Scandium(III) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

(68)Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter.

PURPOSE: Bone metastases are a serious aggravation for patients suffering from cancer. Therefore, early recognition of bone metastases is of great interest for further treatment of patients. Bisphosphonates are widely used for scintigraphy of bone lesions with (99m)Tc. Using the (68)Ge/(68)Ga generator together with a macroyclic bisphosphonate a comparable PET-tracer comes into focus. PROCEDURES: The bisphosphonate DOTA-conjugated ligand BPAMD was labelled with (68)Ga. [(68)Ga]BPAMD was evaluated in vitro concerning binding to hydroxyapatite and stability. The tracer's in vivo accumulation was determined on healthy rats and bone metastases bearing animals by µ-PET. RESULTS: BPAMD was labelled efficiently with (68)Ga after 10 min at 100°C. [(68)Ga]BPAMD showed high in vitro stability within 3h and high binding to hydroxyapatite. Consequently, µ-PET experiments revealed high accumulation of [(68)Ga]BPAMD in regions of pronounced remodelling activity like bone metastases. CONCLUSIONS: (68)Ga BPAMD reveals great potential for diagnosis of bone metastases via PET/CT. The straight forward (68)Ga-labelling could be transferred to a kit-preparation of a cyclotron-independent PET tracer instantaneously available in many clinical sites using the (68)Ge/(68)Ga generator.

Flubendazole metabolism and biotransformation enzymes activities in healthy sheep and sheep with haemonchosis.

The aim of this project was to study the influence of haemonchosis, a common parasitic infection of small ruminants caused by Haemonchus contortus, on the activity of biotransformation enzymes and on in vitro flubendazole (FLU) biotransformation in liver and small intestine of lambs (Ovis aries). Twelve lambs were divided into three groups: non-infected animals, animals orally infected with larvae of H. contortus ISE strain for 7 weeks and for 11 weeks. At the end of the experiment, hepatic and intestinal subcellular fractions were prepared and used for assays of biotransformation enzymes activities and FLU metabolism testing. The activities of hepatic cytochromes P450, flavine monooxygenases and carbonyl-reducing enzymes were decreased in infected animals. UDP-glucuronosyl transferase activity was significantly lower (by 35%) in 11 weeks infected animals than that in control animals. When in vitro metabolism of FLU was compared in control and infected animals, significantly lower velocity of FLU reduction was found in infected animals. Slower FLU reduction may be beneficial for the haemonchosis treatment using FLU, because FLU will remain longer in the organism and could cause longer contact of parasites with FLU.

Biotransformation of flubendazole and selected model xenobiotics in Haemonchus contortus.

Haemonchus contortus is one of the most pathogenic parasites of small ruminants (e.g., sheep and goat). The treatment of haemonchosis is complicated because of frequent resistance of H. contortus to common anthelmintics. The development of resistance can be facilitated by the action of drug metabolizing enzymes of parasites that can deactivate anthelmintics and thus protect parasites against the toxic effect of the drug. The aim of this project was to investigate the Phase I biotransformation of benzimidazole anthelmintic flubendazole in H. contortus and to determine the biotransformation of other model xenobiotics. For this purpose, in vitro (subcellular fractions of H. contortus homogenate) as well as ex vivo (live nematodes cultivated in flasks with medium) experiments were used. The results showed that cytosolic NADPH-dependent enzymes of H. contortus metabolize flubendazole via reduction of its carbonyl group. The apparent kinetic parameters of this reaction were determined (V'max=39.8+/-2.1 nM min(-1), K'm=1.5+/-0.3 microM). The reduction of flubendazole in H. contortus is stereospecific, the ratio of (-):(+) enantiomers of reduced flubendazole formed was 90:10. Reduced flubendazole was the only Phase I metabolite found. Effective reduction of other xenobiotics with carbonyl group (metyrapon, daunorubicin, and oracin) was also found. Significant activity of carbonyl-reducing enzymes may be important for H. contortus to survive the attacks of anthelmintics or other xenobiotics with carbonyl group.

[Use of dinitrophenols in ion-pair extraction spectrophotometry of cationic tensides]. / Pouzití dinitrofenolu pri iontove párové extrakcní spektrofotometrii kationických tenzidu.

The application of 2,4-dinitrophenol and 2,6-dinitrophenol as reagents for a ion pair extraction spectrophotometry was tested. The ion pair extraction spectrophotometry experiments were carried out using a simplified procedure (test tube method). Four cationic tensides were used as model analytes. After the optimal conditions of the assay were being determined, the influence of the concentration excess of the reagents on the absorbance of the chloroform extract was investigated. Calibration curves were constructed; an estimation of limits of quantitation was performed and apparent molar absorption coefficients were determined. The obtained results show that both investigated dinitrophenols are suitable for the studied purpose.

[The present status of andrology in the Czech Republic]. / Soucasný stav andrologie v Ceské republice.

Andrology is defined as a branch of science and medicine dealing with the male reproductive organs in animals and in men and with the diseases of these organs. Included in this definition are all related specialized branches of science (Definition of the International Society of Andrology). This definition is very wide for the perspectives of andrology it is not optimal. In Czech Republic the Andrological Section of the Czech Urological Society was founded in March 1998. This section aims to disseminate knowledge on andrology by coordination and organization of congresses, conferences and courses in andrology, to encourage the development of basic and clinical research in andrology, to facilitate the collaboration by distribution information and to encourage sponsoring of publication related to the field of andrology.

[Determination of cetrimide and chlorhexidine diiodide in microparticles of a biodegradable copolymer based on lactic acid]. / Stanovení cetrimidu a dijodidu chlorhexidinia v mikrocásticích z biodegradabilního kopolymeru na bázi kyseliny mlécné.

The procedure of the determination of cetrimide and chlorohexidine diiodide in polymer microparticles was proposed and verified. The described procedure combines the spectrophotometric method to determine chlorohexidine diiodide and the non-aqueous titration to determine the sum of nitrogen bases. To verify the ability of the proposed procedure to yield reliable results, the determinations of repeatability and accuracy were performed. The results confirmed the suitability of the proposed procedure for the indicated purpose. Using the procedure, samples were successfully analysed during the development of the new antiseptic powder containing antiseptic drugs in a biodegradable polymer.

[Erectile dysfunction--present possibilities of treatment]. / Erektilní dysfunkce--soucasné moznosti lécby.

Paper brings the basic information in pathophysiology, diagnostics and differential diagnostics in causes of the erectile dysfunction and provides an overview of the contemporary therapeutic possibilities, including the new substance--sildenafil citrate (VIAGRA). It is stressed that sufficient knowledge and responsibility in the indication of therapy may highly support positive contribution of the erectile dysfunction and differentiate patients of the potential risk. At present, adequate form of treatment of erectile and sexual dysfunction exists for almost every patient. New remedies have broaden possibilities of treatment, however, they have not done the indication or therapy easier.

Effect of substituents on microsomal reduction of benzo(c)fluorene N-oxides.

The potential benzo(c)fluorene antineoplastic agent benfluron (B) displays high activity against a broad spectrum of experimental tumours in vitro and in vivo. In order to suppress some of its undesirable properties, its structure has been modified. Benfluron N-oxide (B N-oxide) is one of benfluron derivatives tested. The main metabolic pathway of B N-oxide is its reduction to tertiary amine B. A key role of cytochrome P4502B and P4502E1 in B N-oxide reduction has been proposed in the rat. Surprisingly, B N-oxide is reduced also in the presence of oxygen although all other N-oxides undergo reduction only under anaerobic conditions. With the aim to determine the influence of the N-oxide chemical structure and its redox potential on reductase affinity, activity and oxygen sensitivity five relative benzo(c)fluorene N-oxides were prepared. A correlation between the redox potential measured and the non-enzymatic reduction ability of the substrate was found, but no effect of the redox potential on reductase activity was observed. Microsomal reductases display a high affinity to B N-oxide (apparent K(m) congruent with0. 2 mM). A modification of the side-chain or nitrogen substituents has led to only a little change in apparent K(m) values, but a methoxy group substitution on the benzo(c)fluorene moiety induced a significant K(m) increase (ten-fold). Based on kinetic study results, the scheme of mechanism of cytochrome P450 mediated benzo(c)fluorene N-oxides reduction have been proposed. All benzo(c)fluorene N-oxides under study were able to be reduced in the presence of oxygen. Changes in the B N-oxide structure caused an extent of anaerobic conditions preference. The relationship between the benzo(c)fluorene N-oxide structure and the profile of metabolites in microsomal incubation was studied and important differences in the formation of individual N-oxide metabolites were found.

[An unusual complication of myxoma of the left atrium]. / Neobvyklá komplikace myxomu levé srdecní predsíne.

The authors give an account of a 59-year-old female patient with a myxoma of the left atrium which was complicated by repeated multiple embolizations into the systemic circulation. The cause of death after a successful operation was haemorrhage into the abdominal cavity from a ruptured spleen, as a result of a new lienal infarction after embolization of a portion of the myxoma into the lienal artery, 24 before the operation. The authors emphasize the necessity of immediate removal of an intracardiac formation as soon as it is detected.