Evaluation of the clinical safety of gadodiamide injection, a new nonionic MRI contrast medium for the central nervous system: a European perspective.

Gadodiamide injection is a new nonionic paramagnetic, extracellular contrast medium. Its safety at a dose of 0.1 mmol/kg body weight was evaluated in a large European multicentre trial on adults referred for contrast-enhanced MRI of the central nervous system. Safety analysis was performed on 2102 patients, in whom adverse events during and up to 24 h after injection were recorded. Adverse events related or possibly related to gadodiamide injection were observed in 102 patients. Injection-associated reactions classified as discomfort (sensation of heat or coldness, pain or pressure at the injection site) occurred in 37 patients (1.8%) and other adverse events (e.g. headache, nausea) were observed in 65 patients (3.1%). No serious adverse event was reported. Efficacy analysis, performed on 2273 patients, and based on comparison of T1- and T2-weighted images before and T1-weighted images after injection showed that more diagnostic information was obtained after gadodiamide injection in 1424 (62.6%) patients: management of 386 (17.0%) patients was affected by the new information given and that a new diagnosis was made in 755 (33.3%) patients. Gadodiamide injection was shown to be safe and well tolerated. It represents a nonionic alternative to the current products for MRI of the central nervous system.

[Clinical evaluation of the tolerability of gadodiamide, a new nonionic contrast agent in MRI of the central nervous system]. / Evaluation clinique de la tolérance du gadodiamide, nouvel agent de contraste non-ionique pour l'IRM du système nerveux central.

Gadodiamide injection (Gd-DTPA-BMA) is a new non-ionic paramagnetic contrast agent for which the safety at the dose 0.1 mmol/kg was evaluated during a European multicentre study on a large population of adult patients who had an MR examination of the central nervous system with contrast medium. The safety analysis was performed on 2,102 patients by recording the adverse events observed during injection and up to 24 hours after the injection. Adverse events due or probably due to gadodiamide injection were observed in 102 patients (4.4%) with injection-site associated discomfort (heat, coldness, pain at the injection site) in 37 patients (1.8%) and adverse events other than discomfort (headache, nausea, vomiting) in 35 patients (3.1%). No adverse events of severe intensity or death were reported during the trial. Gadodiamide injection was shown to be safe and well tolerated and represents a non-ionic alternative to the current products in the field of MR imaging of the central nervous system.

A method for determining the relative effect of ligands on A-T and G-C base pairs in DNA: applications to metal ions, protons and two amino acids.

A new method is described for the study of specific interactions of low-molecular ligands with the base pairs of DNA. This method is based on the comparative analysis of melting temperature changes in DNAs of different GC-content in the presence of low molecular weight ligands. In this paper, the method is applied to Mn2+, Ni2+, Co2+ ions, deprotonation, amino acids, beta-alanine and gamma-aminobutyric acid (gamma-ABA). Differences in Tm are affected not only by the changes of relative stability of AT- and GC-pairs, but also by other factors. A theoretical analysis of the sequence specificity of low-molecular ligands on the base pairs in DNA molecules characterized by a high degree of sequence heterogeneity is also presented.

[Selective effect of ionization of nitrogen bases on the thermostability of AT- and GC-pairs of DNA]. / Izbiratel'noe vliianie ionizatsii azotistykh osnovanii na termostabil'nost' AT- i GTs-par DNK.

The ionization specific influence of nitrogen bases on thermostability of AT- and GC-pairs of DNA has been investigated by the method of DNAs melting temperature analysis. It has been shown that the change of temperature interval of DNA helix-coil transition when changing pH environment is due to specific ionization of AT- and GC-pairs of nitrogen bases.

Differences in the central hypotensive actions of alpha-methyldopa and clonidine in the spontaneously hypertensive rat: contribution of neurons arising from the B3 and the C1 areas of the rostral ventrolateral medulla.

The rostral ventrolateral medulla (RVLM) is the proposed site of origin of bulbospinal excitatory vasomotor neurons, and this brainstem area gives rise to chemically distinct populations of neurons, including serotonin-containing neurons of the B3 group and epinephrine-containing neurons of the C1 group, which independently serve sympathoexcitatory functions. In the present study, we sought to establish (a) whether distinct and chemically specific pathways originating in the C1 or B3 regions are involved in the antihypertensive effects of alpha-methyldopa (methyldopa) and clonidine and (b) if so, whether these effects are related to an activation of alpha-adrenoceptors in these areas. Microinjections of methyldopa (6 nmol) or clonidine (5 nmol) were made in the C1 or B3 area in intact spontaneously hypertensive rats (SHR), pretreated with 5,7-dihydroxytryptamine (5,7-DHT) or with phentolamine. The microinjection of clonidine into both the B3 and the C1 area caused a rapid decrease in arterial pressure, whereas microinjection of methyldopa lowered the arterial pressure only after injection into the B3 area. Pretreatment with intracerebroventricular (i.c.v.) 5,7-DHT attenuated the hypotension produced by microinjection of clonidine into the B3 area, suggesting that this effect is mediated by serotonin-containing neurons. Central pretreatment with phentolamine reduced the hypotensive effects produced by injection of clonidine into either area and of methyldopa into the B3 region, consistent with previous suggestions that these central effects are mediated through alpha-adrenoceptors. These results suggest that both serotonin-containing and epinephrine-containing neurons contribute to the central action of clonidine, whereas the effects of methyldopa injection in RVLM appear to be mediated by serotonin-containing but not by epinephrine-containing neurons.

Changes in serotonin metabolism in the rat raphe magnus and cardiovascular modifications following systemic administration of clonidine and other central alpha 2-agonists: an in vivo voltammetry study.

By using the in vivo voltammetry, it was demonstrated that an injection of clonidine induced both cardiovascular modifications (hypotension and bradycardia) and a decrease in the level of 5-hydroxyindolacetic acid (5-HIAA) in the ventromedial B3 serotonergic (5-HT) cell bodies of the medulla oblongata of the rat. The cardiovascular effects of clonidine and of two other imidazolic compounds (detomidine and medetomidine) are likely to be related to their alpha 2 adrenoceptor agonist properties since hypotension and bradycardia were completely antagonized by idazoxan. The decrease in levels of 5-HIAA, induced by these three imidazolic compounds is likely to represent the combination of two additional mechanisms: (i) the stimulation of the alpha 2 adrenoceptors which could contribute to 55% of the decrease observed for the extracellular 5-HIAA and (ii) the interaction with a non-alpha 2 site (through a putative imidazole recognition site), corresponding to the part of the decrease (about 45%) which was not prevented by idazoxan.

[DNA helix-coil transition in alkaline medium]. / Perekhod spiral'-klubok DNK v shchelochnoi srede.

Dna helix-coil transition in th alkaline medium was considered theoretically and experimentally. On the basis of the theory and experimental comparison the DNA double-stranded form deprotonation was revealed.

[Effect of aflatoxin B1 on DNA enzymatic methylation and secondary structures of the rat liver]. / Vliianie aflatoksina B1 na fermentativnoe metilirovanie i vtorichnuiu strukturu DNK v pecheni krys.

Methylation and secondary structure of DNA in rat liver versus time of aflatoxin B1 (AfB1) treatment were studied. A 50% drop in 5-methylcytosine level in liver DNA as compared with control was observed long before tumor development. Also, certain changes in DNA secondary structure were seen. The DNA changes were more pronounced in the F1 progeny of rats inoculated with AfB1 at the terminal stage of gestation.

[Selective effect of ligands on AT- and GC-pairs of DNA bases]. / Izbiratel'noe vliianie ligandov na AT- i GTs-pary osnovanii DNK.

A method is proposed for investigating the specific influence of ligands on DNA AT- and GC-pairs based on the comparison of the width of transition temperature interval of DNA with a strongly pronounced block-structure and dependence of the control DNA melting temperature on their GC-content. Such a comparison allows to define separately the contribution of nonspecific effects causing a change of the width of transition temperature interval. The method is used for studying the specific influence of beta-alanine and nu-aminobutyric acid on AT- and GC-pairs.

In vivo voltammetry in the B3 group of serotonin neurons of the rat medulla oblongata after drug-induced modifications of arterial pressure.

Differential normal pulse voltammetry (DNPV) using an electrochemically treated carbon fiber electrode was applied to the investigation of the in vivo changes in extracellular 5-hydroxyindoleacetic acid (5HIAA) in the B3 group of serotonin neurons during experimental manipulations of arterial pressure. Drug-induced hypertension (phenylephrine infusion) caused, during the infusion, an increase in extracellular 5HIAA concentration which continued to rise, reaching +100% 2 hours after stopping the infusion. In contrast, drug-induced hypotension (sodium nitroprusside infusion) was not associated with any change in extracellular 5HIAA during the infusion while the return to the initial arterial pressure caused a progressive increase in the electrochemical signal, reaching +50% one hour after stopping the infusion. These data show that the extracellular 5HIAA concentration is increased when the arterial pressure increases, a result which suggests that B3 serotonin neurons could have a vasodepressor role in the central regulation of arterial pressure.

[Changes in the structure of DNA induced by sarcolysine in vivo and in vitro]. / Izmeneniia v strukture DNK, indutsiruemye sarkolizinom in vivo i in vitro.

Secondary structure and the rate of methylation of DNA, isolated from normal and malignant liver tissues (sarcoma 45) were studied in vivo and in vitro in presence of sarcolysine. The differential melting curve (DMC) in the DNA from malignant tissue was shifted, compared with that of the liver DNA, to the low temperature side and was characterized by appearance of an additional peak in the region of 50-60 degrees. A considerable increase in the level of methylation has been also noted in the DNA from malignant tissue. Sarcolysine caused a partial restoration of the DMC patterns and decreased by 20% the content of m5C in vivo; the DMC of the DNA from malignant tissue retained practically all its low-temperature features in vitro. The data obtained suggest that sarcolysine does not act directly on the DNA from malignant tissue but participates in an intermediate process, exhibiting a selective action on DNA.

[DNA conformation and thermostability of aqueous solutions of beta-alanine and gamma-aminobutyric acid]. / Konformatsiia i termostabil'nost' DNK v vodnykh rastvorakh beta-alanina i gamma-aminomaslianoi kisloty.

It has been shown that at low concentrations of rare amino acids (from 10(-3) M to 10(-1) M of the substance) stechiometric complexes amino acid -- DNA are formed, which bring about partial substitution of counterions screening phosphate groups and to a change of spatial structure of DNA water molecules. The DNA-solvent molecular interactions are changed, accompanied by an abrupt decrease of helix-coil enthalpy transition which leads to the unwinding of DNA double helix. In the region of amino acid high concentrations (greater than 1-1,5 M) a rise of thermostability and winding of DNA double helix is observed. It has been established that B----C-like conformational transition stimulated by the rise of DNA thermostability is a result of counterions dehydration and the increase of effective ionic strength of the solution which is due to the rise of amino acid-zwitterions content in it.

[DNA conformation and thermostability in urea aqueous solutions]. / Konformatsiia i termostabil'nost' DNK v vodnykh rastvorakh mocheviny.

It is suggested from the character of the change of circular dichroism spectra that in the presence of urea winding of DNA double helix takes place within the bounds of B-family of forms. It is shown that the realized conformation of DNA differs from the experimentally known forms of DNA belonging to B-family. Urea destabilizes the DNA molecules without connection with helical and melt pairs of DNA nitrous bases. Urea affects the conformational state of DNA by water destruction around DNA, which is accompanied by dehydration of DNA and basic metal ions.