In vitro studies on the transdermal formulation containing pentoxifylline microspheres with poly-L-lactide.

In this study, microspheres of Pentoxifylline (PTX) obtained with poly-L-lactide were investigated for drug-polymer ratios of 1:1, 1:5 and 1:10 and the HPLC results of PTX in the microspheres indicated that 1:5 drug-polymer ratio had the highest loading efficiency. For HPLC analysis acetonitrile-water (40:60) was selected as the mobile phase because it yielded the most favorable k' values. Retention times are 4.51 and 7.88 min. for PTX and internal standard (phanecetin), respectively. Calibration curves were linear (r2 > 0.999) in the range of 0.5-10 mg/ml with no significant difference from the origin. Then, matrix controlled transdermal systems containing plain drug or microspheres of drug were prepared. Carrageenan was chosen as a matrix polymer. In vitro release data of the formulations were evaluated kinetically. The results obtained indicate that PTX containing microspheres can be incorporated in carrageenan matrices to form a transdermal therapeutic system.

Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo-4,5-imidazolidinedione derivatives.

Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazide (2) was converted to new 1-substituted benzylidene/furfurylidene-4- [2-(3,4-dimethoxyphenyl)ethyl]-3-thiosemicarbazides (3) which furnished 2-(substituted benzylidene/furfurylidene) hydrazono-3-[2-(3,4-dimethoxyphenyl)ethyl]thiazolidin-4-ones (4) and 1-(substituted benzylidene/furfurylidene)-amino -3-[2-(3,4-dimethoxyphenyl)ethyl]-2-thioxo-4,5-imidazolidinedio nes (5) on reaction with chloroacetic acid and oxalyl chloride, respectively. The structure of 5 was confirmed by X-ray diffraction studies performed on 5a. 4 and 5 were evaluated for their potentiating effects on pentobarbital induced hypnosis. Most of the compounds caused remarkable increases in pentobarbital sleeping time.

Determination of aminoglutethimide enantiomers as dansyl derivative in human plasma by HPLC with fluorescence detection.

Determination of aminoglutethimide enantiomers as a dansyl derivative in plasma by HPLC has been achieved using cellulose tris(3,5-dimethylphenyl carbamate) chiral stationary phase known as Chiralcel OD, and a mobile phase consisted of ethanol-cyclohexane-methanol (95:5:2 v/v/v). The limit of detection for each enantiomer of aminoglutethimide using fluorescence detector was 20 ng ml-1.

Synthesis and pharmacology of new dithiocarbamic acid esters derived from phenothiazine and diphenylamine.

2-Methylthio-10-[(N,N-disubstituted-thiocarbamoylthio)acetyl]- phenothiazines (4a-g) and N-(3-methylthiophenyl)-N-[(N,N-disubstituted- thiocarbamoylthio)acetyl]phenylamines (5a-g) were synthesized by subsequent treatment of 2-methylthio- 10-chloroacetylphenothiazines (1) and N-(3-methylthiophenyl)-N-chloroacetylphenylamine (2) with potassium salts of N,N-disubstituted dithiocarbamic acid derivatives (3a-i). The structures of the compounds were determined by analytical and spectral (IR, 1H NMR, 13C NMR, EIMS) methods. The antihistaminic and anticholinergic activities of 4a, 4c, 4e-g, 5a-c, 5e, and 5 g were evaluated in comparison with H1-receptor antagonist mepyramine and nonselective cholinergic antagonist atropine. In the first series of experiments, the cumulative concentration-response curves to histamine (10(-8)-10(-4) M) and acetylcholine (10(-8)-10(-4) M) were constructed in seperate fundus strips. The test compounds exhibited marked antihistaminic activity at 10(-6) M concentration but compounds did not influence acetylcholine induced contractions. Concentration-related experiments carried out on 4 g and 5 g revealed that a moderate antihistaminic activity was present at 10(-7) M concentration of the compounds and became strong at higher concentrations. In the second series of experiments, the cumulative concentration-response curve to histamine (10(-9)-10(-4) M) was constructed in guinea-pig ileum segments. Maximal responses were obtained by 10(-6)-3 x 10(-6) M concentrations of histamine in ileum segments. Similar inhibitions of histamine contractions were also obtained with the test compounds. Their inhibitory effectiveness was evaluated by comparing the pA2 values.

Synthesis and preliminary anticonvulsant activity evaluation of new 2-thioxo-4,5-imidazolidinedione derivatives.

A series of 1-substituted benzylideneamino-2-thioxo-3-allyl-4,5-imidazolidinediones (2a-j) were synthesized by the cyclization of 1-substituted benzylidene-4-allylthiosemicarbazides (1a-j) with oxalyl chloride in anhydrous ethereal medium. The structures of 2a-j were confirmed by analytical and spectral data (IR, 1H-NMR and EIMS). All synthesized compounds were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet) induced seizures. Among the compounds tested, 2b and 2h exhibited some activity in anticonvulsant identification (Phase I) trials in mice.

Synthesis and preliminary CNS depressant activity evaluation of new 3-[(3-substituted-5-methyl-4-thiazolidinon-2-ylidene)hydrazono]-1H-2- indolinones and 3-[(2-thioxo-3-substituted-4,5-imidazolidinedion-1-yl) imino]-1H-2-indolinones.

A series of (+/-) 3-[(3-substituted-5-methyl-4-thiazolidinon-2- ylidene)hydrazono]-1H-2-indolinones (2a-h) and 3-[(2-thioxo-3-substituted-4,5-imidazolidinedion-1-yl)imino] -1H-2-indolinones (3a-g) were synthesized by the cyclization of 3-(4-substituted-thiosemicarbazono)-1H-2-indolinones (1a-h) with ethyl 2-bromopropionate in anydrous ethanolic medium and oxalyl chloride in anhydrous diethyl ether, respectively. The structures of 2 and 3 were confirmed by analytical and spectral data (IR, 1H NMR, 13C NMR, and EIMS). The configuration of 3 was assigned on the basis of 1H NMR and 13C NMR data. 2c, 2d, 2g, 2h, and 3a-g were evaluated for anticonvulsant activity against maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScMet) induced seizures. Among the compounds tested, only 2d exhibited some activity in anticonvulsant identification (Phase I) trials in mice. 2a, 2b, 2d, 2g, 2h, and 3a-g were additionally tested for potentiating effects on pentobarbital induced hypnosis in mice. All of the test compounds increased the sleeping time of pentobarbital significantly (p < 0.05) and the most potent compound was found to be 3a.

Synthesis and hypnotic activity of some 2-thioxo-4,5-imidazolidinedione derivatives.

Several 1-Substituted benzylideneamino-2-thioxo-4,5-imidazolidinedione derivatives were synthesized 2a-i, characterized and evaluated for hypnotic activity. The tested compounds increased the sleeping time to a significant value (p < 0.001).