Absence of convulsive liability of doripenem, a new carbapenem antibiotic, in comparison with beta-lactam antibiotics.
beta-Lactam antibiotics have been suggested to have some degree of convulsive activity and neurotoxicity in experimental animals as well as in clinical situations. We examined the convulsive activities of a new carbapenem antibiotic, (+)-(4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(3S,5S)-5-[(sulfamoylamino)methyl]-3-pyrrolidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxic acid monohydrate (doripenem) using several animals and compared them with beta-lactam antibiotics. In intravenous (IV) injection studies, imipenem/cilastatin, at 400/400mg/kg produced seizure discharges on electroencephalogram (EEG) accompanied with clonic convulsions in rats. Meropenem showed only wet dog shaking behavior at 200 and 400mg/kg. Doripenem caused no changes in the EEG and behavior in rats at 400mg/kg. Imipenem/cilastatin IV potentiated the pentylenetetrazol (PTZ)-induced convulsions in mice at 250/250 mg/kg, while meropenem, panipenem/betamipron, cefazolin or doripenem did not cause any marked effects at up to 500 mg/kg. In mouse intracerebroventricular (ICV) injection studies, imipenem, panipenem and cefazolin induced clonic convulsions in a dose-dependent manner in mice. Doripenem and meropenem did not induce convulsions at up to 100 microg/mouse. In dog ICV injection studies, imipenem produced generalized seizure discharge with clonic convulsions at 100 microg/dog. Meropenem also produced spikes or seizure discharges at 100, 300 and 1,000 microg/dog. However, doripenem had no effects on the EEG and behavior in dogs at any doses. In in vitro binding studies, imipenem, panipenem, cefazolin and meropenem inhibited [(3)H]muscimol binding to the GABA(A) receptor in mouse brain homogenates while doripenem did not cause any inhibition at up to 10mM. In addition, doripenem had no influence on the anti-convulsant actions of valproic acid in the PTZ- or bicuculine-induced convulsive model. These results clearly indicate that doripenem has no convulsive activity, suggesting that its neurotoxicity may be negligible in clinical use.
Horiuchi
Masahito
M
Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Kimura
Megumi
M
Tokumura
Miwa
M
Hasebe
Nobuyoshi
N
Arai
Tohko
T
Abe
Kohji
K
D000409:Alanine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology; D015780:Carbapenems / Q000008:administration & dosage / Q000494:pharmacology*; D003292:Convulsants; D004285:Dogs; D000077726:Doripenem; D004347:Drug Interactions; D004569:Electroencephalography; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D000077731:Meropenem; D051379:Mice; D008813:Mice, Inbred ICR; D010433:Pentylenetetrazole; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced; D013845:Thienamycins / Q000494:pharmacology; D014635:Valproic Acid / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D015780:Carbapenems; D003292:Convulsants; D013845:Thienamycins; C047207:N-benzoylalanine; D014635:Valproic Acid; D000077726:Doripenem; D000077731:Meropenem; D000409:Alanine; C039536:panipenem; D010433:Pentylenetetrazole