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.
Department of Drug Safety Evaluation, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan.
Masahito
M
Horiuchi
Megumi
M
Kimura
Miwa
M
Tokumura
Nobuyoshi
N
Hasebe
Tohko
T
Arai
Kohji
K
Abe
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