pituitrin and atosiban

Embryo transfer, the final stage of IVF/embryo transfer (IVF/ET) treatment, independently influences treatment outcome.Successful embryo implantation following embryo transfer, among other factors, is also dependant on uterine receptivity.Uterine contractile activity may adversely affect the implantation. Although increased contractions have been found in approximately 30% of patients undergoing embryo transfer, to date it has not been a subject to any diagnosis or therapy. Pharmacological tocolytics may be expected to improve pregnancy rates; however, targeting uterine adrenergic receptors, calcium channels or prostaglandin synthesis has since proven ineffective. The novel class of drugs which could be the most useful in this indication is oxytocin antagonists. In animal models, oxytocin significantly reduced embryo implantation rates, and this was reversed by an oxytocin antagonist. In humans, peptidyl oxytocin and mixed vasopressin V1A/oxytocin antagonists have been found to significantly reduce uterine contractions in egg donors undergoing mock embryo transfer. It has further been demonstrated that the vasopressin V1A/oxytocin receptor antagonist atosiban can improve pregnancy success in patients with recurrent IVF failures. This article reviews the uterine oxytocin/vasopressin V1A receptor systems and their potential influence on embryo implantation. It is suggested that the clinical application of oxytocin antagonists might improve results of IVF/ET treatment.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Embryo Implantation; Female; Humans; Indoles; Infertility; Oligopeptides; Oxytocin; Pregnancy; Pyrrolidines; Receptors, Oxytocin; Reproductive Techniques, Assisted; Tocolytic Agents; Uterine Contraction; Vasopressins; Vasotocin

Oxytocin is involved in the regulation of preterm and term labor but the exact effect mechanisms are not fully understood. A regulatory action by vasopressin may also exist. The concentrations of oxytocin and vasopressin V1a receptors in myometrium from pregnant women are high before and in the beginning of labor both preterm and at term. Atosiban has high affinity for both these receptors and is a competitive oxytocin and vasopressin antagonist. The inhibitory effect of Atosiban on oxytocin induced activity on isolated myometrium correlates significantly with the concentration of the oxytocin receptors. Inhibition of preterm contractions with Atosiban was first reported by Akerlund et al 1987. Goodwin et al compared the effect of Atosiban to placebo in threatening preterm labor and the antagonist was in this trial significantly more effective than placebo in reducing the frequency of contractions (55% vs. 23%, p < 0.001). The same authors also reported successful tocolysis with the drug in actual preterm labor. Atosiban is currently in phase III of clinical development and seems to have the same effectiveness but fewer side-effects compared to beta-mimetics. These properties suggests that Atosiban may offer advantages over existing therapies in acute treatment of preterm labor.

Topics: Female; Hormone Antagonists; Humans; Obstetric Labor, Premature; Oxytocin; Pregnancy; Vasopressins; Vasotocin

A model to study the effect of vasopressin V1a antagonist in dysmenorrhea.. A double-blind, randomized, placebo-controlled, cross-over trial was performed. Eight patients with primary dysmenorrhea and eight tuballigated, healthy subjects participated on days 1-2 of two consecutive menstruations. At each menstruation a bolus injection of 10 pmol/kg of vasopressin was administered before and during infusion of either 300 microg/min of atosiban or placebo. Intrauterine pressure was measured as area under the curve throughout the experiments. Ischemia markers in plasma and pain recorded by a visual analog scale were measured before and after each vasopressin injection as well as before and after the start of either atosiban or placebo infusion.. Vasopressin injections elevated area under the curve in both healthy volunteers and dysmenorrhea subjects. The vasopressin-induced rise in area under the curve was lower during atosiban administration than during infusion of placebo in both groups. None of the ischemia markers differed between or within groups at vasopressin injections or atosiban/placebo infusions. In subjects with dysmenorrhea the increase in pain following the administration of vasopressin was significantly lower during atosiban than during placebo infusion. Healthy volunteers experienced only slight discomfort after the vasopressin injections.. Atosiban reduces vasopressin-induced intrauterine pressure in both healthy volunteers and dysmenorrheics, and reported pain in subjects with dysmenorrhea. The ischemia markers are not a useful biomarker index in women with dysmenorrhea. The dysmenorrhea pain evoked by vasopressin correlated poorly with area under the curve, which may suggest that the effect is mediated by more than one V1a-like receptor. We conclude that this model with recordings in healthy women is useful in the evaluation of drug candidates for primary dysmenorrhea.

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Area Under Curve; Biomarkers; Cross-Over Studies; Double-Blind Method; Dysmenorrhea; Female; Hormone Antagonists; Humans; Ischemia; Pain Measurement; Prospective Studies; Receptors, Vasopressin; Treatment Outcome; Uterine Contraction; Vasopressins; Vasotocin

We compared menstrual pain, uterine contractility and blood circulation, and plasma concentrations of vasopressin and prostaglandin F(2alpha) metabolite in women with versus without primary dysmenorrhea, and determined the effects of a vasopressin antagonist, 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin (Atosiban), on these parameters. Our results do not support the contention that vasopressin is involved in the etiology of dysmenorrhea, plasma concentrations of vasopressin being similar in dysmenorrheic women and controls, and the vasopressin antagonist Atosiban having no effect on menstrual pain, intrauterine pressure or uterine artery pulsatility index in dysmenorrheic women.

Topics: Adult; Blood Flow Velocity; Cross-Over Studies; Dinoprost; Double-Blind Method; Dysmenorrhea; Female; Hormone Antagonists; Humans; Uterine Contraction; Uterus; Vasopressins; Vasotocin

Restraint stress (RS) is an unavoidable stress model that triggers activation of the autonomic nervous system, endocrine activity, and behavioral changes in rodents. Furthermore, RS induces secretion of oxytocin into the bloodstream, indicating a possible physiological role in the stress response in this model. The presence of oxytocin receptors in vessels and heart favors this possible idea. However, the role of oxytocin secreted in RS and effects on the cardiovascular system are still unclear. The aim of this study was to analyze the influence of oxytocin on cardiovascular effects during RS sessions. Rats were subjected to pharmacological (blockade of either oxytocin, vasopressin, or muscarinic receptors) or surgical (hypophysectomy or sinoaortic denervation) approaches to study the functional role of oxytocin and its receptor during RS. Plasma levels of oxytocin and vasopressin were measured after RS. RS increased arterial pressure, heart rate, and plasma oxytocin content, but not vasopressin. Treatment with atosiban (a Gi biased agonist) inhibited restraint-evoked tachycardia without affecting blood pressure. However, this effect was no longer observed after sinoaortic denervation, homatropine (M2 muscarinic antagonist) treatment or hypophysectomy, indicating that parasympathetic activation mediated by oxytocin secreted to the periphery is responsible for blocking the increase in tachycardic responses observed in the atosiban-treated group. Corroborating this, L-368,899 (oxytocin antagonist) treatment showed an opposite effect to atosiban, increasing tachycardic responses to restraint. Thus, this provides evidence that oxytocin secreted to the periphery attenuates tachycardic responses evoked by restraint via increased parasympathetic activity, promoting cardioprotection by reducing the stress-evoked heart rate increase.

Topics: Animals; Antidiuretic Hormone Receptor Antagonists; Baroreflex; Blood Pressure; Heart Rate; Male; Muscarinic Agonists; Oxytocin; Parasympatholytics; Rats, Wistar; Receptor, Muscarinic M2; Receptors, Vasopressin; Restraint, Physical; Stress, Psychological; Tachycardia; Tropanes; Vasopressins; Vasotocin

The oxytocin/vasopressin signalling system is conserved across the animal kingdom. In insects, the role of oxytocin-type (inotocin) neuropeptides has only been studied in locusts, beetles and ants, but their physiology continues to be poorly understood. One reason for this knowledge deficit is the lack of available research tools to complement functional genomics efforts. Consequently, ligands to probe insect inotocin receptors are essential. In this study, we sought to identify novel agonists and antagonists of the inotocin receptor from the representative model species Tribolium castaneum and Lasius niger. Drawing upon known ligands of the human receptors, we examined the pharmacology of the plant-derived cyclotide kalata B7 and the synthetic oxytocin analogue atosiban. Kalata B7 is a weak partial agonist of both inotocin receptors. This is the first reported direct interaction of cyclotides with an insect receptor, an observation that may explain their presumed role in herbivore defence. Furthermore, we discovered atosiban is an antagonist of the Tribolium receptor, which may provide a useful probe to investigate the functionality of inotocin signalling in beetles and related insect species. Our findings will enable further examination of insect inotocin receptor pharmacology and physiology, and may trigger studies to comprehend the interaction of plant cyclotides and insects.

Topics: Animals; Ants; Cyclotides; Hormone Antagonists; Oxytocin; Receptors, Oxytocin; Receptors, Vasopressin; Signal Transduction; Tribolium; Vasopressins; Vasotocin

A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.

Topics: Chemistry, Pharmaceutical; Drug Design; Female; Humans; Kinetics; Ligands; Models, Chemical; Molecular Conformation; Obstetric Labor, Premature; Oxytocin; Pregnancy; Receptors, Oxytocin; Receptors, Vasopressin; Vasopressins; Vasotocin

The aim of the present study was to investigate the effect of systemic oxytocin (OT) and vasopressin (VP) on the motility of stomach and duodenum. Two plastic balloons made of condom were inserted into stomach and duodenum to monitor the change of mean pressure. Intravenous injection of OT (0.1-0.8 microg kg(-1)) or VP (0.02-0.08 IU kg(-1)) dose-dependently increased the stomach and duodenum pressure. Pretreatment of atosiban (1 microg kg(-1)), the specific OT receptor (OTR) antagonist, attenuated the excitatory effect of OT or VP on the pressure of stomach and duodenum. Pretreatment of V1880 (1 microg kg(-1)), the specific V1 receptor blocker, did not influence this effect. So we conclude that both of OT and VP injected systemically increased the gastric and duodenum motility via OTR.

Topics: Animals; Dose-Response Relationship, Drug; Gastrointestinal Motility; Hormone Antagonists; Male; Manometry; Oxytocin; Rabbits; Receptors, Oxytocin; Receptors, Vasopressin; Vasopressins; Vasotocin

Oxytocin is released in response to a meal. Further, mRNA for oxytocin and its receptor have been found throughout the gastrointestinal (GI) tract. The aim of this study was therefore to examine whether oxytocin, or the receptor antagonist atosiban, influence the gastric emptying.. Ten healthy volunteers (five men) were examined regarding gastric emptying at three different occasions: once during oxytocin stimulation using a pharmacological dose; once during blockage of the oxytocin receptors (which also blocks the vasopressin receptors) and thereby inhibiting physiological doses of oxytocin; and once during saline infusion. Gastric emptying rate (GER) was assessed and expressed as the percentage reduction in antral cross-sectional area from 15 to 90 min after ingestion of rice pudding. The assessment was performed by real-time ultrasonography. At the same time, the feeling of satiety was registered using visual satiety scores.. Inhibition of the binding of endogenous oxytocin by the receptor antagonist delayed the GER by 37 % compared to saline (p = 0.037). In contrast, infusion of oxytocin in a dosage of 40 mU/min did not affect the GER (p = 0.610). Satiation scores areas in healthy subjects after receiving atosiban or oxytocin did not show any significant differences.. Oxytocin and/or vasopressin seem to be regulators of gastric emptying during physiological conditions, since the receptor antagonist atosiban delayed the GER. However, the actual pharmacological dose of oxytocin in this study had no effect. The effect of oxytocin and vasopressin on GI motility has to be further evaluated.

Topics: Adult; Antidiuretic Hormone Receptor Antagonists; Area Under Curve; Female; Gastric Emptying; Hormone Antagonists; Humans; Infusions, Intravenous; Male; Middle Aged; Oxytocics; Oxytocin; Pyloric Antrum; Satiety Response; Sodium Chloride; Ultrasonography; Vasopressins; Vasotocin

Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antidiuretic Hormone Receptor Antagonists; Blotting, Southern; Brain; Cell Differentiation; Embryo, Mammalian; Flow Cytometry; Gene Expression; In Situ Hybridization; Indoles; Mice; Neurophysins; Organ Culture Techniques; Oxytocin; Pyrrolidines; Receptors, Oxytocin; Receptors, Vasopressin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; T-Lymphocyte Subsets; Thymus Gland; Vasopressins; Vasotocin

To compare a newly developed oxytocin antagonist, FE 200 440, with atosiban and ANTAG III, as to potency and selectivity of inhibitory effects on oxytocin- and vasopressin-induced myometrial responses. FE 200 440 has high affinity for the human cloned oxytocin receptor, approximately 300-fold that for the vasopressin V(1a) receptor, whereas atosiban binds well to both receptors.. In vitro study of human myometrial contractility. The Research Laboratory of the Department of Obstetrics and Gynecology, Lund University Hospital, Sweden.. Forty-seven term-pregnant women not in labour who were delivered by caesarean section.. Concentration-response curves with oxytocin and arginine vasopressin on isolated myometrial strips were recorded in control experiments, in the presence of atosiban in concentrations of 25, 250 and 750 nmol/L, and after pretreatment with ANTAG III and FE 200 440, both in concentrations of 2.5, 25 and 250 nmol/L.pA(2) values (i.e. an index of inhibitory action).. With oxytocin as the agonist, the median pA(2) values for atosiban, ANTAG III and FE 200 440 were 10.6, 9.5 and 8.3, respectively. With vasopressin as the agonist, the pA(2) values for atosiban and ANTAG III were 8.8 and 8.7, whereas no inhibitory effect of FE 200 440 was seen in five out of six experiments.. The new analogue FE 200 440 is a selective oxytocin antagonist and, in contrast to atosiban and ANTAG III, has practically no effect on vasopressin-induced contractions of isolated term-pregnant human myometrium.

Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Female; Humans; Oxytocin; Pregnancy; Receptors, Oxytocin; Uterine Contraction; Vasopressins; Vasotocin

These experiments were performed to study the effect of oxytocin (OT) and it's specific receptor on gallbladder motility in rabbits. The fasted New Zealand white rabbits (2.0-2.5 kg) were anaesthetized by urethane (1 g/kg). The gallbladder pressure was recorded continuously to monitor the gallbladder motility. Systemic OT (0.01, 0.02, 0.04 mg/kg, iv) did not affect the gallbladder pressure, but dose-dependently increased the frequency of phasic contraction. Five min after OT administration (0.04 mg/kg, iv), the strength of phasic contraction increased to 0.23 +/- 0.08 mmHg/min (P < 0.01, n = 6). The gallbladder motility returned to normal 15 min later after OT treatment. Intravenous injection of atosiban (0.04 mg/kg, iv), an OT receptor antagonist, decreased the strength of gallbladder phasic contraction but did not affect gallbladder pressure. Pretreatment of atosiban (0.04 mg/kg, iv) completely abolished the systemic OT effect on gallbladder. Vasopressin (VP) (0.1 - 0.5 IU/kg, iv) dose-dependently decrease the gallbladder pressure but did not affect the phasic contraction. MK-329 (0.4 mg/kg, iv), the CCK-A receptor antagonist, L-365, 260 (0.4 mg/kg, iv), the CCK-B receptor antagonist and atropine (0.2 mg/kg, iv), the M receptor antagonist, did not affect the OT effect on gallbladder motility. We suggest that endogenous OT regulates gallbladder phasic contraction through specific OT receptor. This effect is independent of the peripheral CCK and M receptors.

Topics: Animals; Atropine; Female; Gallbladder Emptying; Hormone Antagonists; Male; Muscarinic Antagonists; Oxytocin; Rabbits; Receptors, Cholecystokinin; Receptors, Oxytocin; Vasoconstrictor Agents; Vasopressins; Vasotocin

Previous experiments have indicated that arterial hypotension increases plasma oxytocin (OT) levels in rats and that OT infused intravenously causes an increase in plasma renin activity (PRA). The goal of the present study was to determine whether systemic administration of an OT receptor antagonist would attenuate the increase in PRA that is normally evoked by arterial hypotension in rats. In conscious male rats, intravenous injection of hydralazine or diazoxide produced sustained hypotension and evoked a significant increase in PRA, as expected. Intravenous infusion of an OT receptor antagonist did not alter the hypotension induced by hydralazine or diazoxide, but it did markedly blunt the induced increase in PRA. The OT receptor antagonist also blunted the hypotension-evoked increase in heart rate and plasma vasopressin levels, suggesting that the antagonist may have generally disrupted afferent signaling of hypotension. Thus hypotension-evoked OT secretion may contribute to cardiovascular homeostasis by enhancing baroreceptor signals that stimulate increases in renin secretion, vasopressin secretion, and heart rate during arterial hypotension in rats.

Topics: Animals; Diazoxide; Heart Rate; Hormone Antagonists; Hydralazine; Hypotension; Kinetics; Male; Oxytocin; Rats; Rats, Sprague-Dawley; Renin; Vasodilator Agents; Vasopressins; Vasotocin

We report the solid phase synthesis of four pairs of L- and D-thienylalanine (Thi/D-Thi) position two modified analogues of the following four oxytocin (OT) antagonists: des-9-glycinamide [1-(beta-mercapto-beta,beta-pentamethylene propionic acid), 2-O-methyltyrosine, 4-threonine]ornithine-vasotocin (desGly(NH2)9,d (CH2)5[Tyr(Me)2,Thr4]OVT) (A); the Tyr-(NH2)9 analogue of (A), d(CH2)5[Tyr(Me)2,Thr4,Tyr-(NH2)9]OVT (B); the Eda9 analogue (where Eda = ethylenediamine) of (A), d(CH2)5[Tyr(Me)2, Thr4, Eda9]OVT (C); and the retro Tyr10 modified analogue of (C), d(CH2)5[Tyr(Me)2, Thr4, Eda9<--Tyr10]OVT (D). The eight new analogues of A-D are (1) desGly(NH2),d(CH2)5[Thi2,Thr4]OVT, (2) desGly(NH2),d(CH2)5[D-Thi2,Thr4]OVT, (3) d(CH2)5[Thi2, Thr4,Tyr-(NH2)9]OVT, (4) d(CH2)5[D-Thi2,Thr4,Tyr-(NH2)9]OVT (5) d(CH2)5[Thi2,Thr4Eda9]OVT, (6) d(CH2)5[D-Thi2,Thr4,Eda9]OVT, (7) d(CH2) [Thi2,Thr4,Eda9<--Tyr10]OVT, (8) d(CH2),[D-Thi2,Thr4,Eda9<--Tyr10]OVT. We also report the synthesis of (C). Peptides 1-8 and C were evaluated for agonistic and antagonistic activities in in vitro and in vivo OT assays, in in vivo vasopressor (V1a receptor) assays and in in vivo antidiuretic (V2 receptor) assays. None of the eight peptides nor C exhibit oxytocic or vasopressor agonism. Peptides 1-8 are extremely weak V2 agonists (antidiuretic activities range from < 0.0005 to 0.20 U/mg). Peptide C is a weak mixed V2 agonist/antagonist. Peptides 1-8 and C exhibit potent in intro (no Mg2+) OT antagonism (anti-OT pA2 values range from 7.76 to 8.05). Peptides 1-8 are all OT antagonists in vivo (estimated in vivo anti-OT pA2 values range from 6.54-7.19). With anti-V1a pA2 values of approximately 5-5.80, peptides 1-8 exhibit marked reductions in anti-V1a potencies relative to those of the parent peptides A-D (anti-V1a pA2 range from 6.48 to 7.10) and to l-deamino[D-Tyr(Et)2, Thr4]OVT (Atosiban, trade name Tractocile) (anti-V1a pA2-6.14). Atosiban has recently been approved in Europe for clinical use for the prevention of premature labour (Pharm. J. 264(7-100): 871). Peptides 1-8 exhibit striking gains in in vitro anti-OT/anti-V1a selectivities with respect to the parent peptides A, B, C and D and to Atosiban. Peptides 1-8 exhibit anti-OT (in vitro)/anti-V1a selectivities of 450, 525, 550, 450, approximately 1080, 116, 355, 227 respectively. The corresponding values for A-D and Atosiban are 30, 4.2, 4.3, 2.6 and 37. With the exception of peptide 6, the remaining seven peptides exhibit 3-18-fold gains in

Topics: Biological Assay; Chromatography, Thin Layer; Drug Design; Hormone Antagonists; Methyltyrosines; Oxytocin; Peptide Biosynthesis; Peptides; Receptors, Vasopressin; Vasopressins; Vasotocin

Our purpose was to study myometrial oxytocin and type V1 vasopressin receptors, the in vitro contractile effects of these hormones, and the influence of an oxytocin antagonist.. Women delivered by cesarean section preterm (n = 51) and at term (n = 71), with and without labor contractions, gave myometrium for the estimation of oxytocin and V1 vasopressin receptors. The in vitro myometrial effects of the peptides and the influence on these of the competitive oxytocin receptor blocking agent 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin were also tested.. The median concentration of oxytocin receptors was 116 fmol/mg protein (range 15 to 372 fmol/mg protein) in patients delivered preterm not in labor, 134 fmol/mg protein (27 to 1421 fmol/mg protein) in the beginning of labor, and 46 fmol/mg protein (9 to 140 fmol/mg protein) in advanced labor. At term the corresponding concentrations were 172 (25 to 629), 223 (24 to 414), and 70 (21 to 92) fmol/mg protein. The concentration of V1 vasopressin receptors also decreased in advanced labor. In advanced labor after oxytocin infusion a reduction in the concentration of the receptor for this hormone was observed, which appeared to be related to the duration and dose of treatment. Oxytocin receptors did not vary between women with different indications for cesarean section. The oxytocin effects in vitro and the degree of inhibition by the antagonist of oxytocin responses correlated with the concentration of oxytocin receptors but not with that of V1 vasopressin receptors. No correlation was seen between the response to vasopressin and concentrations of oxytocin or V1 vasopressin receptors.. The effect of oxytocin on the myometrium in pregnancy is mediated by an oxytocin receptor, whereas vasopressin acts on both oxytocin and vasopressin receptors. The initiation of labor both preterm and at term may be primarily related to increased release of oxytocin, which is locally produced in the uterus and not detectable in the plasma, but oxytocin and vasopressin receptors may play a role in the regulation of labor. The analog 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin, which blocks both the oxytocin and the V1 vasopressin receptor, should inhibit labor both preterm and at term, the former confirming results of recent clinical studies in Sweden and the United States.

Topics: Cesarean Section; Female; Humans; Myometrium; Obstetric Labor, Premature; Oxytocin; Pregnancy; Receptors, Oxytocin; Receptors, Vasopressin; Reference Values; Uterine Contraction; Vasopressins; Vasotocin

The aim of this study was to study the pharmacokinetics of antocin, the tocolytic oxytocin antagonist [Mpa1, D-Tyr2(Et), Thr4, Orn8]-oxytocin.. Antocin was injected intravenously as a bolus dose (5 mumol). Blood samples were taken at intervals for 240 minutes. In addition, the binding of 125I-Tyr10-antocin to blood constituents was determined and compared with 125I-AVP and 125I-[Mpa1, D-Arg8]-vasopressin (desmopressin).. Eight healthy, non-smoking adults, three male and five female.. Antocin was measured using a specific radioimmunoassay after prior extraction of the plasma. Plasma binding was estimated using polyethyleneglycol precipitation.. The rate of plasma disappearance of antocin was best fitted by a biexponential curve. The clearance of antocin was 23.5 +/- 7.6 l/h, the volume of distribution was 13.1 +/- 3.8 l and the biological half-life was 39.0 +/- 4.1 minutes. A greater proportion of 125I-Tyr10-antocin bound to plasma proteins (33.5%) and red blood cells (13%) than did 125I-AVP, 125I-desmopressin and unlabelled desmopressin.. The half-life was longer and the clearance of antocin was less than that found in a previous study when a non-specific antiserum was used. This is most likely because of the extended blood sampling time period which revealed the biphasic decay pattern. The higher plasma clearance of antocin compared to oxytocin and desmopressin may be explained by its increased binding to blood constituents rather than by differences in enzymatic degradation of the molecules.

Topics: Adult; Arginine Vasopressin; Blood Proteins; Erythrocytes; Female; Half-Life; Humans; Iodine Radioisotopes; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding; Tocolytic Agents; Vasopressins; Vasotocin

The pharmacokinetics in the human of 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT), was studied after iv and intranasal administration in 11 subjects at 12 experiments each route. The plasma concentration of the analogue was analysed by means of an arginine vasopressin antibody, which cross-reacted with dE-TVT to 4.7%. When given intravenously as bolus injection (10 nmol/kg/body weight), the total body clearance amounted to 0.623 +/- 0.099 (SEM) l/h kg and the half-life to 16.2 +/- 2.4 min. After intranasal administration (100 nmol/kg/body weight), the bioavailability was 10.5 +/- 2.9%. Peak concentrations in plasma appeared 2-8 min after iv and 10-45 min after intranasal administration. At the end of an observation period of 2 h measurable amounts in plasma were still found in one of the iv and seven of the intranasal experiments. It is concluded that the moderately long half-life is suitable for the treatment of hospitalized patients in premature labour where promising results with intravenous infusion (50 micrograms/min) of dE-TVT have been obtained. It is still uncertain whether or not the absorption of dE-TVT is sufficient for intranasal administration to out-patients with uterine hyperactivity in late pregnancy and to patients with primary dysmenorrhoea, where significant relief of symptoms were seen after iv administration (10 micrograms/kg body weight).

Topics: Administration, Intranasal; Adult; Biological Availability; Female; Half-Life; Humans; Injections, Intravenous; Male; Metabolic Clearance Rate; Oxytocin; Radioimmunoassay; Vasopressins; Vasotocin

In order to develop inhibitors of vasopressin (VP) and oxytocin (OXY) action on uterine activity, 1-deaminated vasotocin derivatives with modifications at positions 2, 4 and 8 were developed. Two of the most effective analogues in the rat, 1-deamino-2-D-Tyr(OEt)-4-Val-8-Orn-vasotocin (dE-VVT) and 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-vasotocin (dE-TVT) were now tested on human nonpregnant myometrium obtained at hysterectomy in fertile age and on pregnant myometrial tissue obtained at elective cesarean section. The effect was compared with that of a previously synthesized analogue 1-deamino-Tyr(OEt)-oxytocin (dE-OXY) which has already been tested in nonpregnant and pregnant women in vivo. Both of the new analogues competitively inhibited the action of the posterior pituitary hormones. On the nonpregnant uterus dE-VVT was about five times and dE-TVT almost twenty-five times more potent than dE-OXY in inhibiting the effects of VP. On pregnant myometrium, dE-TVT inhibited oxytocin action about as effectively as a five-fold stronger concentration of dE-OXY, and dE-VVT slightly less. A moderate agonistic effect of dE-OXY on pregnant myometrium was found, whereas it was minimal with dE-VVT and not detectable at all with dE-TVT. It appears that these two analogues, particularly dE-TVT, would be interesting for clinical testing both in dysmenorrhea, where increased VP secretion could be of etiological importance, and in premature labor where an increased myometrial concentration of OXY receptors has been demonstrated.

Topics: Adult; Female; Humans; In Vitro Techniques; Myometrium; Oxytocin; Pregnancy; Uterine Contraction; Vasopressins; Vasotocin