Synthesis and pharmacological activity of two derivatives of the amide of valproic acid.

Valproic acid (VPA), a synthetic branched-chain fatty acid, and its pro-drug the primary amide (VPD) are effective and widely used anti-epileptic agents. Although the use of VPA has grown in recent years, major side effects are still associated with this drug. We presume that it is possible, without loosing the VPD pharmacological profile, to obtain new compounds by undertaking substitutions in the CONH group. N,N'-bis-(2-propylpentanoyl)- 1,2-ethanediamine (3) and N,N'-bis-(2-propylpentanoyl)-1,3-propanediamine (4) were obtained from VPA (1) using a method reported in the literature. The chemical structures of the new compounds were demonstrated by elemental analysis, IR, and 1H NMR spectroscopy. Both compounds are less toxic and more effective in protecting the animals from death caused by PTZ than VPD after intraperitoneal administration to mice.

Synthesis, toxicity and immunomodulating activity of Co(II), Ni(II), Cu(II) and Zn(II) complexes of L(-)-2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole (levamisole).

Co(II), Ni(II), Cu(II) and Zn(II) complexes of levamisole (LMS) were prepared and characterized by elemental analyses, IR spectroscopy, 1H and 13C NMR and mass spectrometry. The following general formula was derived: M(LMS)2Cl2, where M = Co, Ni, Cu, Zn. It was established that LMS behaved as a monodentate ligand and the coordination was accomplished through the N-7 atom. The toxicity and the immunomodulating activity of the complexes on mice and rats in comparison with uncomplexed LMS was assayed. The metals in the complexes exerted different changes in the toxicity of LMS. The complex containing Zn(II) was less toxic and manifested higher immunomodulating activity than LMS.

Biochemical and morphological studies on the effects of anthocyans and vitamin E on carbon tetrachloride induced liver injury.

The effects of the natural antioxidants-anthocyans and vitamin E (in a solubilized pharmaceutical form) on carbon tetrachloride-induced liver injury in rats are studied. The changes in the activity of serum transaminases (ALAT and ASAT), the content of the reduced glutathione and cytochrome P-450 as well as the intensity of the processes of lipid peroxidation are assessed. The anthocyans exert a protective effect comparable to that of vitamin E on liver cells. The favorable effects of the combination of the antioxidants on the content of the reduced glutathione and on the processes of lipid peroxidation are more intensely expressed. The morphological changes occurring in hepatocytes correlate with the results of the biochemical studies. It is evident that both substances have a marked hepatoprotective activity.

Pharmacokinetics of vephylline--a new N-substituted theophylline derivative.

Vephylline (7,2-bis-2-hydroxyethylamino-1, 3-dimethylxanthine tartarate) is a xanthine derivative with high bronchodilating activity, low toxicity, and weak effects on the central nervous system. The aim of this study is to determine the pharmacokinetic parameters of vephylline after intravenous and oral (in solution and in tablets) administration to rabbits. Vephylline (dose 50 mg/kg b.w. intravenousely and orally in solution and dose 53.5 mg/kg b.w. in the form of tablets) is administered to the rabbits in an autocontrol crossover design at 7-days intervals. After the intravenous administration the distribution is relatively fast (t1/2 alpha = 3.28h). High values of the apparent volume of distribution--12.15 1/kg suggest tissue accumulation. Elimination is considerably slower (t1/2 beta = 19,00 h) than distribution. After oral administration of the drug in solution the absorption half-life is short and the bioavailability is relatively high. Peak plasma levels are attained at the first hour. The differences in the distribution and elimination patterns for vephylline and theophyline could determine a longer effect for the new bronchodilating drug. The results are discussed in regard to the future clinical application of vephylline.

Correlations between the pharmacological effects and the pharmacokinetic behaviour of tetraminol.

Tetraminol (trans-2-hydroxyethylamino-3-hydroxy-5,8-dimethoxy-1,2,3, 4-tetrahydronaphthalene hydrochloride) is a newly synthesized antihypotensive agent. Its pressor activity is accompanied by a compensatory slowing down of heart rate. Changes in plasma levels after intravenous administration of 1 and 2 mg/kg b.w. to rats and rabbits can be fitted to a two-compartment open pharmacokinetic model (previous communications). Experiments were carried out with simultaneous registration of effects on blood pressure (R1) and heart rate (R2). Mathematical treatment of data for R1 and R2 revealed that changes with time can be described by biexponential equations of the type: R1i = A1i.e-a1it+B1i..e-a21t. Three different ways to correlate the data from the pharmacological and pharmacokinetic experiments were tried: 1) For the time interval during which the pharmacological response changes in the range Rimax- 20 to Rimax- 80% there exists a linear relationship with a high degree of statistical significance between the changes in the effects and plasma levels. 2) In the lambda 1-phase of the drug distribution there also exists a linear relationship between the effects and plasma levels. This is so because Tetraminol exhibits its pressor effect by direct stimulation of alpha-adrenergic receptors in the walls of the peripheral blood vessels. 3) Most suitable for expressing the relationship which exists between the pharmacological effects and the plasma concentration of Tetraminol for the entire time interval is the nonlinear function of the type: Ri/(Rimax - Ri) = QiCsi.