percutaneous resorption of a transdermal therapeutic system].

Percutaneous absorption of isosorbide dinitrate (ISDN), determined from plasma concentrations of ISDN and its metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN), was studied in 8 healthy subjects aged 19 to 25 years following application of a single plaster containing 40 mg ISDN to the hairless skin on the left side of the chest for 72 h. ISDN and mononitrates were measurable in plasma 2 h after application and maximal concentrations for ISDN and mononitrates occurred after 12-16 h and 16 h, respectively. Mean areas under the curves values corrected for the body surface (BS) (AUC0-72 h.BS of 1074, 815 and 3584 nmol.m2.h/l for ISDN, IS-2-MN and IS-5-MN are equivalent to area ratios of 1, 0.8 and 3.3. ISDN metabolism following transdermal application is less extensive than after oral application. The molar nitrate concentration including metabolites, however, is comparatively low reaching approximately 60-80 nmol/l.

Administration, Cutaneous↗
PubMed2002

Fissurectomy and isosorbide dinitrate for chronic fissure in ano not responding to conservative treatment.

BACKGROUND: Although lateral sphincterotomy heals chronic fissure in ano in over 90 per cent of cases it is a surgical technique with inherent complications. To avoid such complications, chronic fissure in ano was treated by fissurectomy in this study. To enhance postoperative tissue perfusion allowing stable wound healing, fissurectomy was combined with temporary chemical sphincterotomy by a nitric oxide donor cream. METHODS: Seventeen consecutive patients (ten women) with chronic fissure in ano not responding to conservative management underwent diathermy fissurectomy. After operation patients used a 1 per cent isosorbide dinitrate cream. Postoperative follow-up continued until wounds had healed, at which time anal endosonography was performed. A telephone inquiry into fissure recurrence and continence status was made. RESULTS: Seventeen patients underwent fissurectomy, without postoperative complications. All wounds had healed within 10 weeks. No fissure recurrence was seen after a median follow-up of 29 months. Histopathology showed non-specific scar tissue without signs of internal anal sphincter fibrosis. Postoperative endosonography showed no evidence of new internal sphincter defects. CONCLUSION: In the treatment of chronic anal fissure not responding to chemical sphincterotomy with nitric oxide donors, fissurectomy in combination with isosorbide dinitrate cream may be a sphincter-sparing surgical technique.

Adult↗