Supra-additive toxic interaction of nicotine with antihistamines, and enhancement by the proconvulsant pentylenetetrazole.
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)
Sewell
R G
RG
Nanry
K P
KP
Kennedy
J
J
Stiger
T R
TR
Harmon
R E
RE
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
D006634:Histamine H1 Antagonists; D014309:Tripelennamine; D009538:Nicotine; D004155:Diphenhydramine; D010433:Pentylenetetrazole