title: Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.
abstract: Antihistamines are being increasingly administered in combination with various other agents, with adverse drug reactions the frequent result. The present study consisted of two experiments. Experiment 1 examined the toxicological response of rats to nicotine tartrate (0.0, 2.0, 4.0, and 8.0 mg/kg) in combination with either of two H1-histamine receptor antagonists, the ethylene diamine tripelennamine HCl (0.0, 16.0, 32.0, and 64.0 mg/kg) or the aminoethyl ether diphenhydramine HCl (0.0, 32.0, 64.0, and 96.0 mg/kg). Adult female rats received intraperitoneal injections when housed 12 per cage and toxicological response (number dead per group) was assessed 24 hours post-treatment. The results showed that over the dose ranges employed, and when given alone, nicotine was completely non-lethal, tripelennamine was virtually non-lethal and diphenhydramine was toxic only at the highest dose (5 of 12, at 96.0 mg/kg). However, when nicotine and the antihistamines were delivered in combinations, the toxicological response was markedly altered. Tripelennamine in combination with nicotine yielded supra-additive interaction, with the degree of potentiation being a simple linear function of nicotine within each dose of tripelennamine. The interaction between nicotine and diphenhydramine was more complicated, with certain dose combinations yielding supra-additivity, yet with others yielding antagonism. It was suggested that seizure-precipitated cardiopulmonary collapse was the immediate cause of death, plausibly mediated by central mechanisms. As such, Experiment 2 examined the influence of adding the proconvulsant pentylenetetrazole (PTZ) (0.0, 10.0, and 20.0 mg/kg) to nicotine (0.0, 2.0, 4.0, and 8.0 mg/kg)-tripelennamine (0.0 and 32.0 mg/kg) combination treatments. Effects were assessed both at 1.0 and 24.0 hours post-injection.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.forename: R G
authors.initials: RG
authors.lastname: Sewell
authors.forename: K P
authors.initials: KP
authors.lastname: Nanry
authors.forename: J
authors.initials: J
authors.lastname: Kennedy
authors.forename: T R
authors.initials: TR
authors.lastname: Stiger
authors.forename: R E
authors.initials: RE
authors.lastname: Harmon
mesh_terms: D000818:Animals; D004155:Diphenhydramine / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D006634:Histamine H1 Antagonists / Q000633:toxicity*; D009538:Nicotine / Q000633:toxicity*; D010433:Pentylenetetrazole / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014309:Tripelennamine / Q000633:toxicity
chemical_list: D006634:Histamine H1 Antagonists; D014309:Tripelennamine; D009538:Nicotine; D004155:Diphenhydramine; D010433:Pentylenetetrazole