α,α-Diphenylsuccinimide: Evaluation of Anticonvulsant and Hydrophobic Properties

Jones, Gary L.; Amato, Robert J.; Jones, Mary F.

doi:10.1002/jps.2600730307

Cited by 3 publications

(1 citation statement)

References 12 publications

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“…All data were acquired in male CF#l strain white mice, except for the LD50 of phenytoin, which was determined in male dd-strain white mice. aData for phenytoin and phenobarbital were taken from Jones et al [1984], except for the LD50 values, which were taken from Nakamura et al [1965] and Vida et al [1973], respectively. ' -, values have not been reported.…”

Section: Analysis Of Brain and Blood Concentrationsmentioning

confidence: 99%

Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione

Jones

1990

Drug Development Research

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Jones, G.L.: Anticonvulsant potency and toxicity of 5,5-diphenyl-2,4-oxazolidinedione.Drug Dev. Res. 21 :19-27, 1990.The anticonvulsant ED50 of 5,5-diphenyl-2,4-oxazolidinedione (DPO) was determined in male CF#1 mice by a standard maximal electroshock method, and compared with that for phenytoin (PHT) and phenobarbital (PB). Acute neurotoxicity (T050) and acute lethall?\i (LD50) were also determined. These parameters are reported with respect to i.p. dosage, and blood and brain concentrations. The anticonvulsant ED50 (308 mg/kg) of DPO was significantly less than that of either PHT (7.1 mg/kg) or PB (19.0 mg/kg). The same order of potency was observed when expressed in terms of blood or brain concentrations, although important quantitative differences were noted. Neurotoxicity was observed with doses of DPO required for anticonvulsant action (TD50 = 335 mgikg). Furthermore, acute lethality (LD50 = 373 mg/kg) was observed at doses not significantly different (P >.05) than the ED50. Doses between the ED50 and LD50 produced profound motor incoordination, seizures, and coma. Because of its extremely narrow margin of safety, DPO would not be considered a likely candidate for evaluation as a therapeutic agent in man. However, a greater understanding of its pharmacology is desirable because, in spite of its structural similarity to PHT, it contrasts sharply in certain properties.

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Section: Analysis Of Brain and Blood Concentrationsmentioning

confidence: 99%

Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione

Jones

1990

Drug Development Research

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Acute toxicity induced by 2‐aryl‐N‐methylsuccinimides

Rankin

Shih

Teets

et al. 1990

J of Applied Toxicology

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Phensuximide (PSX) is a 2-arylsuccinimide useful in the treatment of absence seizures. PSX is a mild urotoxicant and is structurally related to N-phenylsuccinimide (NPS) and its antifungal derivatives. Since substitution of the phenyl ring of NPS with chloro or tert-butyl groups can produce compounds with enhanced nephrotoxic potential, it was felt that similar substitutions on the phenyl ring of PSX also might produce derivatives with enhanced nephrotoxic potential. Three derivatives of PSX were prepared and tested: 2-(3-chlorophenyl)-N-methylsuccinimide (CPMS); 2-(4-tert-butylphenyl)-N-methylsuccinimide (BPMS) and 2-(3,5-dichlorophenyl)-N-methylsuccinimide (DPMS). In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle (sesame oil, 2.5 ml kg-1) and renal function monitored at 24 and 48 h. Only minor changes in renal function were noted with the PSX derivatives. BPMS and DPMS (1.0 mmol kg-1) treatment induced mild renal tubular necrosis and thickening of the glomerular membranes. However, no significant morphological changes were noted in ureters, bladder or liver in any treatment group. In a second set of experiments, rats were pretreated with phenobarbital (75 mg kg-1 day-1, i.p., 3 days) followed by a single i.p. injection of DPMS (0.4 or 1.0 mmol kg-1) or DPMS vehicle. Renal function was monitored as before. Phenobarbital pretreatment did not markedly enhance the functional nephrotoxicity induced by DPMS (0.4 mmol), but tubular necrosis was greater than observed in non-phenobarbital-pretreated rats receiving DPMS (1.0 mmol kg-1). In addition, hepatotoxicity was observed as the appearance of numerous non-staining vacuoles in hypertrophied hepatocytes. In the phenobarbital plus DPMS (1.0 mmol kg-1) treatment group, all rats died by 48 h. Prior to death, rats exhibited increased proteinuria (+3), hematuria (+3) and blood urea nitrogen concentration. At 24 h, kidneys from rats treated with phenobarbital plus DPMS (1.0 mmol kg-1) exhibited extensive proximal tubular necrosis and numerous glomeruli with thickened membranes. Hepatotoxicity was more pronounced than with phenobarbital plus DPMS (0.4 mmol kg-1) at 48 h and urinary bladders had focal areas of erythrocytes pooling below the epithelial lining. These results demonstrate that although NPS and PSX are structural analogs, chemical substitutions that enhance the nephrotoxic potential of NPS do not have a similar effect on PSX. In addition, DPMS can induce urotoxicity in a manner similar to that observed for PSX and probably induces toxicity via one or more metabolites.

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Chapter 2. Anticonvulsant Agents

Liebman¹,

Schneider²

1985

Annual Reports in Medicinal Chemistry

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α,α-Diphenylsuccinimide: Evaluation of Anticonvulsant and Hydrophobic Properties

Cited by 3 publications

References 12 publications

Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione

Anticonvulsant potency and toxicity of 5,5‐diphenyl‐2,4‐oxazolidinedione

Acute toxicity induced by 2‐aryl‐N‐methylsuccinimides

Chapter 2. Anticonvulsant Agents

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