Biomedical subjects

G Falkay

Publications and source records attributed to G Falkay.

At least 19 recordsLinked to original sources

PubMed2003

Synergism between beta 2-adrenoceptor agonists and subtype-selective alpha 1A-adrenoceptor antagonists in the tocolytic effect on pregnant rat uterus in vitro.

1. Despite great efforts in recent decades, premature birth is still a leading cause of perinatal morbidity and mortality. beta2-Adrenoceptor agonists are frequently used as tocolytics, although their use is rather controversial. Previous animal studies have revealed that blockade of alpha1A-adrenoceptors results in relaxation of the pregnant rat myometrium. 2. The aim of the present study was to investigate the uterus relaxant effect of the beta2-adrenoceptor agonists (terbutaline, ritodrin) applied together with the subtype-selective alpha1A-adrenoceptor antagonists (WB 4101, 5-methylurapidil) in an in vitro rat model. The main objective of the experiments was to clarify whether there was an additive or a potentiating synergism between the two drug classes. 3. Myometrial rings were taken from female, 22-day pregnant (end-term) Sprague-Dawley rats. Electrical field stimulation (EFS) was used to elicit rhythmical contractions. Non-cumulative concentration-response curves were constructed to the beta2-adrenoceptor agonists and the alpha1A-adrenoceptor antagonists alone and to beta2-adrenoceptor agonists co-administered with the alpha1A-adrenoceptor antagonists. 4. Both groups of drugs inhibited EFS-induced contractions in a dose-dependent way. Administering the beta2-adrenoceptor agonists in combination with the alpha1A-adrenoceptor antagonists resulted in a significant decrease in the EC50 and an increase in the maximal contraction inhibiting effect. 5. The potentiating synergism that has been revealed between beta2-adrenoceptor agonists and alpha1A-adrenoceptor antagonists in the uterus relaxant effect may be of great clinical importance because it could improve the efficacy of therapy of preterm delivery.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2002

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.

Animals↗

PubMed2001

Characterization of late-pregnant rat uterine contraction via the contractility ratio in vitro significance of alpha1-adrenoceptors.

The aim of this study was to characterize the ability of late-pregnant (days 15-22) rat uterine tissue rings to contract in response to electric field stimulation in vitro. For this purpose, maximum rhythmic contractions were elicited by optimum choice of the period time and the pulse width, the two main parameters of electric field stimulation. In parallel, the plasma 17beta-estradiol and progesterone levels were determined. It was found that the contractility ratio, i.e. the quotient of the optimum pulse width and the period time, is a good parameter with which to express the contractility. The larger the contractility ratio, the better the ability to contract. Evaluation of the area under the curve did not furnish information relating to the contractility in this method. A very close correlation was observed between the contractility ratio and the quotient of the 17beta-estradiol and progesterone levels on different days, demonstrating that the in vitro ability characterized by the contractility ratio is in keeping with the physiological regularity. There was also a very close correlation between the contractility ratio and the quotient of the alpha1- and beta-adrenergic receptors, suggesting the main role of the numbers of alpha1-receptor in pregnant uterine contractility. It is believed that this is the first in vitro model to give a numerical measure concerning the ontogeny of uterine contractility in late pregnancy.

Animals↗

PubMed2001

Study of in vitro and in vivo dissolution of theophylline from film-coated pellets.

Tests were performed on the influence of polymer coating films on the rates and the extents of in vitro and in vivo liberation of theophylline from pellets. Uncoated and coated pellets were used in the experiments. The coating material was Eudragit L; The film thickness was varied. The in vivo liberation of theophylline was studied in rabbits. The serum level of the released drug measured with a TDX Analyser. No appreciable difference was observed between the uncoated and the coated pellets as concern the maximum release data, but a significant shift was found in t(max) for Eudragit L coated pellets.

Acrylic Resins↗

PubMed2001

Antioxidant activity of leaves of Salvia species in enzyme-dependent and enzyme-independent systems of lipid peroxidation and their phenolic constituents.

The protective effects of eleven Salvia species native to Europe against enzyme-dependent and enzyme-independent lipid peroxidation were evaluated. The 50% aqueous methanolic extracts of the leaves of all tested plants were found to be more effective than the positive control alpha-tocopherol acid succinate. The extracts of S. candelabrum, S. ringens, S. tomentosa, S. nemorosa, and S. glutinosa displayed considerable concentration-dependent antioxidative effects that were comparable to those of the medicinal and aromatic plant S. officinalis. The concentrations of flavonoids, hydroxycinnamic acids and total phenolic compounds in each extract were quantified with the aim of clarifying the connection between activity and chemical composition.

Animals↗

PubMed2001

Use of antisense oligonucleotides to verify the role of the alpha(1A)-adrenergic receptor in the contractility of the rat uterus post partum.

The adrenergic system plays a major role in the regulation of the contractility of the uterus during pregnancy. This study investigated the role of the alpha(1A)-adrenergic receptor (AR) in this regulation. The use of partial phosphorothioate antisense oligodeoxynucleotides (AONs) permitted the sequence-selective inhibition of AR gene expression. AONs were injected together with a cationic liposomal carrier agent into the post partum rat uterus. Incubation for 12 or 24 h with the most effective AON (480-AON) caused a 58.7 or 53.0% inhibition, respectively, of the expression of the alpha(1A)-AR density, whereas incubation for 36 or 48 h resulted in only a 38.8 or 26.7% inhibition, respectively. The decrease of the alpha(1A)-AR density by 480-AON was demonstrated by Western blot analysis and a radioreceptor binding assay on rat uterus preparations 24 h after delivery. The changes in the contractility of the uterus after AON treatment were measured on isolated rat uterine tissue by electric field stimulation. The significant decrease in the ability of the uterus to contract was indicated by the area under the curve method. The electric field studies revealed that the specific alpha(1A)-blockers 5-methylurapidil and WB 4101 inhibited the rhythmic contraction by about 74 and 70% in the control uteri and by 25 and 20% in 480-AON-treated uteri, respectively. The curves for the beta-mimetic (terbutaline) and alpha(1D)-antagonist (BMY7370) inhibitors were unchanged after 480-AON treatment of the uteri. These results suggest the importance of the alpha(1A)-AR in the tocolytic effect exerted by the alpha(1)-antagonist, although high concentrations of antagonists can not exclude the role of alpha(1D)-ARs, too. Additionally, these prove that the knockdown transformation by AONs offers a useful animal model for the investigation of receptors controlling the function of uterine tissue.

Adrenergic Antagonists↗

PubMed2001

[Influence of adrenergic denervation on uterine contractility of pregnant rats in vitro].

The aim of the present study was to investigate the functional changes in the sympathetic nerves in the rat myometrium during pregnancy by electric field stimulation (EFS) in vitro. In our experiments the contractility of the rat myometrium were registered at 5, 10, 15, 18, 20, 22 (term) day of pregnancy, in non pregnant rats and in 6-OH-dopamine pretreated rats. The parameters of EFS were the following: pulse width 0.6 ms, frequency range of nerve stimulation 1-70 Hz, supramaximal voltage 40 V. We concluded that low pulse width and low frequency stimulation is selective for adrenergic nerves. We found that during pregnancy a gradual drop-out of low frequency induced uterine smooth muscle contraction appears. It is surprising that very low frequency stimulation has no effect on the 5th day of pregnancy although the same frequency stimulation causes contraction on the 10th day. By the 22nd day of pregnancy the rat uterus shows the same responsiveness to nerve stimulation as it is detected in 6-OH-dopamine pretreated non pregnant rats. The adrenergic denervation of the pregnant uterus does not mean that it loses the ability to respond to cathecholamines since non-synaptic adrenergic receptors exist in the late pregnant rat uterus.

Animals↗

PubMed2001

[Pharmacological models to investigate the role of the adrenergic system on post-partum rat uterus].

The adrenergic system plays a major role in the regulation of the pregnant uterine contractility. Our aim was to develop an experimental animal model to study the role of the alpha 1A-adrenergic receptor (AR) in uterine motor activity by antisense oligonucleotides (AONs). AONs were injected with DOTAP and pluronic gel into the uterine lumen of post-partum rats 2-3 hours after delivery. The decrease of the alpha 1A-AR density by AON was demonstrated by RT-PCR method, Western blot analysis and radioligand binding assay on rat uterus preparations 24 h after delivery. The changes in the contractility of the uterus were measured on isolated rat uterine tissue by electric field stimulation (EFS). The EFS investigation demonstrated that the effect of the specific alpha 1A-blocker 5-methylurapidil and WB4101 was significantly decreased in the AON-treated rat uterus as compared to the control group but the effect of the beta-mimetic terbutalin and alpha 1D-antagonist BMY7378 was unchanged. Our result suggest that the alpha 1A-ARs play a very important role in the regulation of uterine contractility, and may serve as the basis for a subsequent new group of tocolytics (uterus selective alpha 1-antagonists), which may lead to more selective therapy than currently used beta-mimetics.

Adrenergic alpha-Antagonists↗

PubMed2000

Synthesis and biological activity of a new progestogen, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3, 20-dione acetate.

The progestational activity of second- and third-generation progestins in oral contraceptives were markedly increased by addition of an 18-methyl group. A new progestin, the 18-methyl analog of Nestorone, 16-methylene-17alpha-hydroxy-18-methyl-19-norpregn-4-ene-3,2 0-dione acetate (10), was synthesized. The relative binding affinity and biologic activity of 10 was compared with Nestorone, levonorgestrel, and progesterone using a binding assay for rat progesterone receptors, the Clauberg assay in the rabbit, and by assessing pregnancy maintenance in the rat. These studies, as summarized in Table 4, show that 10 is three to ten times more potent than Nestorone. The addition of the 18-methyl group to Nestorone markedly increased its potency as noted above, but is unlikely to change its rate of delivery from sustained release systems. 10 should be ideally suited for administration by implants or small skin patches.

Animals↗

PubMed1999

Jatrophane diterpenoids from Euphorbia peplus.

From the pro-inflammatory active extract of Euphorbia peplus, a new diterpene polyester (1) based on the jatrophane skeleton was isolated together with the known compounds 2-5. The irritant activities of some jatrophane diterpenes (2, 3 and 6-9) were also investigated: only compound 2 was found to exert a weak pro-inflammatory activity on mouse ear.

Animals↗

PubMed1999

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.

Animals↗

PubMed1999

Protective effects of the aerial parts of Salvia officinalis, Melissa Officinalis and Lavandula angustifolia and their constituents against enzyme-dependent and enzyme-independent lipid peroxidation.

The antioxidant effects of aqueous methanolic extracts from three medicinal Lamiaceae species were investigated in enzyme-dependent and enzyme-independent lipid peroxidation systems. All these extracts caused a considerable concentration-dependent inhibition of lipid peroxidation. Phenolic components present in the plant extracts were evaluated for antioxidant activity and were found effective in both tests. Their concentrations in each extract were determined by TLC-densitometry.

Antioxidants↗

PubMed1999

Ontogeny of imidazoline binding sites in the human placenta.

INTRODUCTION: Non-adrenergic imidazoline binding sites (IBS) were described as pharmacologically distinct from alpha2-adrenergic receptors. Recently it was shown that the human placenta is the richest source of IBS, however, no function has been assigned to this new putative receptor. As concerns the presence of alpha2-adrenoceptors in the human placenta, it was reported that no alpha2-receptors were detected in human placental membranes with the radiolabelled alpha2-adrenoceptor antagonist [3H]rauwolscine or the alpha2-adrenoceptor agonist [3H]clonidine. This scientific contradiction has been solved when the authors have recently demonstrated that IBS and alpha2-adrenoceptors coexist in human term placental membranes. STUDY OBJECTIVE: Scientific literature does not provide any information regarding the ontogeny of IBS. The present study intended to determine the density of IBS and alpha2-adrenoceptors in correlation with gestational age. MATERIALS AND METHODS: Human first and second trimester placentas (6-10 and 14-18 weeks of gestation, respectively) were obtained immediately following the interruption of gestation, third trimester placentas (38-40 weeks) were obtained after normal vaginal delivery. Human placental membrane fractions were prepared and radioligand binding assays were performed in duplicate, using [3H]RX 821002 and [3H]RX 781094 (idazoxan) as radioligands. RESULTS: According to the results of the binding assays, the concentration of alpha2-adrenoceptors decreased with the advancing gestational age. In contrast with this pattern, the density of IBS significantly increased. CONCLUSION: Our present results demonstrated that the density of IBS shows a significantly increasing tendency throughout gestation. The unique position of the placenta between maternal and fetal circulations determines its function as a mediator in transport mechanisms. The increasing expression of IBS in the growing placenta might suggest a role for these sites in the mediation of the transport of nutrients, ions, etc.

Female↗

PubMed1998

Endocrine and thermal responses to GnRH treatment and prediction of sperm output and viability in holstein-Friesian breeding bulls.

A study was conducted to determine changes in serum LH and testosterone concentrations and in scrotal surface temperature (SST; measured with infrared thermography) following GnRH treatment and to predict the number of spermatozoa collected and the proportion that were viable. Holstein-Friesian breeding bulls (n = 22, average age, 24.3 m.o.; range, 15 to 41 m.o.) were examined twice 30 d apart. Concurrently, semen was collected twice weekly with an artificial vagina. Treatment with GnRH (100 micrograms, i.m.) increased (P < 0.0001) serum LH and testosterone concentrations and increased (P < 0.0001) SST (range 0.6 to 1.1 degrees C; P < 0.05) at the top and bottom of the scrotum. In regression models to predict the total number of spermatozoa, significant independent variables included ultrasonic echotexture of the testes (negative slope), scrotal width (positive slope) and SST at the bottom of the scrotum 45 min after GnRH treatment (positive slope). In regression models to predict the percentage of live spermatozoa, ultrasonic echotexture was a significant independent variable (negative slope). Measurement of testicular ultrasonic echotexture and SST after GnRH treatment augmented measurement of testicular size for predicting the number and percentage of live spermatozoa.

Animals↗

PubMed1998

Computer analysis of video and ultrasonographic images for evaluation of bull testes.

The objectives of this study were to determine relationships between scrotal size (SC; estimated from a video image) and testicular size, and between ultrasonographic echotexture of the testis and seminiferous tubule area in bulls. Video images of the scrotum of 49 Holstein-Friesian (H-F) bulls were recorded and digitized. Scrotal width and length were measured with custom software. After slaughter, scrotums (containing testes) were excised, SC and testicular height, width and volume were measured, and the testes were examined ultrasonographically. Correlations between SC and testicular width or volume (r = 0.86, P < 0.001 and r = 0.84, P < 0.001, respectively) were much higher than those between scrotal width and testicular width or volume (r = 0.23, P < 0.11 and r = 0.28, P < 0.06). Histological examination of the testes was performed in 31 of the bulls. Ultrasonographic echotexture of the testes (determined with custom software) was highly correlated (r = -0.5, P < 0.005) with seminiferous tubule area. Although SC was superior to video imaging for estimating testicular size, ultrasonographic imaging of the testes has considerable potential for the evaluation of testicular function in bulls.

Animal Husbandry↗

PubMed1998

Morphologic, endocrine and thermographic measurements of testicles in comparison with semen characteristics in mature Holstein-Friesian breeding bulls.

Twenty Holstein-Friesian breeding bulls (62-79 months of age) were examined 3 times, at 30-day intervals. Scrotal thermograms for assessment of scrotal surface temperature (SST) and blood samples for plasma testosterone concentrations were taken just before and then 45 and 90 min, respectively, after treatment with GnRH (50 micrograms, Gonavet, i.m. per bull). Following GnRH treatment, there generally were significant increases in mean values of both top SST (range, -0.1 to 1.4 degrees C) and bottom SST (range, 0.3 to 1.8 degrees C). Scrotal circumference was highly repeatable but SST and video-measurements of scrotal dimensions were less repeatable, because apparently they were affected by ambient temperature. Plasma testosterone concentrations before GnRH treatment were more repeatable than those after GnRH treatment. Correlations between examinations of 0.67 to 0.81 and -0.14 to 0.47, respectively, but the converse was true for SST measurements. Semen was collected with an artificial vagina 3 times per week for 12 weeks starting 2 weeks before the first examination. The total number of spermatozoa per ejaculate was highly repeatable and the percentage of motile and live spermatozoa were relatively consistent. Separate regressions for each variable and for each examination were conducted for these 3 semen characteristics as dependent variables. For the number of spermatozoa per ejaculate and for the percentage of motile spermatozoa, significant independent variables were plasma testosterone concentrations and difference between top and bottom SST, respectively. The slopes of these equations were nearly all negative and the R2 was from 0.15 to 0.42. For prediction of the percentage of live spermatozoa, both SST gradient and plasma testosterone concentrations were significant independent variables. For these regressions, the slopes were negative and the regression coefficients were generally lower than for the other 2 dependent variables (range, 0.16 to 0.25). Treatment with GnRH and assessment of SST and plasma testosterone concentrations have some correlation with the semen production in the mature bull.

Animals↗

PubMed1998

Evidence of non-synaptic regulation of postpartum uterine contractility in the rat.

Myometrial tissue rings from postpartum rats (24 h after delivery) were studied in vitro by electric field stimulation, and the alpha1/beta2-adrenoceptor ratio was determined by a radioligand binding technique. Pregnancy-denervated uterine rings were stimulated by long-duration pulses (100 ms). The contractions were inhibited by beta2-agonists (terbutaline and fenoterol) and alpha-antagonists (phentolamine, urapidil and yohimbine) in a concentration-dependent manner. Their effects were not altered by the adrenergic neuron-blocking agent bretylium. The alpha-antagonists (except phentolamine) elicited the same maximal inhibition as the beta2-agonists. Receptor assays revealed that the alpha1/beta2 ratio was about 2 in the measured uteri. It was concluded that the inhibitory effects of alpha-antagonists and beta2-agonists are mediated via non-synaptic adrenoceptors of the denervated postpartum rat uterus. The same inhibitory activity could be explained by the greater amount of alpha-receptors. It is believed that this is the first functional proof of the existence of non-synaptic alpha1-adrenoceptors in smooth muscle.

Adrenergic beta-Agonists↗

PubMed1998

Do alpha 2-adrenoceptors and imidazoline binding sites coexist in the human term placenta? Evidence from direct binding studies.

Alpha2-Adrenergic receptors and non-adrenergic imidazoline binding sites (IBS) in human placental membranes were investigated by means of the radioligands [3H]-RX 821002 and [3H]-RX 781094 (idazoxan) respectively. Human term placentae (38-40 weeks) were obtained immediately after vaginal delivery. The specific binding of the alpha2-subtype-selective [3H]-RX 821002 confirms the presence of alpha2-adrenoceptors in the human placenta, while [3H]-idazoxan binds to non-adrenergic IBS. The sites were characterized by displacement analyses with various imidazoline and non-imidazoline drugs. The presence of an endogenous ligand for IBS has not yet been demonstrated. Clonidine displacing substance (CDS) was recently identified as agmatine; it recognizes both alpha2 and imidazoline receptors. This phenomenon was studied in crude placental membranes. The studies revealed that: (i) alpha2-adrenoceptors coexist with non-adrenergic IBS in human placental membranes; (ii) there is a strong probability that alpha2-adrenoceptors and IBS are pharmacologically distinct; and (iii) agmatine binds to placental alpha2 and imidazoline receptors with different affinities.

Binding, Competitive↗