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[Anticovulsant activity of N-(p-sulfamoyl-phenyl)-succinimide derivatives (author's transl)].

A series of newly synthesized N-phenyl-substituted derivatives of succinimide were screened for anticonvulsant activity. Addition of a sulfonamide group in the p-position was of great consequence for the anticonvulsant effect. Substitution of a halogen in the m- or o-position improved activity against electroshock induced seizures. Pentylenetetrazole convulsions could only be prevented by few of these substances in smaller than 200 mg/kg oral doses. Activity could be further enhanced by adding more aliphatic or aromatic groups to the succinimide ring. The lethal doses of most of the active succinimides were higher than 5000 mg/kg p.o. With sublethal doses mice sometimes become drowsy and had myoclonic seizures and/or diarrhoea. At therapeutic dose levels kinetic disturbances, potentiation of pentobarbitone hypnosis or analgesia were rarely observed.

Analgesics

Use of cyclopentyl ester protection for aspartic acid to reduce base catalyzed succinimide formation in solid-phase peptide synthesis.

A study was conducted to determine the effect of amino acid sequence and aspartyl protecting group on the rate of base catalyzed succinimide formation in the solid-phase synthesis of aspartyl peptides. The peptides H-Ala-Asp-Gly-Phe-OH and H-Ala-Asp-Leu-Phe-OH were synthesized by the solid-phase method with cyclopentyl or benzyl protection for the beta-carboxyl of aspartic acid. The results showed that the cyclopentyl ester was notably less susceptible to succinimide formation by treatment with tertiary amine than was the benzyl ester, and that the difference could have significant consequences for the synthesis of the large peptides which contain reactive sequences such as Asp-Gly.

Amino Acid Sequence

Effect of N-(3,5-dichlorophenyl)succinimide on the histological pattern and incidence of kidney tumors induced by streptozotocin rats.

The effect of the nephrotoxic substance, N-(3,5-dichlorophenyl)succinimide, on the histological pattern and incidence of kidney tumors induced by streptozotocin in rats was studied. In groups administered streptozotocin alone or in combination with nicotinamide, the histological pattern and the incidence of kidney tumors in rats were similar; renal cell tumors developed in 1 of 9 rats (11.1%) and in 2 of 17 rats (11.8%), respectively. However, post-treatment with N-(3,5-dichlorophenyl)succinimide increased the induction of epithelial tumors by streptozotocin, and embryonal cell tumors were also induced nearly as frequently. Administration of nicotinamide alone did not result in the development of kidney tumors.

Adenoma, Islet Cell

Enzymic oxidation alpha to the acetylenic group in the metabolism of N-(5-pyrrolidinopent-3-ynyl)-succinimide (BL 14) in vitro.

1. The product of alpha-acetylenic oxidation of N-(5-pyrrolidinopent-3-ynyl)-succinimide (BL 14) by rat liver preparations was identified as N-(5-pyrrolidino-2-hydroxypent-3-ynyl)succinimide, by mass spectral analysis of metabolites of deuterium-labelled and non-labelled substrate. 2. The synthesis and physicochemical characteristics of the metabolite are reported. 3. Substantial amounts of the metabolite were obtained in preparations from phenobarbital-treated rats, while only minute amounts were formed by non-induced preparations. 4. Evidence for the involvement of an inducible cytochrome P-450 system in effecting this alpha-acetylenic oxidation is presented.

Alkynes

Potential long-acting anticonvulsants. 1; Synthesis and activity of succinimides containing an alkylating group at the 2 position.

The synthesis of succinimide derivatives in which alkylating groups have been attached to the 2 positions of the ring or to the para position of the 2-phenyl substituent is described. The alkylating groups used were (a) alpha-haloacetyl, (b) alpha-haloacetamido, (c) maleimido, and (d) maleamyl. These compounds were prepared as potential long-acting anticonvulsants. Several of these derivatives exhibited activity against metrazole-induced seizures comparable to phensuximde, The maleimide 16 and the bromoacetamido derivative 23 exhibited a duration of action of at least 3.5 h.

Animals

Potential long-acting anticonvulsants. 2. Synthesis and activity of succinimides containing an alkylating group on nitrogen or at the 3 position.

The synthesis of succinimide derivatives in which alkylating groups have been attached to the imide nitrogen or to the 3 position of the ring is described. The synthesis of one bis-alkylating derivative 19 is also described. The alkylating groups used were (a) alpha-haloacetyl, (b) alpha-haloacetamido, (c) maleamyl, and (d) maleimido. These compounds were prepared as potential long-acting anticonvulsants. None of the compounds showed activity against maximal electroshock or metrazole-induced seizures.

Alkylating Agents

[Treatment of atypical absences with a combination of succinimide and dipropylacetate (author's transl)].

Fifteen epileptic patients with mild seizures of the narcolepsy type were treated with a combination of succinimide (average dose 750 mg) and dipropylacetate (average dose 1,200 mg), medication with each drug alone having brought no success. The combination of drugs stopped the seizures in eleven patients, in three they almost stopped and in one the frequency of seizures was halved. An E.E.G. was recorded in twelve, with improvement in each. Side effects occurred in five patients (nausea, vomiting, singultus and fatigue), but the drug had to be discontinued in only one instance.

Adolescent

Effect of succinimide on hyperoxaluria in the rat estimated value of the different dosing methods of oxaluria.

In the female rat intoxicated with ethylene glycol the oxaluria increases with the degree of intoxication. The increase is less in the animals treated with succinimide. The comparative study of the results of the dosages made with gas-liquid-chromatography and by various colorimetric methods show that this later gives varying results and underestimates high concentrations of oxalic acid. The result is that any study based on results of dosages of urinary oxalic acid made by colorimetry must be taken with some reserve, and this on whether the oxalic lithiasis is experimentally induced or human, or whether its evolution is spontaneous or influenced by a therapeutic.

Animals

Gas-chromatographic analysis for succinimide anticonvulsants in serum: macro- and micro-scale methods.

A gas-chromatographic analysis for the succinimide anticonvulsant drugs--ethosuximide, methsuximide, and phensuximide--in 1.0 ml of serum was modified to improve its reliability, speed, and precision. A separate procedure for 10-100 mul of serum was also developed. Neither method requires an initial preparation of derivatives. The working range of each method is about 10-100 mg/liter for the macro-method, 2-100 mg/liter for the micro-method. The methsuximide metabolite, N-desmethylmethsuximide, is included in both methods. Concentrations of N-desmethylmethsuximide in the blood of two patients with petit mal epilepsy are reported.

Animals

Gas--liquid chromatographic microdetermination of underivatized ethosuximide (alpha-ethyl-alpha-methyl succinimide) in plasma or serum.

A gas-liquid chromatographic procedure for the microdetermination of ethosuximide is described. Ethosuximide is extracted from acidified plasma or serum into chloroform containing an internal standard alpha,alpha-dimethyl-beta-methyl succinimide. Part of the initial chloroform extract is gently evaporated, the residue redissolved in n-heptane at 60 degrees C, and an aliquot analyzed by gas-liquid chromatography. The procedure is rapid, reliable, sensitive, and specific. It requires a 25--50 microliter sample for a single estimation, has a detection threshold of less than 10 micromol/liter, and is suitable for routine clinical use.

Chromatography, Gas