General pharmacological studies on N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate. 1st communication: effect on the central nervous system.
The pharmacological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent, on the central nervous system were studied in various experimental animals as compared with those of disopyramide, mexiletine and lidocaine, and the following results were obtained. 1. Acute toxicity of SUN 1165 in mice was similar to that of mexiletine, and twice as potent as compared with that of disopyramide and lidocaine. Main acute toxic symptoms of SUN 1165 were muscle relaxation, ataxia, clonic convulsions, tremor and a decrease in spontaneous activity in mice, rats and rabbits. In addition to these symptoms, vomiting in dogs was observed. These toxic symptoms were similar to those of lidocaine. In the case of disopyramide, ataxia, tremor and a decrease in spontaneous activity were observed in mice and rats. On the other hand, mexiletine caused central nervous excitatory symptoms, that is, tremor, Straub tail, clonic convulsions, jumping, running and opisthotonus in mice and rats, and vomiting in dogs. 2. SUN 1165 even at large doses (50-100 mg/kg p.o.) exerted no significant effects on the following changes: hexobarbital-induced induced hypnosis, oxotremorine-induced tremor, apomorphine-induced hypothermia, reserpine-induced ptosis and hypothermia, 5-hydroxytryptophan syndrome and fighting behavior in mice, and conditioned avoidance response in rats. 3. An ineffective dose of SUN 1165 (12.5 mg/kg p.o.) on spontaneous locomotor activity was lower than of disopyramide and lidocaine, however, higher than that of mexiletine. 4. SUN 1165 at large doses showed antagonistic action on toxic extensor seizures induced by maximal electroshock, picrotoxin, or strychnine in mice, but anticonvulsive effects of SUN 1165 were less potent than those of mexiletine and lidocaine. SUN 1165 had no effect on clonic convulsions induced by pentetrazol and pictrotoxin in mice, while both mexiletine and lidocaine prolonged the duration of clonic convulsions. 5. The muscle relaxant effect of SUN 1165 (50%-toxic dose, TD50 = 30 mg/kg p.o.) was more marked than that of lidocaine (TD50 = 92 mg/kg p.o.) on traction test in mice. However, effect of SUN 1165 (TD50 = 62 mg/kg p.o.) on motor incoordination was similar to that of disopyramide, mexiletine and lidocaine on the rotarod test in mice. 6. The analgesic effect of SUN 1165 was as weak as that of disopyramide, mexiletine and lidocaine on chemically and mechanically-induced pain response in mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Hirotsu
I
I
Laboratory of Experimental Pharmacology, Suntory Institute for Biomedical Research, Osaka, Japan.
Kihara
T
T
Nakamura
S
S
Hattori
Y
Y
Hatta
M
M
Kitakaze
Y
Y
Takahama
K
K
Hashimoto
Y
Y
Miyata
T
T
Ishihara
T
T
D000284:Administration, Oral; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000517:prevention & control; D002415:Cats; D002490:Central Nervous System / Q000187:drug effects*; D055598:Chemical Phenomena; D002621:Chemistry; D004206:Disopyramide / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D004285:Dogs; D004569:Electroencephalography; D005260:Female; D007035:Hypothermia / Q000188:drug therapy; D008012:Lidocaine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D008801:Mexiletine / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012640:Seizures / Q000188:drug therapy; D014202:Tremor / Q000139:chemically induced / Q000188:drug therapy; D014839:Vomiting / Q000139:chemically induced
D000889:Anti-Arrhythmia Agents; D008801:Mexiletine; D008012:Lidocaine; C042288:pilsicainide; D004206:Disopyramide