Noncompetitive nature of oxytocin antagonists with general structure Mpa(1)Xxx(2)Sar(7)Arg(8).

Eight oxytocin (OT) antagonists with general structure Mpa(1)Sar(7)Arg(8), substituted at position 2 with conformationally constrained and bulky amino acids, were synthesized and pharmacologically tested. Binding affinities and selectivities of compounds for OT, and vasopressin receptor subtypes were investigated. In vitro effects of antagonists were evaluated via inhibition of OT-induced contractions of isolated guinea-pig uterus. The abilities of OT antagonists to inhibit spontaneous contractility in 24 h postpartum rat uterus were investigated. These peptides exhibited pseudoirreversible pharmacological properties, and comprise a novel group of OT antagonists for potential clinical use. Their noncompetitive pharmacological nature can be of therapeutic benefit through a sustained effect on myometrium.

[Synthesis and in vitro receptor analysis of new potential oxytocin antagonists]. / Uj potenciális oxitocin antagonisták szintézise és in vitro receptoranalitikai vizsgálata.

Oxytocin (OT) itself and the sensitivity of the uterus to OT play a crucial role in the initiation of both normal and pathologically early delivery. It recognition of the complex mechanism of action suggests that specific OT antagonists are of therapeutic value in postponing early contractions. In this study neurohypophyseal hormone analogues containing Sar in position 7, Arg in position 8, and various conformationally restricted or bulky derivatives of phenilalanine and tryptophan amino acids in position 2 were prepared to design more potent and selective OT antagonists. We determined the ligand-receptor binding characteristics of these newly synthetized peptides in the presence of [3H]oxytocin and [3H]vasopressin on isolated guinea-pig uterus, rat liver and kidney inner medulla plasma membranes. In the case of each peptides we calculated the Ki values and the selectivity ratio. The binding to the OT receptor was dramatically decreased for the Trp-derivatives containing analogues, while the Phe-derivatives containing analogues displayed a relatively high receptor affinity and have a relatively high OT/VP1 receptor selectivity.

In vivo effects of 2-substituted [Mpa1Sar7Arg8]-oxytocin antagonists on postpartum rat.

A set of oxytocin antagonists consisting of [Mpa1Sar7Arg8]-oxytocin substituted by various conformationally restricted or bulky D amino acids at position 2 were synthetized and biologically tested. In in vivo pharmacological investigations, the effects of these peptides were examined on the spontaneous motor activity of postpartum rat. Three of the newly prepared peptides proved at least as effective in inhibiting uterine contractions as clinically investigated atosiban.

Synthesis of oxytocin antagonists containing conformationally constrained amino acids in position 2.

Analogues of oxytocin containing D-Trp, 2-amino-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (Atc) or 1,2,3,4-tetrahydro-beta-carboline-1-carboxylic acid (Car) with R or S configurations in position 2 were synthetized, and their receptor bindings were tested on isolated guinea-pig uterus, rat liver and rat kidney inner medulla plasma membranes. The peptides were synthetized in the solid phase by using racemates of Car and Atc. The resulting diastereomeric mixtures were separated by means of RP-HPLC. The binding to the oxytocin receptor was somewhat decreased for the Atc isomers and dramatically decreased for both R- and S-Car, while the D-Trp-containing analogue displayed a relatively high receptor affinity. However, the V1 receptor affinities were almost the same as those of the parent peptide for the Car-containing analogues and dramatically decreased for the S-Atc substituted analogue, which has a relatively high OT/V1 receptor selectivity of 44.5.

[Immunoscintigraphy in the diagnosis of ovarian carcinoma]. / Imunoscintigrafie v diagnostice ovariálního karcinomu.

The authors define the place of immunoscintigraphy (IS), a diagnostic method which differs qualitatively from the usual examination methods (US-ultrasonography, CT-computed tomography) in the management of ovarian cancer when monitoring the response to therapy and for detection of subclinical manifestations of the disease. The author explains the principle of the method which involves a highly specific antigen-antibody reaction. Possibilities to influence the accuracy of the examination and results of a clinical perspective study are submitted the objective of which was to test the possible use of this diagnostic method under our conditions. In a group of 66 women (with an established diagnosis of ovarian cancer or a newly detected ovarian tumour) 76 IS examinations were made and the finding was confirmed by biopsy. The results of the histological examination were also a criterion of the accuracy of IS and CT examinations resp. The material for biopsy was obtained on operation, second look operation, by fine needle biopsy or on necropsy. The authors evaluate 65 IS examinations. The accuracy of the examination was evaluated as very satisfactory (84%), the sensitivity 89%, specificity 79%, there was a minimal number of falsely positive findings (9.2%) and falsely negative ones (6.2%). An analysis of possible reasons of failure of IS examinations is made. The authors evaluate the contribution of IS and its place among diagnostic methods in the treatment and follow up of women with ovarian cancer.

[Plasma volume in polycystic kidney disease]. / Plazmatický volum u polycystické choroby levin.

Hypertension is a common and serious complication of autosomal dominant polycystic kidney disease (ADPKD), occurring early in the course of the disease. Disorders of tubular transport of sodium and increased plasma and blood volume (PV and BV), as a consequence, are thought to be involved in the pathogenesis of hypertension in ADPKD. In order to evaluate PV and BV in early stage of ADPKD, PV and BV were measured with radioactive serum albumin dilution technique. Three groups of subjects with normal glomerular filtration rate were studied: ADPKD hypertensive (ADPKD H, n = 10, age: 36.2 +/- 8.7 y), ADPKD normotensive (ADPKD N, n = 15, age: 33.4 +/- 7.4 y), and healthy volunteers (C, m = 8, age: 32.6 +/- 6.8 y). PV and BV expressed per kilogram of body weight did not differ among the 3 groups. When PV and BV were expressed per meter square of body surface area, diminished BV in the group ADPKD H in comparison to ADPKD N and group c (p < 0.05) was found, other parameters did not differ between the 3 groups. In conclusion--our results do not support the hypothesis of a significantly increased PV and BV of patients with ADPKD prior to the onset of hypertension.

[Detection of cerebropathy in neurologic and psychiatric diseases]. / Prukaz cerebropatie u neurologických a psychiatrických chorob.

The authors made a comprehensive examination of 16 patients--epileptics, alcoholics, psychotic subjects and patients after cerebral contusion. The patients were subjected to a neurological, psychiatric, psychological examination as well as to a morphological examination (X-ray, CT, NMR), physiological examination (EEG, polysomnography, evoked potentials), immunological examination and SPECT. The majority of patients had positive CT and SPECT findings suggesting focal brain damage. These results could be explained only in exceptional cases by injury, the majority was of unknown aetiology. With this corresponded focal EEG abnormalities and in particular sleep disorders, sometimes subjective but always detectable by objective methods. There was always a shortage of REM, sometimes also NONREM sleep. Half the patients were subjected to an immunological examination which was always positive and comprised elevated acute stage proteins and proteins associated with the stress reaction. Numerous data in the literature and the authors' experience indicate that the mentioned pathological findings are not incidental and form, independently on the aetiology, an integrated unit for which the term cerebropathy can be used. A primary role is played by the epileptic focus and its quality, i.e. above all the rate of discharge and site and humoroergic systems of the brain stem, in particular their efficiency and mutual balance. The events have a programmed sequence. At the beginning an epileptic focus develops which influences the surrounding area, secondary and tertiary foci are formed and the thalamo-cortical system is affected. Soon this is followed by an apparent influence of the epileptic activity on structures of the brain-stem. The consequence are changes affecting sleep, mood, mental performance, immunity, endosecretion and paroxysms. Subsequently individual symptoms are already prepared but have a different latency of manifestation and the latter depends also on external provoking influences. The thalamo-cortical reaction is characterized by the manifestation of epileptic paroxysms and sets in after a different interindividual incubation following injury. The same applies to the hippocampal reaction manifested by the organic psychosyndrome. Some symptoms such as changes of immunity, sleep or endosecretory function are not necessarily manifested if the influence of the focus on structures of the brain-stem is not sufficiently intense. Conversely if the effect on the brain-stem and limbic structures is greater and the effect on the thalamo-cortical system smaller, psychotiform behaviour develops. Then there are marked changes of phoria, dynamogeny, rate, affectivity, sleep and hormonal secretion and its equilibrium.

Neurohumoral relations in neurological and psychiatric patients.

Sixteen patients-epileptics, alcoholics, psychotics and post-contusion cases-were subjected to neurological, psychiatric, psychological, morphological (X-ray, CT, NMR), physiological (EEG, polysomnography, evoked potentials), immunological and SPECT examination. Most had CT and SPECT signs of focal brain damage. The results were but exceptionally due to injury, most were of unknown etiology. This tallied with EEG focal abnormalities, mainly sleep disorders, sometimes subjective ones, but invariably detectable objectively. In each case there was REM, in some also NONREM sleep deficiency. Half of the cases were tested immunologically, each time with positive results: increased levels of acute-phase protein and stress-reaction proteins. As copious literature and our experience show, the above pathological condition, rather than being accidental, constitute regardless of etiology, an integrated entity which could be called "programme cerebropathy". The primary role is played there by the epileptic focus and its properties, in particular, the speed of discharge and localization and brain stem humoroergic systems, i.e., their performance and mutual balance. There is a program sequence of events, first, and epileptic focus acting on the neighborhood, the rise of secondary and tertiary foci, and influence over the thalamocortical system. Soon afterwards, epileptic activity begins to act on brain-stem structures. This results in changes in sleep, mood, psychic output, immunity, endosecretion, and in paroxysms.

[The effect of extracorporeal shock-wave lithotripsy on renal function]. / Vliv litotrypse extrakorporálními rázovými vlnami na renální funkce.

Using the method of phase scintigraphy, the authors examined 48 patients who were treated by means of extracorporeal shock-wave lithotripsy. The authors proved at the 5% of significance that the development or deterioration of renal functions does not depend on the localization of the concrement and the number of shock-waves needed for disintegration. The authors confirmed the significant effect of the size of concrement on the lesion of renal function--all stones larger than 30 mm lead in 100% to a varying deviation, as compared with the examination made before extracorporeal shock-wave lithotripsy. Obesity has also a significant effect on the development or deterioration of lesions of renal function. From the total number of patients where after lithotripsy a lesion of renal function developed or deteriorated 70.6% were obese! After 24 months in two patients deterioration of the condition, as compared with the initial state, was proved.

[Stress perfusion tomography of the myocardium using the 201 thallium isotope in cardiac surgery--evaluation of initial results]. / Zátezová perfúzní tomografie myokardu pomocí izotopu 201talia v kardiochirurgii--hodnocení prvních výsledku.

Initial results of evaluation of scintigraphic examinations by means of the isotope 201thallium indicate the importance of this method in cardiosurgery, in particular in the postoperative evaluation of the effect of bypass operations. In patients with an objective improvement on the postoperative scintigrams also subjective improvement of the condition was recorded.