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Aims Patients with migraine may receive the 5-HT 1B/1D agonist, rizatriptan (5 or 10 mg), to control acute attacks. Patients with frequent attacks may also receive propranolol or other b-adrenoceptor antagonists for migraine prophylaxis. The present studies investigated the potential for pharmacokinetic or pharmacodynamic interaction between b-adrenoceptor blockers and rizatriptan.Methods Four double-blind, placebo-controlled, randomized crossover investigations were performed in a total of 51 healthy subjects. A single 10 mg dose of rizatriptan was administered after 7 days' administration of propranolol (60 and 120 mg twice daily), nadolol (80 mg twice daily), metoprolol (100 mg twice daily) or placebo. Rizatriptan pharmacokinetics were assessed. In vitro incubations of rizatriptan and sumatriptan with various b-adrenoceptor blockers were performed in human S9 fraction. Production of the indole-acetic acid-MAO-A metabolite of each triptan was measured.Results Administration of rizatriptan during propranolol treatment (120 mg twice daily for 7.5 days) increased the AUC(0,?) for rizatriptan by approximately 67% and the C max by approximately 75%. A reduction in the dose of propranolol (60 mg twice daily) and/or the incorporation of a delay (1 or 2 h) between propranolol and rizatriptan administration did not produce a statistically signi®cant change in the effect of propranolol on rizatriptan pharmacokinetics. Administration of rizatriptan together with nadolol (80 mg twice daily) or metoprolol (100 mg twice daily) for 7 days did not signi®cantly alter the pharmacokinetics of rizatriptan. No untoward adverse experiences attributable to the pharmacokinetic interaction between propranolol and rizatriptan were observed, and no subjects developed serious clinical, laboratory, or other signi®cant adverse experiences during coadministration of rizatriptan with any of the b-adrenoceptor blockers. In vitro incubations showed that propranolol, but not other b-adrenoceptor blockers signi®cantly inhibited the production of the indole-acetic acid metabolite of rizatriptan and sumatriptan. Conclusions These results suggest that propranolol increases plasma concentrations of rizatriptan by inhibiting monoamine oxidase-A. When prescribing rizatriptan to migraine patients receiving propranolol for prophylaxis, the 5 mg dose of rizatriptan is recommended. Administration with other b-adrenoceptor blockers does not require consideration of a dose adjustment.

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SUMMARYIndicine E-oxide, an antitumor agent possessing an unusual type of potential alkylating capacity, was recently selected for clinical trial. Radioactive-labelled indicine E-oxide was sought for studies of its biological properties relating t o antitumor activity and toxicity. Available indicine E-oxide was reduced to indicine, and the alkaloid ester was hydrolyzed to its component compounds, retronecine and (-)-trachelanthic acid. The radioactive label was then introduced into the hydroxymethyl grouping of retronecine by a previously reported procedure involving oxidation of retronecine to methyl l,Z-dehydro-?I3 -hydroxy-8a-pyrrolizidine-1-carboxylate followed by reduction of the methoxycarbonyl grouping with LiAl H4.Recombination of the alcohol and the carboxylic acid, a heretofore challenging problem in syntheses of pyrrolizidine alkaloid esters, was achieved using an adaptation of the mild esterification procedure recently reported by Hassner and Alexanian.By this method, indicine was obtained following reaction of retronecine, the isopropylidene derivative of (-)-trachelanthic acid, and E,"-dicyclohexylcarbodiirnide in the presence of 4-(dimethylamino)pyridine in toluene. Tritium-labelled indicine thus formed was then treated with g-chloroperoxybenzoic acid to give labelled indicine g-oxide. RESULTS AND DISCUSSIONThe basic synthetic steps used consisted of, first, the hydrolysis of indicine to its fundamental moieties ( -h a c h e l a n t h i c acid (111) and retronecine (IV), followed by introduction of a label into retronecine, and finally, the reassembly of constituents (111 and IV) to produce labelled indicine (see Scheme 1). The recombination was the k e y step in the task since methods for converting retronecine to [9- HI -retronecine are known (6,7) and, furthermore, the total synthesis of retronecine Syntheses of both retronecine and (-)-trachelanthic acid have been reported( 8 , lo), but their synthetic union to produce indicine has not heretofore been described. Other Ssubstituted monoesters of retronecine (and stereoisomeric heliotridine) have been prepared from the pyrrolizidine alcohol via t h e corresponding chloromethyl compound and the sodium salt of the appropriate acid (11-14).Reported examples utilize widely divergent isolation efforts; some products apparently were isolated readily, but the countercurrent distribution technique was used for others. Reported yields range from 13% (for 9-heliotrylretronecine) Thin-layer chromatography (TLC) used to monitor reactions and to examine products for homogeneity was done on Analtech precoated (250 pm) silica gel