Seizures induced by theophylline and isoniazid in mice.
Isoniazid-induced seizures respond poorly to anticonvulsants but well to pyridoxine (Vitamin B6); theophylline produces difficult-to-treat seizures with substantial morbidity and mortality. Theophylline therapy depresses plasma pyridoxal-5'-phosphate (PLP), the active metabolite of pyridoxine, suggesting that theophylline-induced seizures might be amenable to treatment with pyridoxine. Our study established the dose-response relationship for convulsions due to isoniazid and theophylline in mice and determined if pyridoxine antagonized such seizures. Female CD-1 outbred mice weighing 25 to 30 g were used. Clonic seizures had clonic activity lasting 5 sec; tonic seizures had loss of the righting reflex with tonic hindlimb extension. Groups of 10 mice received single doses of 50, 100, 150, 200, 250 or 300 mg aminophylline/kg i.p. or 100, 150, 200, 250, 300 or 350 mg isoniazid/kg i.p. and were observed for seizures or death. Pyridoxine or saline with aminophylline or isoniazid were administered simultaneously. The LD50 for aminophylline was 266 mg/kg; for isoniazid it was 160 mg/kg. Doses of 150 mg aminophylline/kg or 100 mg isoniazid/kg did not induce seizures. Pyridoxine with aminophylline or isoniazid did not alter the frequency or time of onset of seizures or death. This was unexpected because pyridoxine antagonizes theophylline-induced seizures in mice and reverses isoniazid-induced seizures in humans. We found no evidence that PLP depletion in mice is a mechanism for seizures induced by isoniazid or aminophylline in a fashion similar to isoniazid in humans.
Bonner
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Department of Pediatrics, Scott & White Clinic and Memorial Hospital, Scott, Sherwood and Brindley Foundation, Texas A&M University Health Science Center, College of Medicine, Temple 76502, USA.
Peterson
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SL
Weir
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MR
D000818:Animals; D000995:Antitubercular Agents / Q000633:toxicity; D001993:Bronchodilator Agents / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D007538:Isoniazid / Q000633:toxicity*; D051379:Mice; D011732:Pyridoxal Phosphate / Q000097:blood; D011736:Pyridoxine / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy; D013806:Theophylline / Q000633:toxicity*
D000995:Antitubercular Agents; D001993:Bronchodilator Agents; D011732:Pyridoxal Phosphate; D013806:Theophylline; D011736:Pyridoxine; D007538:Isoniazid