Potential mutagenicity, embryotoxicity, and teratogenicity of calcium ketopantoyl aminobutyrate.

We studied mutagenic, embryotoxic, and teratogenic properties of calcium ketopantoyl aminobutyrate, a preparation proposed as a new drug. Long-term oral administration of calcium ketopantoyl aminobutyrate produced no mutagenic, embryotoxic, and teratogenic effects.

Allergic and immunotoxic effects of calcium ketopantoyl aminobutyrate.

We studied the allergic and immunotoxic effects of a new promising medicinal preparation calcium ketopantoyl aminobutyrate. Calcium ketopantoyl aminobutyrate produced no negative effects on general mechanisms of humoral and cellular immunity. This preparation did not modulate the anaphylactic reaction to bovine serum, exhibited no mitostatic and lymphotoxic properties, had no effect on the delayed-type hypersensitivity response, and did not produce active cutaneous anaphylactic reaction.

[Antihypoxant and antiamnesic effects of calcium ketopantoylaminobutyrate].

Experimental investigation of calcium ketopantoylaminobutyrate (Ca-KPAB), a new drug with a structure close to that of pantogam, showed that Ca-KPAB exhibits a pronounced antihypoxant effect on the normobaric and histotoxic hypoxia models. The new drug also produced a more pronounced antiamnesic action as compared to that of pantogam. A significant decrease in the effective drug dose in the case of Ca-KPAB is explained by its ability to readily bypass the blood - brain barrier.

[Toxicological characterization of calcium ketopantoylaminobutyrate]. / Toksikologicheskoe issledovanie keto-pantoilaminobutirata kal'tsiia.

The investigation of toxicity of calcium ketopantoylaminobutyrate (Ca-KPAB) showed that this newly synthesized compound belongs to the class of low-toxicity substances. The LD 50 of Ca-KPAB for oral administration is lower than that of pantogam. No toxicity manifestations and local irritant activity was observed upon chronic administration of Ca-KPAB. The therapeutic index of Ca-KPAB is more than 17 times that of pantogam.

[Comparative investigation of calcium ketopantoylaminobutyrate and pantogam: tranquilizer activity]. / Sravnitel'noe issledovanie ket-pantoilaminobutirata kal'tsia i panogama: izuchenie sedativnoi aktivnosti.

Comparative study of the sedative (calming) properties of the new drug calcium ketopantoylaminobutyrate (Ca-KPAB) and the reference drug pantogam (calcium homopantotenate) showed that the newly synthesized compound produces a more pronounced calming action in several standard neuropharmacological tests (spontaneous motor activity, barbiturate antagonist, etc.) and exhibits some additional advantages. Thus, a slight modification of the chemical structure made possible a significant reduction in the effective drug dose.

[A comparative study of the permeability across the hemato-encephalic barrier and of the effect on cerebral blood flow of the new neurotropic agent calcium ketohomopantothenate and of pantogam]. / Sravnitel'noe issledovanie pronitsaemosti cherez gematoéntsefalicheskii ba'er i vliianiia na mozgovoi krovotok novogo neirotropnogo sredstva--ketogomopantotenata kal'tsiia i pantogama.

The permeability through the blood-brain barrier of N-(4-hydroxy-3,3 dimethyl-2-oxo-1-butiryl) gamma-aminobutyric acid calcium salt, a new neurotropic drug calcium ketohomopantothenate (KPA-Ca), was studied in comparison with that of calcium homopantothenate, pantogam (P) Liquid chromatography analysis showed that after oral administration of KPA-Ca and P both forms of these agents, namely, oxy- and keto- derivatives of homopantothenic acid, were found in the brain of experimental rats, the KPA-Ca (ketoform) content being higher. Pharmacological studies showed that KPA-Ca penetrates the blood-brain barrier in greater amounts and causes a higher effect on the rate of cerebral blood flow when it is administered per os in a dose of 50 mg/kg.

[Comparative study of permeability of derivatives of gamma-aminobutyric and gamma-hydroxybutyric acids through hemato-encephalic barrier]. / Sravnitel'noe izuchenie pronitsaemosti cherez gematoéntsefalicheskii bar'ier preparatov proizvodnykh g-aminomaslianoi i g-oksimaslianoi kislot.

The authors studied the permeability of the blood-brain barrier (CEB) to two nootropics: calcium ketogomopantothenate (KRA-Ca), a GABA derivative, and and calcium salt of oxybutyrate (OB-Ca), a derivative of GOBA. It was established that both preparations penetrate the CEB easily and are found in the brain at different intervals after their administration. However, essential differences in the distribution constant of these drugs were disclosed: KPA-Ca permeated the CEB more intensively and was accumulated in larger amounts in the late-term intervals.

Interaction of muscle glycogen phosphorylase b reconstituted from apoenzyme and analogs of pyridoxal-5'-phosphate with specific ligands.

Phosphorylase b from rabbit skeletal muscles was reconstituted with analogs of PLP containing residues -CH(2)-CH(2)-COOH, trans-CH=CH-COOH or -C=-COOH at position 5. Replacing native coenzyme in the phosphorylase molecule with any PLP analog tested leads to the decrease in the enzyme affinity for the allosteric inhibitor, FMN. Phosphorylase b reconstituted with analogs of PLP shows the greater ability for association in tetramers in the presence of 1 mM AMP than native enzyme.

[Reconstruction of muscle glycogen phosphorylase b from an apoenzyme and pyridoxal-5'-phosphate and its analogs. Interaction of apophosphorylase and the reconstructed enzyme with specific ligands]. / Rekonstruktsiia myshechnoi glikogenfosforilazy b iz apofermenta i piridoksal'-5'-fosfata i ego analogov. Vzaimodeistvie apofosforilazy i rekonstruirovannogo fermenta so spetsificheskimi ligandami.

Sedimentation methods were used to study the effects of modification of the pyridoxal-5'-phosphate (PLP) molecule at the 5th position on the affinity of reconstituted muscle glycogen phosphorylase b for the substrate (glycogen) and the allosteric inhibitor (FMN) as well as on the enzyme capacity to association induced by AMP. Reconstituted phosphorylase b was obtained with PLP analogs containing at the 5th position -CH2-CH2-COOH (analog I), trans-CH=CH-COOH (analog II) or -C identical to COOH (analog III) residues. Reconstitution of phosphorylase b is accompanied by the recovery of the enzyme quaternary structure. Phosphorylase b reconstituted with PLP or analogs I, II and III is not distinguished practically from the native enzyme in its affinity for glycogen. Substitution of the native coenzyme in the phosphorylase molecule with any tested PLP analog leads to lower enzyme affinity for FMN. Microscopic dissociation constants of the FMN-enzyme complexes increase in the following order: enzyme.I < enzyme.II < enzyme.III. Phosphorylase b reconstituted with analogs I, II and III differs substantially from the native enzyme in its capacity to association in the presence of 1 mM AMP: the reconstituted enzyme is represented practically by only the tetrameric form.

[Analogs of 3'-dephospho-CoASH with a phosphodiester bond as substrates of the S-acetylation reaction, catalyzed by acetyl-CoA-synthetase fom rabbit myocardium]. / Analogi 3'-defosfo-CoASH s fosfodiéfirnoi sviaz'iu kak substraty reaktsii S-atsetilirovaniia, kataliziruemoi atsetil-CoA-sintetazoi miokarda krolika.

A number of earlier unknown 3'-dephospho-CoASH analogues with the pyrophosphate fragment replaced by an ester or phosphodiester bond were synthesized and tested in S-acetylation reaction, catalyzed by acetyl-CoA synthetase (EC 6.2.1.1) from rabbit myocardium. 3'-Dephospho-CoASH analogues with a phosphodiester bond, e.g. (Ia), had a lower affinity and diminished kinetic parameters than 3'-dephospho-CoASH (Km = 1 and 0.2 mM, respectively). The adenine substitution in (Ia) by guanine or hypoxanthine (but not cytosine) residue resulted in a loss of substrate properties. 3'-Dephospho-CoASH with an ester bond were not capable of accepting acetate under conditions used and only slightly inhibited the enzymic activity.

Interaction of acetyl-CoA fragments with rat liver acetyl-CoA carboxylase.

The interaction of acetyl-CoA fragments with rat liver acetyl-CoA carboxylase has been studied. Dephosphorylated acetyl-CoA did not actually differ from acetyl-CoA in its substrate properties. Non-nucleotide analogues of the substrate, S-acetylpantatheine and it's 4'-phosphate, also possess substrate properties (Vmax = 1.5% and 15% of the maximal rate value of acetyl-CoA carboxylation, respectively). The nucleotide fragment in the acetyl-CoA molecule produces a marked effect on the thermodynamics of the substrate-enzyme interaction, and is apparently involved in activation and appropriate orientation of the acetyl group in the active site. The better substrate properties of S-acetylpantetheine 4'-phosphate and the inhibitory properties of pantetheine 4'-phosphate, compared to the unphosphorylated analogues, evidence an important role of the 5'-beta-phosphate of 3'-phosphorylated ADP residue in acetyl-CoA binding to the enzyme.

[Substrate specificity of acetyl-CoA-carboxylase from the rat liver]. / Izuchenie substratnoi spetsifichnosti atsetil-CoA-karboksilazy pecheni krysy.

The interaction between acetyl-CoA fragments and rat liver acetyl-CoA carboxylase was studied. It was found that the 3'-phosphate group did not interfere with the enzyme interaction since the substrate properties of acetyl-dephospho-CoA and acetyl-CoA are nearly identical. The non-nucleotide substrate analogs S-acetyl-pantethin and its 4'-phosphate) also displayed substrate properties (V = 1.5% and 15% of the V for acetyl-CoA carboxylation respectively). The nucleotide fragment of the acetyl-CoA molecule produced an appreciable effect on the thermodynamics of this substrate interaction with the enzyme. Its physiological role consists in all probability, in the activation and propes orientation of the acetyl group in the enzyme active center. The far more pronounced substrate properties of S-acetyl pantethin 4'-phosphate and the inhibitory properties of pantethin 4'-phosphate (compared to non-phosphorylated analogs) suggest the essential role of the beta-phosphate residue of ADP in the acetyl-CoA binding to the enzyme. The data obtained suggest also that the hydrophobic region responsible for the acyl radical binding, has a site which specifically recognizes the beta-mercaptoethyl residue of the CoA pantethin fragment. The pivotal role in the acetyl-CoA carboxylase interaction with the substrate is ascribed to the productive binding of the acetyl radical; the contribution of individual fragment of the CoA molecule is variable.

[Effect of repeated injections of GABA on the GABA shunt and various associated reactions in the rat brain]. / Vliianie mnogokratnykh in''ektsii GAMK na GAMK-shunt i nekotorye sviazannye s nim reaktsii v golovnom mozge krys.

Effect of repeated administrations of gamma-amino butyric acid (GABA) at doses corresponding to those which are used in clinical medicine, on the state of GABA-shunt and intensity of alpha-ketoglutarate dehydrogenase and aminotransferase reactions as well as on the level of GABA and glutamate was studied in cerebellum, cortex and trunkus cerebri of rat brain. Administration of GABA (5 injections at a dose of 5 mg/kg) caused distinct alterations in central nervous system, which involved activation of GABA-transaminase, utilizing GABA, and inactivation of glutamate decarboxylase, producing the amine, as well as a decrease of GABA and glutamate levels and an increase in alpha-ketoglutarate utilization and activation of aminotransferase reactions. These alterations were especially distinct in cerebellum, where initial high intensity of GABA shunt functioning and minimal level of GABA were observed. The alterations observed suggest the existence of pronounced stimulating effect of GABA, even at low doses, on reactions of energy metabolism in brain.

Mechanism of the interaction of superoxide ion and ascorbate with anthracycline antibiotics.

The interaction of superoxide ion and ascorbate anion with anthracycline antibiotics (adriamycin and aclacinimycin A) as well as with their Fe3+ complexes has been studied in aprotic and protic media. It was found that both superoxide and ascorbate reduce anthracyclines to deoxyaglycons via a one-electron transfer mechanism under all conditions studied. The reaction of ascorbate anion with adriamycin and aclacinomycin A in aqueous solution proceeded only in the presence of Fe3+ ions; it is supposed that an active catalytic species was Fe3+ adriamycin. It is also supposed that the reduction of anthracycline antibiotics by O2-. and ascorbate in cells may increase their anticancer effect.

[Effects of pyridoxal-phosphate and its 4'- and 5'-substituted analogs on macromolecular structure of Escherichia coli glutamate decarboxylase]. / Vliianie pirodoksal'fosfata i ego 4'- i 5'-zameshchennykh analogov na makromolekuliarnuiu strukturu glutamatdekarboksilazy Escherichia coli.

Interactions of pyridoxal phosphate and its analogs (at pH 6.0) with dimeric glutamate apodecarboxylase (E. coli) were examined by spectrophotometric and CD-titration and by gel electrophoresis. It was shown that 5 equivalents of pyridoxal-phosphate fully restore the catalytic activity and optical properties of the enzyme, whereas 3 equivalents of the coenzyme suffice for reconstitution of the hexameric structure. Similar amounts of the 2 nor PLP adn 5'-methtyl PLP restore the hexameric macromolecule. 15 equivalents of pyridoxine phosphate or 54 -- of pyridoxamine phosphate are required for complete saturation of the apoenzymes binding sites and concomitant reconstitution of the hexameric structure. 5'-deoxy-5'-carboxymethyl pyridoxal, 5'-deoxy-5'-phosphonomethyl pyridoxal and cis-5'-deoxy-5'-phosphonomethylen pyridoxal were merely bound to the dimeric apoenzyme, but failed to restore the enzyme's quaternary structure. Pyridoxal, trans-5'-deoxy-5'-posphonomethylen pyridoxal and pyridoxine analogs substituted in position 5' with carboxyl or phosphonyl group did not interact with the apodecarboxylase.