Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:APRD00528 (Monit)
 35,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To avoid the development of nitrate tolerance secondary to relatively constant elevated plasma nitrate concentrations, intermittent nitrate dosing has been advocated. However, a nitrate-free interval may induce a rebound increase in myocardial ischaemia, and thus increase anginal symptoms during the latter portion of the dosing interval. This was suggested by the results of recent studies in which nitroglycerin patches were administered intermittently with a 12 h nitrate-free interval. The present investigation was carried out to determine whether a controlled-release formulation of 60 mg isosorbide-5-mononitrate (5-ISMN) would produce such a rebound phenomenon. Seventy-nine patients, who had participated in four crossover, placebo-controlled studies in which the treatment arms lasted for between 1 and 2 weeks, were reviewed. These studies had assessed the efficacy of this nitrate preparation by exercise testing and each had included exercise testing at the end of each treatment phase, 24 h after the last medication had been administered. There were no differences noted in the time to onset of angina, the time to onset of 1 mm ST segment depression or the total exercise duration between the two treatment phases, indicating an absence of rebound phenomena at the end of the dosing interval. The reason for the absence of a detectable pre-dose rebound is unclear, but the plasma concentration profile of 5-ISMN produced by the presently used preparation, resulting in a nitrate-low instead of nitrate-free interval, may have contributed.
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PMID:Absence of pre-dose rebound phenomena with once daily 5-ISMN in a controlled-release formulation. 162 73

1. Plasma concentrations and some haemodynamic parameters known to be affected by nitrates, were monitored in healthy volunteers who received three different dose regimens of isosorbide-5-mononitrate (5-ISMN) over 5 day study periods. 2. No haemodynamic tolerance was found in the 60 mg once-daily dose schedule which produced high plasma concentrations during the daytime but concentrations no greater than 100 ng ml-1 at night. In contrast, a dose regimen of 60 mg followed by 30 mg 12 h later and thereafter every 8 h until the fifth day induced complete haemodynamic tolerance. With this dose regimen the minimum plasma concentrations were never below 300 ng ml-1. A significant attenuation of haemodynamic effects was also found with the third dose regimen, 60 mg followed by 30 mg 6 h later for 5 days, which produced minimum plasma concentrations of between 100 ng ml-1 to 300 ng ml-1; the degree of attenuation rose as trough plasma concentrations increased. 3. In conclusion, 60 mg 5-ISMN in a controlled-release (Durules) preparation given once daily was the only dose regimen not inducing nitrate tolerance.
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PMID:Plasma profile and haemodynamic tolerance to isosorbide-5-mononitrate in controlled-release form. 163 73

Imdur contains isosorbide-5-mononitrate (IS-5-MN) in a controlled-release (Durules) formulation. It has a significant anti-anginal effect when taken once daily at a dose of 60 mg. This anti-anginal effect persists during long-term treatment without the development of tolerance; once-daily treatment produces a plasma nitrate profile that is high enough to give anti-anginal protection during the daytime, but low enough during the latter part of the dosage interval to avoid the development of tolerance. Evidence shows that once-daily Imdur is equivalent in efficacy to plain tablets of IS-5-MN and isosorbide dinitrate taken three times daily at the same total daily dosage (60 mg), and to the calcium antagonist diltiazem (60 mg three times daily). In addition, the anti-anginal protection provided by Imdur in combination with beta-blocker treatment is superior to that achieved with beta-blocker treatment alone. In long-term studies Imdur has been shown to be well tolerated.
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PMID:Clinical experience with Imdur in angina pectoris. A review. 197 59

Nitrates are well established in the treatment of angina pectoris and the presence of sulfhydryl groups seems to be fundamental to nitrate-induced vasodilatation. The present study was performed to elucidate if large oral doses of N-acetylcysteine (NAC, 2,400 mg X 2), a donor of sulfhydryl groups, given together with a single oral dose of the long-acting nitrate, isosorbide-5-mononitrate (5-ISMN, 60 mg), would modify the nitrate effect evaluated by exercise testing before and after additional sublingual doses of nitroglycerin (NTG). Ten patients with angina pectoris and angiographically proven significant coronary artery disease were included. All patients received a baseline therapy with beta blockers. None of the patients had developed nitrate tolerance at inclusion. NAC/5-ISMN treatment significantly prolonged the total exercise time as compared with placebo/5-ISMN (7.7 +/- 2.1 min vs. 6.8 +/- 1.7 min, p less than 0.05). This increase was of such magnitude that no further effect was obtained after additional NTG doses. This study demonstrated that increased availability of sulfhydryl groups can increase the exercise capacity in angina pectoris patients treated with 5-ISMN without nitrate tolerance.
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PMID:N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients evaluated by exercise testing. 246 64

Twenty-four patients with severe stable angina pectoris were included in a randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of a controlled-release preparation of isosorbide-5-mononitrate (ISMN-CR) 60 mg once daily or twice daily as adjunctive treatment to a beta blocker. In bicycle ergometer exercise tests performed 4 h after study drug intake, total exercise time and time until 1-mm ST-depression increased significantly during both regimens as compared with placebo (p less than 0.05). However, only the 60-mg once-daily regimen was significantly better than placebo with regard to time until angina pectoris. The results indicate that ISMN-CR 60 mg once daily is effective as adjunctive to beta-blocker treatment, and nitrate tolerance appeared to develop during the twice-daily regimen. In 10 of the patients, the effect of additional sublingual nitroglycerin (NTG) was studied. Exercise time after NTG remained remarkably constant throughout all study periods. Exercise time was significantly prolonged after additional NTG and independent of the dose level of ISMN-CR. This indicates that cross-tolerance to NTG was not induced during sustained treatment with ISMN-CR.
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PMID:Efficacy of controlled-release isosorbide-5-mononitrate as adjunctive treatment to beta-blocking agents in patients with stable angina pectoris. 247 13

32 patients with stable angina pectoris who had been receiving a controlled-release formulation Durules of isosorbide 5-mononitrate (Imdur) 60 to 120 mg daily with concomitant beta-blocker therapy for at least 1 year were entered into a study to evaluate possible rebound phenomena from the abrupt withdrawal of isosorbide 5-mononitrate and to determine whether nitrate tolerance had developed. Isosorbide 5-mononitrate was abruptly withdrawn and substituted with placebo for 2 weeks, after which the active drug was reintroduced. No deterioration of exercise performance could be detected during withdrawal of therapy, but an increase was seen after reinstitution. No tolerance was found for systolic blood pressure and ST segment changes or for the number of anginal attacks and short-acting glyceryl trinitrate tablets consumed. Three patients had to be hospitalised because of a sudden deterioration of symptoms on withdrawal of isosorbide 5-mononitrate. It was concluded that isosorbide 5-mononitrate in Durules has a beneficial effect and that tolerance does not appear to be clinically relevant.
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PMID:Abrupt withdrawal of isosorbide 5-mononitrate (Imdur) after long term treatment in stable angina pectoris. A preliminary report. 288 19

Glyceryl 2-nitrate (G-2-N), which is the major metabolite of glyceryl trinitrate (GTN, Nitro Mack, glyceryl 1-nitrate (G-1-N) and isosorbide-5-nitrate (IS-5-N, Mono Mack) were examined in a comparative study. The haemodynamic and antianginal properties and the spasmolytic activity on blood vessels were investigated in the rat and dog. Also examined were the pharmacokinetics of G-2-N in the rat and of oral GTN in the dog. Strips of rat aorta contracted with potassium chloride or with norepinephrine were relaxed by G-2-N, but somewhat more weakly than with IS-5-N or G-1-N. After oral administration to the anaesthetized rat or to the conscious dog G-2-N exhibited antianginal and hypotensive activity for 6 h. The duration of action of orally administered GTN in the dog depended on the concentration used and was between 15 and 360 min. The half-life of elimination of G-2-N in the rat came to 2 h, and the substance was 100% bioavailable. The concentrations of G-2-N found in the walls of rat vena cava caudalis and rat aorta abdominalis were twice as high as those in blood or plasma. After oral administration of GTN to the conscious dog, G-2-N is the main metabolite, followed by G-1-N, glyceryl 1,2-dinitrate (1,2-GDN), and glyceryl 1,3-dinitrate (1,3-GDN). After a large oral dose of GTN (30 mg/kg), G-2-N contributes to the pharmacodynamic effect from the 3rd h or earlier.
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PMID:[The pharmacology and pharmacokinetics of glycerol-2-nitrate]. 311 68

Homogenates of selected segments of the rabbit gastrointestinal tract (GIT) were studied for their ability to biotransform isosorbide dinitrate (ISDN) and glyceryl trinitrate (GTN) to their mono- and di-nitrate metabolites, respectively. In addition, preferential formation of certain metabolites was investigated by examination of the patterns of metabolites formed by the various homogenates. After a 30-min incubation of ISDN with GIT homogenates (pH 7.4, 37 degrees C), the percent disappearance of ISDN and the ratio of isosorbide-2-mononitrate (2-ISMN) to isosorbide-5-mononitrate (5-ISMN) were as follows: stomach, 32%, 0.8; duodenum, 65%, 0.1; jejunum, 59%, 0.2; ileum, 38% , 1.2; cecum, 33%, 2.7; and colon, 32%, 3.4. After a 5-min incubation of GTN with GIT homogenates, the percent disappearance of GTN and the ratio of glyceryl-1,3-dinitrate (1,3-GDN) to glyceryl-1,2-dinitrate (1,2-GDN) were as follows: duodenum, 54%, 0.65; ileum, 73%, 0.68; and colon, 61%, 0.17. Incubation of 2 x 10(-7) M ISDN with mucosal and muscularis homogenates of duodenum, jejunum, and ileum resulted in significant losses of ISDN with an equimolar formation of the mononitrate metabolites. Most of the metabolic activity for ISDN resided in the mucosal layer of each section. The ratio of 2-ISMN to 5-ISMN varied in each section (stomach to colon) and cross section (mucosal versus muscularis) of the GIT. We conclude that the metabolism of ISDN and GTN by the GIT may contribute to the high clearance of these organic nitrates, and the low oral bioavailability of ISDN. Also, multiple mechanisms appear to be involved in the biotransformation of ISDN and GTN in the rabbit GIT.
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PMID:Patterns of isosorbide dinitrate and glyceryl trinitrate metabolites formed by selected segments of the rabbit gastrointestinal tract. 313 Sep 74

In a single-blind study of 6 weeks' duration, 32 patients with stable angina pectoris, who had been receiving controlled-release, Durules, isosorbide-5-mononitrate (Imdur) 60 to 180 mg daily for at least 1 year, were assessed after abrupt withdrawal of the nitrate. After 2 weeks of placebo treatment nitrate therapy was re-instituted, and the patients followed for another 2 weeks. The possibility of development of tolerance and rebound phenomena was also investigated. Three patients experienced severe anginal symptoms necessitating hospitalization when controlled-release isosorbide-5-mononitrate was withdrawn abruptly. Patients complained of more severe anginal symptoms during the placebo period, experienced more frequent anginal attacks and used more glyceryl trinitrate tablets than during active treatment. ST segment changes during exercise were more pronounced with placebo. After controlled-release isosorbide-5-mononitrate was re-introduced, these variables indicated significant improvement. On the other hand, no deterioration occurred in exercise performance during the placebo phase. Responsiveness to glyceryl trinitrate was maintained, as shown by comparisons of exercise tests performed after the long term treatment and during the placebo phase. Controlled-release isosorbide-5-mononitrate retains a beneficial effect in patients with angina pectoris during prolonged use, although some attenuation of the effect is seen. Abrupt withdrawal of the drug is not recommended because of the possibility of severe exacerbation of anginal symptoms, although no clearcut rebound phenomena were seen.
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PMID:Abrupt withdrawal of isosorbide-5-mononitrate in Durules (Imdur) after long term treatment in patients with stable angina pectoris. 314 92

A capsule formulation containing 50 mg of isosorbide mononitrate has been developed, 30% of which is in a nonsustained-release form to ensure rapid attainment of initial plasma levels. The remaining 70% is in a sustained-release form that ensures a long-lasting effect and the convenience of once-daily dosing. This formulation of sustained-release isosorbide mononitrate (Elantan LA 50 mg) provides plasma levels greater than 100 ng/ml for 17 hours after oral administration. For the remaining 7 hours, the nitrate plasma level ranges between 50 and 100 ng/ml.
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PMID:Sustained-release isosorbide mononitrate (50 mg): optimization of a once-daily dosage form for long-term treatment of angina pectoris. 334 35


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