title: Anti-ischaemic response to sublingual nitroglycerin during oral administration of isosorbide dinitrate in patients with stable angina pectoris: when does cross-tolerance occur?
abstract: The purpose of this study was to evaluate the efficacy of sublingual nitroglycerin (NTG) during treatment with oral sustained-release isosorbide dinitrate (ISDN) in two doses: 80 mg and 120 mg. In a double-blind crossover design study 38 men with stable angina initially received either an oral placebo (OP) or ISDN. All patients received either NTG 0.5 mg or sublingual placebo (SLP) 2.5 h after OP ingestion, but only NTG 2.5 h after ISDN. The same pattern was used in the first ingestion and in long-term OP or ISDN therapy for 7 days (OP and ISDN every 6 h, and ISDN once daily). The efficacy of NTG was evaluated by analyzing walking time to ischaemia (WTI) during exercise tests performed 5 minutes after NTG or SLP administration, and the efficacy of ISDN 2 h and 6 h after oral ingestion. In the first ingestion NTG significantly improved WTI ( p < 0.0001) by 42.7% after OP, by 46.5% after 80 mg ISDN and by 52.1% after 120 mg. After long-term OP therapy NTG prolonged WTI ( p < 0.01) by 15.6%, during once-daily ISDN treatment, an 80 mg dose prolonged WTI by 22.8% and a dose of 120 mg by 36.5%. However, NTG did not improve WTI in q.i.d. therapy. Six hours after the first 80 mg ISDN ingestion WTI improved ( p < 0.0001) by 66.0%, and after 120 mg by 58.4%. Following once-daily therapy ISDN prolonged WTI ( p < 0.0001) by 27.2% after an 80 mg dose and by 36.2% after a dose of 120 mg. No improvement was observed in q.i.d. treatment. Thus, severe tolerance to ISDN abolishes the anti-ischaemic effects of NTG, and appropriate regimens of ISDN have considerable anti-anginal effects during chronic administration.
authors.affiliation: 2nd Department of Coronary Artery Disease, National Institute of Cardiology, Warsaw, Poland. Marek.7372069@pharmanet.com.pl
authors.forename: Marek Antoni
authors.initials: MA
authors.lastname: Kośmicki
authors.forename: Hanna
authors.initials: H
authors.lastname: Szwed
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Sadowski
mesh_terms: D000328:Adult; D000787:Angina Pectoris / Q000188:drug therapy*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000627:therapeutic use; D005996:Nitroglycerin / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D020030:Nitric Oxide Donors; D005996:Nitroglycerin; D007548:Isosorbide Dinitrate