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PubMed1997

High-dose isosorbide dinitrate for myocardial revascularization with composite arterial grafts.

BACKGROUND: Composite arterial grafting for myocardial revascularization is a surgical technique in which free arterial conduits are proximally attached to an in situ internal mammary artery. METHODS: Composite arterial grafting was performed in 78 patients with internal mammary artery (n = 24), inferior epigastric artery (n = 21), or radial artery (n = 33) connected to the internal mammary artery. Overall, 254 distal anastomoses were performed (average number, 3.3 per patient), 225 of which were arterial. All patients were treated postoperatively with high-dose isosorbide dinitrate (4 to 20 mg/h for 24 hours). RESULTS: The in-hospital mortality rate was 2.6% (2 patients). Early recatheterization studies performed 3 weeks (range, 1 to 20 weeks) after operation in 30 patients demonstrated patency rates of 100%, 93%, and 100% for the composite internal mammary artery, inferior epigastric artery, and radial artery groups, respectively. In addition, two inferior epigastric artery conduits had major intraluminal constriction. At a mean follow-up of 20 months (range, 1 to 42 months) all patients are alive, and all but 2 in the inferior epigastric group (97%) are angina free. CONCLUSIONS: This surgical technique can be safely used. On the basis of our experience, the right internal mammary artery and the radial artery are the most suitable conduits for this procedure. High-dose nitrates given perioperatively prevent spasm and ensure early patency rates.

Adult↗
PubMed1998

Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension.

BACKGROUND & AIMS: The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN). METHODS: Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. RESULTS: Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (-24.2% +/- 11% vs. -16.1% +/- 11%; P < 0.01). A reduction in HVPG of > 20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%; P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (P = 0.16). CONCLUSIONS: Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.

Adrenergic alpha-Antagonists↗
PubMed1984

Determination of the partitioning, stability, and metabolite formation of isosorbide dinitrate in human and rat blood using an improved gas-liquid chromatographic assay.

A simple and highly sensitive gas-liquid chromatographic method using electron-capture detection has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rat and human plasma. This method has a limit of quantitation of about 5 ng/ml for the mononitrates and of 1 ng/ml for ISDN using 0.1 ml of plasma, and is thus useful for pharmacokinetic studies of these compounds in small animals, and in humans when the available volume of blood is limited. Using this method, we found the apparent in vitro partitioning ratio of ISDN between erythrocyte and plasma in rat and human blood at 37 degrees C to be 0.22 and 0.13, respectively. In spite of this poor affinity for red blood cells, ISDN degradation in whole blood was mediated primarily via this blood fraction. Loss of ISDN in blood appeared to proceed exclusively through its mononitrate metabolites, resulting in a 6:1 product ratio of the 5-mononitrate to its 2-isomer. These data suggest that although blood degradation of ISDN and erythrocyte partitioning occur per se, these phenomena do not contribute significantly to the very rapid in vivo clearance of ISDN observed in man and in the rat.

Animals↗
PubMed1991

Clean-up of plasma extracts by gel permeation chromatography during analysis of isosorbide nitrates by capillary gas chromatography.

This work describes how gel permeation chromatography (GPC) can be used for sample clean-up to reduce the fouling of the column in an automated on-column injector. The analytes were isolated from plasma together with the internal standard (isomannide dinitrate) by liquid-liquid extraction on Extrelut silica columns. The extracts were evaporated and reconstituted in tetrahydrofuran for separation of the analytes from non-volatile plasma components by GPC on a styrene-divinylbenzene column with 100 A pore size. A programmable autosampler with an additional three-way valve was used for injection and fraction collection. The molecular weight fraction between 100 and 700 a.m.u. was collected and transferred to the on-column autosampler for capillary gas chromatography on a 30-m column butt-connected to a 0.2-m pre-column. The pre-column was replaced after 50 sample injections. When the GPC purification was excluded from the work-up procedure a deposit of non-volatile components was formed at the injection zone of the pre-column which resulted in excessive peak-tailing after only five or six injections of plasma extract. The limit of determination was 0.2 ng/ml plasma for isosorbide dinitrate and 0.4 ng/ml for the mononitrates.

Blood↗
PubMed2003

Isosorbide-5-mononitrate treatment prevents cyclosporin A-induced platelet hyperactivation and the underlying nitric oxide-cyclic guanosine-3',5'-monophosphate disturbances.

INTRODUCTION: The clinical use of cyclosporin A (CsA) is commonly associated with the development of hypertension and increased risk of thromboembolic events. Decreased endothelium-dependent relaxation and increased platelet activation seems to be involved on those side effects, but the underlying mechanisms are not yet elucidated. The present study aimed to evaluate the CsA effect on the platelet NO-cyclic guanosine-3',5'-monophosphate (cGMP) pathway and the putative benefits of concomitant isosorbide-5-mononitrate (IS-5-MN) administration on CsA-induced hypertension and on platelet hyperactivation. MATERIALS AND METHODS: Blood pressures, platelet NO synthase activity and cGMP content, intracellular free calcium concentration ([Ca2+]i) and whole blood platelet aggregation were assessed in three rat groups orally treated, during 7 weeks, with the following diets: orange juice (control group), 5 mg/kg/day of CsA (CsA group) and 150 mg/kg/day, b.i.d., of IS-5-MN for 2 weeks and IS-5-MN plus 5 mg/kg/day of CsA for 7 weeks (IS-5-MN+CsA group). RESULTS: IS-5-MN treatment has prevented hypertension development obtained in the solely CsA-treated rats. CsA treatment has inhibited NOS activity, which was reverted by the concomitant IS-5-MN and CsA administration. On the contrary, platelets from CsA-treated rats had cGMP content increased when compared with the control rats. The variation obtained when ISMN was present was less predominant. Therefore, the organic nitrate treatment has prevented platelet hyperactivation, namely, by decreasing thrombin-evoked [Ca2+]i and collagen-evoked platelet aggregation, when compared with the solely CsA-treated group. The preventive effect of IS-5-MN was reinforced by electron microscopy studies of platelet activation. CONCLUSIONS: By increasing [Ca2+]i and aggregation, CsA induces platelet hyperactivation and simultaneously increases cGMP content, which might represent a compensatory inhibitory mechanism. The concomitant IS-5-MN treatment prevents the above-mentioned platelet hyperreactivity and tends to normalize the NO-cGMP pathway as well as the development of hypertension.

Animals↗
PubMedDate not supplied

Nisoldipine versus isosorbide dinitrate in coronary heart disease: results of a double-masked study.

The efficacy and tolerability of a twice-daily dose of 5 mg of nisoldipine versus 40 mg of sustained-release isosorbide dinitrate (ISDN) were compared in a randomized, double-masked study in 91 patients. During the 21-day treatment period, the mean time taken during bicycle ergometry to the appearance of an ST segment depression of at least 0.1 mV compared with the resting value increased from 287 +/- 129 seconds to 391 +/- 150 seconds in the nisoldipine group and from 254 +/- 140 seconds to 350 +/- 191 seconds in the ISDN group. The mean value at the end of treatment calculated by using analysis of covariance was 383 seconds in both groups. The difference between the two treatment groups was not statistically significant. The mean ST segment depression at individually maximal workload decreased from 0.19 +/- 0.07 mV to 0.12 +/- 0.08 mV in the nisoldipine group and from 0.18 +/- 0.07 mV to 0.14 +/- 0.08 mV in the ISDN group. The mean total duration of exercise increased from 420 +/- 161 seconds to 497 +/- 140 seconds in the nisoldipine group and from 425 +/- 167 seconds to 456 +/- 168 seconds in the ISDN group. In the nisoldipine group, 9 patients reported 12 adverse events that were considered to be possibly or probably related to the test medication; in the ISDN group, 13 patients reported 26 adverse events. Although the anti-ischemic effect of the two treatments was comparable, nisoldipine was descriptively superior to ISDN in terms of tolerability.

Aged↗
PubMed2002

Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites.

BACKGROUND/AIMS: beta-blockers effectively prevent first variceal bleeding (FVB) in cirrhotic patients. In patients with ascites, however, their use might be precluded by a high rate of contraindications and side effects. We compared the efficacy and applicability of nadolol and isosorbide-mononitrate (IsMn) in preventing FVB in a population of cirrhotic patients at high risk of variceal bleeding with ascites, who can be frequently intolerant to beta-blockers. METHODS: A total of 80 consecutive cirrhotic patients with ascites and esophageal varices (25% average risk of bleeding at 1 year) were considered, 28 were excluded due to contraindications and 52 were randomly assigned to receive nadolol (n=25) or IsMn (n=27). RESULTS: Frequency of contraindications was greater for beta-blockers than IsMn (35 versus 0%, P=0.001). During 21.3+/-11.6 months of follow-up, side effects forced six patients taking nadolol and four taking IsMn to stop treatment. Bleeding occurred in two patients taking nadolol and ten taking IsMn. The probability of bleeding was significantly lower in the nadolol group (P<0.05), whereas overall survival was similar (seven patients on IsMn and eight on nadolol died, P=0.3). CONCLUSIONS: In patients with ascites IsMn is tolerated but ineffective while nadolol is effective but less tolerated.

Adolescent↗
PubMed2003

Development and evaluation of extended release formulations of isosorbide mononitrate based on osmotic technology.

Extended release formulations of isosorbide mononitrate (IMN), based on osmotic technology, were developed. Target release profile was selected and different variables were optimized to achieve the same. Formulation variables like type (PVP, PEG-4000, and HPMC) and level of pore former (0-55%, w/w of polymer), percent weight gain were found to affect the drug release from the developed formulations. Drug release was inversely proportional to the membrane weight but directly related to the initial level of pore former in the membrane. Burst strength of the exhausted shells was inversely proportional to the level of pore former, but directly affected by the membrane weight. Satisfactory burst strength (more than 320 g) was obtained when PVP was used as pore former (up to 55%, w/w of polymer) at the membrane weight of 7.5% and more. The release from the developed formulations was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Results of SEM studies showed the formation of pores in the membrane from where the drug release occurred. The formulations were found to be stable after 3 months of accelerated stability studies. Prediction of steady-state levels showed the plasma concentrations of IMN to be within the desired range.

Chemistry, Pharmaceutical↗
PubMed1999

Development of a membrane-controlled transdermal therapeutic system containing isosorbide dinitrate.

The formulation of a transdermal delivery system for isosorbide dinitrate (ISDN) was examined. It was found that the target release rate should be 4.01 mg/h per 20 cm2 for optimal dosing. In order to reach such this zero order release rate, a membrane permeation controlled transdermal therapeutic system (TTS) formulation was developed, with ethylene vinyl acetate copolymer (EVAC) and polyethylene (PE) membranes as rate controlling membranes; a carbomer gel was used as the drug reservoir. The release of ISDN from this drug delivery device was studied in vitro using FDA recommended method. PIB adhesive on the EVAC or PE membrane caused a decreased flux of ISDN; the release kinetics fitted Higuchi matrix kinetics. TTS with EVAC membrane release ISDN at a rate much lower than the calculated target release rate, but with PE membranes, the release rate was very close to the target. Release rate studies have revealed that, as the VA content in EVAC membrane increased, the flux of ISDN increased. All these results were compared with the commercial product Frandol(R) Tape S from Japan. It was found that the release rate of Frandol was close to target release rate and fitted matrix kinetics. These results suggested that TTS that contain PE membrane as rate controlling membrane, polyisobutylene (PIB) adhesive and carbomer gel as a reservoir can be applicable as a TTS for ISDN.

Acrylic Resins↗
PubMed2002

Direct injection of aqueous samples in packed column supercritical fluid chromatography of isosorbide-5-mononitrate from drug release testing.

A method for the analysis of aqueous samples of isosorbide-5-mononitrate (5-ISMN) is presented. It is based on packed column supercritical fluid chromatography (SFC) using 20% of 2-propanol in carbon dioxide as the mobile phase and a diol silica column as the stationary phase. Using the described conditions it is possible to quantitate 5-ISMN released from Imdur tablets in gastric media. The precision upon repeated injections was 2% (RSD) at the 20 microg/ml level (n=8), using peak height measurements, when the solution was circulated through the sample loop of the injector. Samples from drug release testing that had been analyzed with reversed phase LC were analyzed with the present method and the results agreed well. It is also possible to monitor the drug released in a dissolution-testing vessel through direct on-line continuous loading (recirculation) of the sample loop of the SFC instrument.

Chromatography↗
PubMed2002

A validated high performance liquid chromatographic method for analysis of isosorbide mononitrate in bulk material and extended release formulations.

A reversed phase HPLC method using C(18) column was developed for the quantitative determination of isosorbide mononitrate (IMN) in the bulk material and extended release dosage forms. The method was specific to IMN and able to resolve the drug peak from the pharmacopoeial impurities and formulation excipients. The method was accurate, precise, and linear within the desired range. In addition to analysis of assay and dissolution samples, the method was successfully used for analysis of drug-excipient compatibility samples of IMN used for development of extended release formulations in our laboratory and their subsequent stability studies. The method was also used for analysis of IMN in commercially available raw material.

Chromatography, High Pressure Liquid↗
PubMed2003

Simultaneous determination of aspirin and isosorbide 5-mononitrate in formulation by reversed phase high pressure liquid chromatography.

A simple, precise and rapid reversed phase HPLC method was developed for the simultaneous estimation of aspirin (AS) and isosorbide 5-mononitrate (ISM) in combined formulation. The method was carried out on a Thermo Quest C18 column using a mixture of water:methanol (water pH adjusted to 3.4 using dilute orthophosphoric acid) and detection was carried out at 215 nm using chlorzoxazone as internal standard. Both the drugs showed linearity in the range of 2-10 microg/ml and limits of quantification was found to be 4 and 40 ng/ml for AS and ISM, respectively.

Aspirin↗
PubMed2000

High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP ventilation combined with conventional treatment for severe pulmonary edema.

OBJECTIVE: To determine the feasibility, safety and efficacy of bilevel positive airway ventilation (BiPAP) in the treatment of severe pulmonary edema compared to high dose nitrate therapy. BACKGROUND: Although noninvasive ventilation is increasingly used in the treatment of pulmonary edema, its efficacy has not been compared prospectively with newer treatment modalities. METHODS: We enrolled 40 consecutive patients with severe pulmonary edema (oxygen saturation <90% on room air prior to treatment). All patients received oxygen at a rate of 10 liter/min, intravenous (IV) furosemide 80 mg and IV morphine 3 mg. Thereafter patients were randomly allocated to receive 1) repeated boluses of IV isosorbide-dinitrate (ISDN) 4 mg every 4 min (n = 20), and 2) BiPAP ventilation and standard dose nitrate therapy (n = 20). Treatment was administered until oxygen saturation increased above 96% or systolic blood pressure decreased to below 110 mm Hg or by more than 30%. Patients whose conditions deteriorated despite therapy were intubated and mechanically ventilated. All treatment was delivered by mobile intensive care units prior to hospital arrival. RESULTS: Patients treated by BiPAP had significantly more adverse events. Two BiPAP treated patients died versus zero in the high dose ISDN group. Sixteen BiPAP treated patients (80%) required intubation and mechanical ventilation compared to four (20%) in the high dose ISDN group (p = 0.0004). Myocardial infarction (MI) occurred in 11 (55%) and 2 (10%) patients, respectively (p = 0.006). The combined primary end point (death, mechanical ventilation or MI) was observed in 17 (85%) versus 5 (25%) patients, respectively (p = 0.0003). After 1 h of treatment, oxygen saturation increased to 96 +/- 4% in the high dose ISDN group as compared to 89 +/- 7% in the BiPAP group (p = 0.017). Due to the significant deterioration observed in patients enrolled in the BiPAP arm, the study was prematurely terminated by the safety committee. CONCLUSIONS: High dose ISDN is safer and better than BiPAP ventilation combined with conventional therapy in patients with severe pulmonary edema.

Dose-Response Relationship, Drug↗
PubMed2003

Preserved endothelial function after long-term eccentric isosorbide mononitrate despite moderate nitrate tolerance.

OBJECTIVES: We sought to investigate the effects of orally administered, long-term, eccentric isosorbide mononitrate (ISMN) on endothelial function. BACKGROUND: Previous studies have shown that nitrate tolerance induced by continuous transdermal glyceryl trinitrate (GTN) is associated with increased vascular superoxide production and endothelial dysfunction. In contrast, it is unclear whether vascular superoxide increases during eccentric administration of oral nitrates, which is a widely used therapeutic dosing regimen. METHODS: New Zealand White rabbits were randomly classified into three groups (n = 10, each) that received either placebo, ISMN at 2 mg/kg body weight per day (ISMN-2), or ISMN at 200 mg/kg body weight per day (ISMN-200) in an eccentric, twice-daily scheme for four months. Animals were sacrificed 3 h after application of the last ISMN dose. RESULTS: The continuously present, lowest ISMN plasma levels (ng/ml) were 4.8 +/- 0.2 in ISMN-2 and 14.5 +/- 4 in ISMN-200 (p = 0.026). Treatment with ISMN had no effect on aortic reactivity to phenylephrine, acetylcholine, or the nitric oxide (NO) donor S-nitroso-N-acetyl-D,L-penicillamine, while the half-maximal effective concentration of ISMN (EC(50)-value in -logM) was shifted from 5.23 +/- 0.03 (placebo) to 4.69 +/- 0.04 (ISMN-200) (p < 0.0001 by analysis of variance). This moderate in vivo nitrate tolerance was not associated with increased aortic superoxide production (5 micromol/l lucigenin). The cumulative (20-min) lucigenin signals (cpm/mg) were 211 +/- 34 (ISMN-200) and 230 +/- 22 (placebo) (p = 0.415). CONCLUSIONS: Long-term treatment with high-dose, eccentric ISMN does not increase vascular superoxide production and/or impair endothelium-dependent vasorelaxation, despite the development of moderate nitrate tolerance. Thus, it is unlikely that long-term anti-ischemic treatment with ISMN aggravates endothelial dysfunction in coronary artery disease.

Acetylcholine↗
PubMed1989

The effects of intravenous nitroglycerin and isosorbide dinitrate on hemodynamics and myocardial metabolism.

Myocardial ischemia before and during coronary artery surgery is significant, because patients who develop perioperative myocardial ischemia have an increased incidence of postoperative myocardial infarctions. Thus, the prevention of ischemic episodes is of great importance. This study was undertaken to (1) compare the effects of intravenous nitroglycerin (NTG) with isosorbide dinitrate (ISDN); (2) investigate if the continuous infusion of nitrates had beneficial effects on cardiac performance and metabolism; and (3) compare the control of blood pressure with the nitrates versus halothane during a standardized anesthetic. Twenty-one patients participated in the study, and all had the following: a radial arterial catheter, peripheral venous catheter, 7F pulmonary artery catheter, and Baim coronary sinus flow catheter. The study was carried out in the prebypass period beginning with awake measurements of baseline parameters, and ending after median sternotomy. The patients were divided into three groups: group 1 received an infusion of NTG; group 2 received an infusion of ISDN; and group 3, the control, received neither nitrate, but halothane was added to control hemodynamics. Measurements were made at the following time intervals: (1) baseline; (2) after 5 minutes of the nitrate infusions while awake (groups 1 and 2); (3) after induction of anesthesia, laryngoscopy, and intubation; and (4) after median sternotomy. In groups 1 and 2, the nitrates were infused at 0.1 mg/kg/h for 5 minutes. Thereafter, blood pressure control and treatment of episodic hypertension were achieved by alteration of the rate of nitrate infusions, or, in group 3, by 0.5% to 2% of inspired halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

Interactions of L-arginine, isosorbide mononitrate, and angiotensin II inhibitors on arterial pulse wave.

BACKGROUND: Deficiency of nitric oxide (NO) production has been implicated in the pathogenesis of increased pulse wave reflection associated with systolic hypertension. We investigated the effects on systolic blood pressure (BP) and pulse wave contour of two nitrate donors, isosorbide mononitrate (ISMN) and L-arginine. METHODS: The subjects were 14 elderly patients chronically treated with antihypertensive agents. In seven of the subjects, agents causing angiotensin II (AII) inhibition (angiotensin-converting enzyme [ACE] inhibitor or AT(1) receptor antagonist, or both) were used. Study entry required systolic BP of 150 to 200 mm Hg, and aortic pulse wave augmentation more than 15 mm Hg. Pharmacodynamic responses to ISMN, L-arginine, and ISMN plus L-arginine, were assessed in double-blind crossover studies by standard sphygmomanometry and applanation tonometry. RESULTS: Peripheral systolic BP, aortic systolic BP, and the aortic augmentation index were decreased (P <.001) by ISMN, irrespective of AII inhibition. L-arginine enhanced these effects (P <.001) in the subjects without AII inhibition, but not in those receiving AII inhibitors. Given without ISMN or AII inhibitors, L-arginine decreased peripheral systolic BP, but to a lesser extent than ISMN. CONCLUSIONS: L-arginine has potential value as an adjunct to ISMN in combination with antihypertensive therapy in elderly patients with systolic hypertension. However, when given with single-dose ISMN, its vasodilator activity may overlap with that of AII inhibitors. Future studies of L-arginine in conjunction with chronic continuous ISMN dosing are warranted.

Aged↗
PubMed1999

The effect of isosorbide dinitrate on placental blood flow and maternal blood pressure in women with pregnancy induced hypertension.

The effect of isosorbide dinitrate (ISDN) on maternal and fetal circulation was assessed in 23 women with pregnancy induced hypertension (PIH). A double-blind randomized design was employed. Each woman was given a sublingual tablet of ISDN (5 mg) or placebo. Maternal blood pressure (BP) and heart rate (HR) were measured before and every 2 min after the medication or placebo, for a total of 20 min. Flow velocity waveforms in the uterine and umbilical arteries were recorded at the same time periods, using pulsed Doppler ultrasound. The ratio of peak systolic to end-diastolic flow velocity (S/D) in those vessels was calculated. After ISDN mean maternal BP fell from 103 +/- 1.8 mm Hg to 90.5 +/- 2.9 mm Hg at 14 min (P < .0001) and mean maternal HR increased from 97.3 +/- 3.8 beats/min to 115.7 +/- 3.5 beats/min at 12 min (P < .0001). The mean S/D in the umbilical artery fell from 3.07 +/- 0.33 to 2.58 +/- 0.23 at 8 min (P < .0007). The mean S/D in the uterine artery fell from 3.27 +/- 0.6 to 2.38 +/- 0.28 at 10 min (P < .0001). In seven of 12 women with an early diastolic notch in the uterine artery flow velocity waveform the notch diminished or disappeared within the first 6 min after the medication. No significant change in any of the measured parameters was observed in the placebo group. Our finding that ISDN altered maternal and fetal hemodynamics in PIH lends support to the further exploration of nitric oxide donors in the treatment and prevention of pregnancy induced hypertension.

Adult↗
PubMed2001

Synthesis, hydrolysis kinetics and anti-platelet effects of isosorbide mononitrate derivatives of aspirin.

Two isomeric aspirin derivatives of isosorbide-5-mononitrate (ISMN) were prepared and evaluated as potential mutual prodrugs of aspirin and nitric oxide. The hydrolysis of both compounds was studied in pH 7.4 phosphate buffer solution, buffered alpha-chymotrypsin solution and 10% buffered rabbit plasma. The benzodioxin-4-one derivative was hydrolysed to salicylic acid and ISMN acetate in buffer solution (t(1/2) 32.1 h), 10% buffered rabbit plasma (t(1/2) 25.7 min) and alpha-chymotrypsin (t(1/2) 86.6 min). The carboxylic acid ester derivative ISMNA was hydrolysed via the salicylate ester in buffer solution (t(1/2) 48.5 h) but was rapidly and almost exclusively hydrolysed to aspirin and ISMN in plasma solution (t(1/2) 2.8 min). The hydrolysis appeared to be enzyme mediated as it was suppressed by co-incubation with eserine. ISMNA was evaluated for its ability to inhibit platelet aggregation in rabbit PRP in response to the following agonists: arachidonic acid (AA) (100 microM), ADP (1.2 microM), phorbol ester (0.5 microM), platelet activating factor (PAF) (5 nM) and the thromboxane mimic U46619 (1.5 microM). ISMNA suppressed platelet response to AA at 1 microM whereas 10 microM aspirin showed no inhibitory effects.

Animals↗