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Polymorph screening is currently one of the most important tasks for innovators and for generic companies from both pharmaceutical and intellectual property rights aspects. The different polymorphs have different physicochemical properties, such as the crystal polymorph-dependent solubility which influences the bioavailability. A former drug candidate obtained from Sanofi Pharmaceutical Company (Hungary) was investigated to explore its polymorphism, to distinguish the morphologies generated by analytical examinations and to investigate their relative stabilities. An Avantium Crystal 16 automatic laboratory reactor system was used for the polymorph studies and the studies of their dissolution. Eight polymorphs were obtained by crystallization and transformation methods then characterized by XRPD, DSC, and Raman spectroscopy, scanning electron microscopy, and light microscopy. All the morphologies could be stored in solid without any form transformation for a long time (2 years investigated). According to the first relative stability results, Form I, III, IVa, V, VI, VII are unambiguously metastable forms. Form II and IVb have similar thermodynamic stabilities, that were higher than those of the other polymorphs. A special dissolution medium was developed in which the eight polymorphs showed clear differences in the rate of dissolution.

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Photoacoustic measurements using a broad frequency band hydrophone were carried out in photosynthetic reaction centers (RC) isolated from Rhodobacter sphaeroides R-26 purple bacteria. Data were extracted on enthalpy and volume changes accompanying the primary steps after excitation in the range of 0-500 microseconds aimed at further characterizing the thermodynamic properties of the RC. Quinone titration showed that the volume contraction accompanying the electron transport is sensitive to the molecular species occupying the secondary quinone site. delta VM = 14.4, 7.7 and 4.3 cm3 molar volume contractions were calculated from the measured parameters for 1, 2 and 0.07 quinone/RC after light excitation. Comparing the enthalpy changes (delta H) to the Gibbs free energy data in the literature, a rather large (26%) entropic contribution to the free energy changes (delta G) is estimated for the P*QAQB-->P+QA-QB electron transport (where QA and QB represent primary and secondary quinones, respectively). This is in contrast to previous estimations that delta G = delta H in these processes. On the other hand, only a small (4%) entropic contribution to the delta G of the P*QAQB-->P+QAQB- process is estimated, in agreement with the literature data. Our results are in good agreement with the data obtained earlier (Edens et al. [2000] J. Am. Chem. Soc. 122, 1479-1485).

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The adsorption capacity and specific adsorption surface area of 13 anti-hypoxia drugs were determined in three chromatographic systems using methanol-carbon tetrachloride, chloroform-carbon tetrachloride and acetonitrile-carbon tetrachloride mixtures as eluents. The retention behaviours of the anti-hypoxia drugs were compared using principal component analysis (PCA). A graphical approximation was used for the inclusion of the standard deviations of both the variables and observations in PCA and the results were visualized by two-dimensional nonlinear mapping and cluster analysis. The results indicated that the graphical approximation can be successfully used for the inclusion of the standard deviation of data in PCA calculations. Nonlinear mapping and cluster analysis resulted in similar, but not identical, classification of drugs and chromatographic systems, indicating that each multivariate method can be successfully used for the comparison of solutes and chromatographic systems.

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The adsorption of tributylphenol ethylene oxide isomers containing various lengths of ethylene oxide chain and positional isomers of tributylphenol on a riverine sediment was studied by thin-layer chromatography combined with high-performance liquid chromatography. The adsorption capacity of the sediment was compared with that of silica, alumina and diatomaceous earth. It was established that the adsorption capacity of the riverine sediment is similar to that of silica. The adsorption of surfactants on the sediment surface is not selective. Neither the length of the ethylene oxide chain nor the position of the butyl substituents on the phenol ring influence significantly the adsorption.

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The anticancer drug taxol was separated and quantitatively determined in bark and foliage of different Taxus species by high-performance liquid chromatography to prove the presence of taxol in Hungarian Taxus species. The measurements were carried out with photodiode array detection using a porous graphitized carbon column, and a water:dioxan 54:46 v/v eluent. Taxol was established as being present in measurable amounts in each Hungarian Taxus species. According to the results bark was richer in taxol than foliage. It could also be observed that the older the bark or foliage, the more taxol it contained. The validation process proved that the method is reliable and can be used for the separation and quantitative determination of taxol in both the bark and foliage of Taxus species grown in Hungary.

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The effects of different sulphonylureas on the electrical cardiac activity were studied in 145 rabbits and in 103 rats as well as in 278 digitalis-treated, non-smoker non-insulin-dependent diabetics on the same therapy at least during the previous three months. In rabbits and rats glibenclamide (0.0032-100 mumol. kg-1) decreased, while tolbutamide and carbutamide (0.008-1000 mumol. kg-1) increased strophantidin toxicity and myocardial ischaemia induced transitory ventricular fibrillation dose-dependently. The differences between the dose-response curve of glibenclamide and those of tolbutamide or carbutamide were significant. In digitalized non-insulin-dependent diabetics, multifocal ectopic ventricular beats could be observed in none among the 80 glibenclamide-treated diabetics, while in 12 cases of the 71 tolbutamide and in 10 cases of the 61 carbutamide treated diabetics. Two of the 66 non-insulin-dependent diabetics receiving only diet and 7 of the 278 age and sex matched, non-smoker, metabolically healthy patients had multifocal ectopic ventricular beats. No significant difference could be found between the therapeutical groups. It was concluded that instead of tolbutamide, glibenclamide must be preferred in digitalis-treated diabetics, when metabolic control is not satisfactorily achieved by diet and regime alone.

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Direct cardiac effects of ionic diatrizoate (Uromiro) and non-ionic iopamidol (Iopamiro) were investigated in "in situ" heart-lung preparation of 19 vagotomized dogs. Diatrizoate was found to induce considerably greater alteration in plasma osmolality and subsequent dehydration of the myocardium compared with iopamidol. Myocardial dehydration resulted in a decrease of left ventricular compliance and in that of cardiac performance. Diatrizoate was shown to influence the myocardium not only by its hyperosmolarity but also by a direct action. Heart rate was reduced by both contrast media.

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The aim of the present study was to examine the left ventricular and haemodynamic parameters during acute hypoxia induced by carbon monoxide intoxication and/or after norepinephrine administration in metabolically healthy and alloxan-diabetic dogs. In metabolically healthy animals after carbon monoxide intoxication followed by norepinephrine administration myocardial oedema occurred with a concomitant elevation of diastolic stiffness in the left ventricular wall, resulting in impaired cardiac performance. In the alloxan-diabetic animals no myocardial oedema developed and therefore no further increase of the originally elevated left ventricular diastolic stiffness could be observed. Close correlations were demonstrable between the enhanced water content and diastolic stiffness of the left ventricular wall in metabolically healthy animals as well as between the myocardial contractile force and cardiac output index in both control and diabetic dogs. In contrast to the controls, following norepinephrine administration per se decrease of cardiac performance could be observed in the alloxan-diabetic animals. Based on these results, it can be concluded that an increase of left ventricular diastolic stiffness impairs the cardiac performance in acute hypoxia following norepinephrine administration both in control and in diabetic animals, even if different reasons are responsible for it.

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In diabetic patients it has been shown that tolbutamide and carbutamide enhanced and glibenclamide did not influence the incidence of digitalis intoxication, or that of multifocal ectopic beats or coupling due to premature ectopic ventricular beats during digitalis therapy. In rabbits glibenclamide decreased and tolbutamide and carbutamide increased strophanthidin toxicity in a dose dependent manner. It was concluded that glibenclamide should be preferred to tolbutamide or carbutamide in digitalis-treated diabetics, when satisfactorily metabolic control is not achieved with a dietary regime alone.

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The aim of the experiment was to clarify whether the altered coronary reactivity in diabetes mellitus might be caused by a general modification of the sympathetic responses. Six of 12 young mongrel dogs of both sexes were made diabetic with alloxan (560 mmol/kg). This amount of alloxan induced a clinically manifest diabetes, however the animals failed to develop ketosis. The remaining six dogs served as controls. The haemodynamic investigation was performed three months after the induction of diabetes. Under pentobarbital anaesthesia (133 mmol/kg) mean arterial blood pressure, blood flow in the left anterior descending coronary artery, myocardial contractile force of left ventricular wall and heart rate were recorded continuously and the conductivity of coronary arterial bed was calculated during electrical stimulation ( 8V , 1-2-4-8-20 s-1) of the cardiac plexus or during the intracoronary infusion of adenosine (30-60-120-240-480 nmol/kg/min). In alloxan-diabetic dogs electrical stimulation evoked vasoconstriction in the coronary arterial bed, while vasodilation was observed in metabolically healthy animals. The vasodilator effect of adenosine was significantly smaller in diabetic than in control dogs. On the other hand there were no differences either in the alterations of heart rate caused by adenosine or in those of myocardial contractile force induced by adenosine or electric stimulation between the two groups. It is concluded that general alteration of sympathetic responses is not, but rather a modified relation of the receptors to the vessel wall might be responsible for the altered vascular responses in diabetes.

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