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PubMed1982

Solid-phase synthesis of peptides via alpha, beta-unsaturated amino acids: oxytocin, simultaneous incorporation of amide functions in COOH-terminal and endo-positions.

Oxytocin was synthesized via the solid-phase method using dehydroalanine as pseudo-protecting group of the carboxyl-terminal as well as the omega-amide functions of asparagine and glutamine in endo-position. Starting with Boc-Gly-Dha-resin and using Boc-L-Asp(Dha-NHEt)-OH and Boc-L-Glu(Dha-NHEt)-OH as precursors of asparagine and glutamine, respectively, oxytocin was assembled in stepwise manner under solid phase synthesis conditions. Treatment of the protected [Glu(Dha-NHEt)4, Asp(Dha-NHEt)5]-oxytocin-Dha-resin with 1 n HCl in glacial acetic acid in the presence of 3 equiv. water removed the peptide from the support with the simultaneous formation of the asparagine and glutamine residues to give the protected nonapeptide amide: Cbz-Cys(Bzl)-Tyr(Bzl)-Ile-Gln-Asn-Cys(Bzl)-Pro-Leu-Gly-NH2, which was deprotected with sodium in liquid ammonia and then oxidized with diiodoethane to give oxytocin. After purification by gel chromatography and countercurrent distribution, the product displayed the chemical and physical properties and oxytocic activity (533 +/- 301U/mg) of a standard oxytocin preparation.

Amino Acids↗
PubMedDate not supplied

Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin.

We report the solid phase synthesis of six analogs of the potent and selective linear AVP vasopressor (V1a receptor) antagonist: Phaa1-D-Tyr(Et)2-Phe3-Gln4-Asn5-Lys6-Pro7-Arg-NH(8)2(A) (where Phaa = phenylacetyl) in which the Phaa1 residue is replaced by hydroxyphenylacetyl (HO-Phaa), hydroxyphenylpropionyl (HO-Phpa) and phenylpropionyl (Phpa) and the D-Tyr(Et)2 and Lys6 residues by D-Tyr(Me)2 and Arg6 substituents. The phenolic-containing peptides were synthesized to test the feasibility of using this approach for the design of high affinity selective ligands for AVP V1a receptors. The following analogs of A were synthesized: 11 [(HO)Phaa1]; 2. [(HO)Phaa1,D-Tyr(Me)2]; 3. [(HO)Phaa1,D-Tyr(Me)2, Arg6]; 4. [(HO)Phaa1,Arg6]; 5. [Phpa1]; 6. [(HO)Phpa1]. All six peptides were examined for agonistic and antagonistic potencies in vasopressor (V1a-receptor) and antidiuretic (V2-receptor) and in vitro oxytocic assays in rats. The affinities of the phenolic-containing peptides for hepatic V1a and uterine receptors were also determined. The phenolic-containing peptides all exhibit potent V1a antagonism. Their anti-V1a pA2 values range from 8.23 to 8.63 (the anti-V1a pA2 value of A = 8.69). Their inhibition constants (Ki in nM) range 0.4 to 1.0. They are weak antidiuretic agonists with activities ranging from 0.022 U/mg to 0.13 U/mg (A = 0.033 U/mg). They all exhibit OT antagonism in vitro. Their anti-OT pA2 values range from 7.28 to 7.71 (A = 7.62). All five phenolic compounds were iodinated using iodine chloride and tested in the same in vivo and in vitro assay system.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

Design and synthesis of highly selective in vitro and in vivo uterine receptor antagonists of oxytocin: comparisons with Atosiban.

We report the solid phase synthesis and some pharmacological properties of seven position two analogues (peptides 1-7) of one of our lead oxytocin antagonists, des-9-glycinamide[1-(beta-mercapto-beta,beta-pentamethylenepropionic+ ++ acid),2-O-methyltyrosine,4-threonine]ornithinevasotocin(desGly+ ++-NH2, d(CH2)5-[Tyr(Me)2,Thr4]OVT) (A). Peptides 1-7 have the following substituents at position two (1) D-Tyr(Me); (2) L-Tyr(Et); (3) D-Tyr(Et); (4) L-Tyr; (5) D-Tyr; (6) D-Phe and (7) D-Trp. These were evaluated for agonistic and antagonistic activities in in vitro and in vivo OT assays, in vivo vasopressor (V1a-receptor) assays and in vivo antidiuretic (V2-receptor) assays. None of the seven peptides exhibits oxytocic or vasopressor agonism. Peptides 1, 2, 4, 6 and 7 are extremely weak V2 agonists (V2 activities range from 0.001 to 0.02 U/mg). Peptides 3 and 5 exhibit weak V2 antagonism (pA2 < 6.0 and < 5.5, respectively). Peptides 1-7 exhibit potent in vitro (no Mg2+) OT antagonism (anti-OT pA2 values range from 7.66 to 8.03). Peptides 1 and 4-7 exhibit potent in vivo OT antagonism. Estimated in vivo anti-OT pA2 values range from 7.06 to 7.79 (peptides 2 and 3 were not tested). With anti-V1a pA2 values of 5.17-6.25 all seven peptides exhibit reduced anti-V1a potencies relative to the parent peptide (A) (anti-V1a pA2 = 6.46). Four of these peptides (4-7) exhibit striking gains in in vitro and in vivo anti-OT/anti-V1a selectivities compared to (A) which has an in vitro selectivity of 30 and an in vivo selectivity of 18. The D-Tyr2 (5), D-Trp2 (7), D-Phe2 (6) and L-Tyr2 (4) analogues of (A) exhibit anti-OT (in vitro)/anti-V1a selectivities = 240, 390, 404 and 540, respectively. The L-Tyr2 (4), D-Trp2 (7), D-Phe2 (6) and D-Tyr2 (5) analogues exhibited anti-OT (in vivo)/anti-V1a selectivities of 72, 80, 88 and 95, respectively. Peptides 4-7 appear to be the most selective peptide OT antagonists reported to date. In this regard it may be noted that they appear to be as or more potent and much more selective than the closely related OT antagonist 1-deamino[D-Tyr(Et)2,Thr4]OVT (Atosiban) which is currently undergoing clinical trial as a potential therapeutic agent for the prevention of premature labor. Atosiban (peptide 8) was resynthesized and pharmacologically evaluated in our laboratories. Atosiban exhibits the following antagonistic potencies. Anti-OT (in vitro, no Mg2+) pA2 = 7.71; anti-OT in vivo pA2 = 7.05; anti-V1a pA2 = 6.14 and anti-V2 pA2 approximately 5.9. Its anti-OT (in vivo)/anti-V1a selectivity is 8. Some of these antagonists may be suitable candidates for evaluation as potential tocolytic agents for use in the treatment of pre-term labor. They could also serve as useful new pharmacological tools for studies on the physiological roles of oxytocin. Finally, the findings presented here provide useful clues for the design of more potent and more selective OT antagonists.

Amino Acid Sequence↗
PubMed1995

A new neurohypophysial peptide, seritocin ([Ser5,Ile8]-oxytocin), identified in a dryness-resistant African toad, Bufo regularis.

From the pituitary neurointermediate lobe of the African toad Bufo regularis, vasotocin, hydrin 2 (vasotocinyl-Gly) and a mesotocin-like peptide have been isolated by HPLC and characterized by mass spectrometry, amino acid sequence and chromatographic coelution with synthetic peptides. The mesotocin-like peptide has been identified as [Ser5,Ile8]-oxytocin in place of mesotocin ([Ile8]-oxytocin) found in all other amphibians investigated to date. The name seritocin is suggested. The molecule is virtually devoid of oxytocic activity on rat uterus in contrast to mesotocin. On the other hand, the molar ratio of hydrin 2 to vasotocin in the pituitary reaches 2, whereas it is about 1 in toads and frogs from temperate regions. B. regularis is an anuran species able to withstand a hot and dry season by burrowing. The possible relationship between occurrence of seritocin and adaptation to arid environment remains to be demonstrated.

Amino Acid Sequence↗
PubMed1998

Biologically active analogues of arginine vasopressin containing conformationally restricted dipeptide fragments.

In this study we described the synthesis and pharmacological properties of five new analogues of arginine vasopressin (AVP). Four of these analogues contained ethylene-bridged dipeptide Phe-Phe in positions 2 and 3; one had two N-Me-Phe residues. All new peptides were tested for vasopressor and antidiuretic activities. We also estimated the uterotonic activities of these compounds in vitro. Three analogues were highly potent V1-antagonists. One of them, namely [Cpa1,(Phe-Phe)2,3,Val4]AVP, which seemed to not interact with either V2 and oxytocic receptors, was outstandingly selective. It is interesting that the high antipressor potency of our second peptide, [(N-Me-Phe)2,3]AVP, was achieved without modification of position 1. Our results open new possibilities for the design of very potent and selective V1-antagonists of AVP.

Animals↗
PubMed1990

Influence of vasotocin and isoproterenol on the in vitro motility of the follicular stalks and infundibulum in the domestic hen.

Since in the hen ovulation and oviposition are in close temporal relationship we studied the effect of vasotocin, the principal neurohypophysial oxytocic substance in birds, on in vitro motility of follicular stalks of the most recently ruptured and largest preovulatory follicle and of longitudinal and circular infundibular strips, both in the absence and the presence of a beta-adrenergic drug (isoproterenol, 1 x 10(-7) mol/l). Infundibular strips were rather insensitive to vasotocin (3 x 10(-9) - 3 x 10(-6) mol/l) either in the absence or presence of isoproterenol. However, tissue strips from the follicular stalks were significantly stimulated by vasotocin (3 x 10(-9) - 3 x 10(-7) mol/l). Isoproterenol attenuated these effects. From these in vitro studies it was concluded that vasotocin may have a facilitating function in the process of ovulation.

Animals↗
PubMed1996

Case report: torsion of a gravid horn of a didelphic uterus.

Acute abdominal pain during pregnancy presents a dilemma as signs and symptoms are often modified. Abdominal massage by traditional birth attendants (TBAs') during early labour is a common practice in the rural population, as it is perceived to give a soothening effect to the labouring mother. Many instances of abruptio placentae were reported in the past by this procedure, and in this case, the clinical picture presented as an abruptio placenta. Malpresentation and failure to progress were the indications for caesarean section despite the fetal demise. Severe post partum haemorrhage and failure to contract despite massive oxytocics resulted in the hysterectomy of the gravid horn, leaving the other horn intact.

Abdominal Pain↗
PubMed1999

A randomized controlled trial comparing midwife-managed care and obstetrician-managed care for women assessed to be at low risk in the initial intrapartum period.

OBJECTIVE: To compare the efficacy of midwife-managed care and obstetrician-managed care for women assessed to be at low risk in the initial intrapartum period. METHODS: 1,050 women assessed to be at low risk on admission to labour ward in the Prince of Wales Hospital participated in this study. By computer-generated random allocation, 563 (54%) women were assigned to Group A (experimental) under midwifery care, and 487 (46%) women to Group B (control) under obstetrician care. The outcomes and complications between the 2 groups were compared. Data were analyzed by 2 x 2 contingency tables and Chi-square. RESULTS: 150 (26.6%) women in the experimental group were taken over by the obstetricians. 46 (30.7%) women were transferred to obstetrician-management for the preference of epidural analgesia. The other reasons for taken over the remaining 104 (69.3%) women were fetal distress, poor progress of labour, complications in first or second stage of labour. The experimental group had less oxytocic augmentation (Chi-square = 7.49, p = 0.006) and the insertion of intravenous infusion (Chi-square = 5.34, p = 0.02). Both groups had similar outcomes on normal delivery, operative vaginal delivery, caesarean section and complications. CONCLUSIONS: Midwife-managed care is as safe as obstetrician-managed care for women who were assessed to be at low risk in the intrapartum period. Routine visit by obstetrician is not necessary and the midwives are able to detect complications in the course of labour and alert the obstetrician for taking the necessary action.

Cesarean Section↗
PubMed2005

Safe techniques in surgery for hysteroscopic myomectomy.

Hysteroscopic myomectomy is regarded as the best treatment for patients with submucous myomata. However, this procedure has a number of associated complications, including uterine perforation, cervical laceration, hyponatremia and hemorrhage, especially in cases of sessile submucous myomata. To avoid these problems, it is important to make well-advised preparations and manipulations both pre- and intraoperatively. The main surgical considerations for safe hysteroscopic myomectomy are shortening the operating time and avoiding cutting too deeply into the myometrium. With these requirements in mind, a combination of techniques using vaporization and a powerful oxytocic agent, such as prostaglandin F-2alpha, appears to be the safest method of carrying out hysteroresectoscopy for unpedunculated sessile submucous myomata.

Female↗
PubMed2006

Analysis of uterine rupture in a tertiary center in Eastern Nepal: lessons for obstetric care.

AIM: To determine the etiologic factors, clinical presentation, management and fetomaternal outcome in cases of rupture of the gravid uterus and propose preventive measures. METHODS: A retrospective analysis of cases of uterine rupture was carried out at B.P. Koirala Institute of Health Sciences, Nepal, between February 1999 and January 2004. RESULTS: There were 126 cases of uterine rupture with incidence of one in 112 deliveries. Twenty-five patients (19.8%) had a cesarean scar. Obstructed labor was the common antecedent factor in the unscarred group (46.5%) and use of oxytocics accounted for maximum ruptures (44%) in the scarred category. Patients with an unscarred uterus presented with hypotension and intrauterine death (89.1%), while abdominal tenderness (76%) and fetal distress (64%) were common modes of presentation in the scarred category. Complete rupture was seen in 84.9% of patients. Lateral wall ruptures (71.3%) necessitating hysterectomy (75.2%) were seen in the unscarred group. Anterior ruptures (92%) and repair (84%) were common in the scarred category. Maternal mortality was 13.5% and perinatal mortality 83.3%; these were both higher in the unscarred uterus. CONCLUSION: The incidence of uterine rupture is high in Eastern Nepal and rupture of the unscarred uterus carries graver risks. Regular antenatal care, hospital deliveries and vigilance during labor with quick referral to a well-equipped center will reduce the incidence of this condition.

Adult↗
PubMed1976

Buccal prostaglandin E2 for induction of labour.

The administration of buccal prostaglandin E2 (PGE2) was evaluated in 30 patients; effective uterine stimulation occurred in 90 per cent of those receiving a dose of 1 mg hourly. Two patients had a prolonged contraction on a single occasion during labour. The unpleasant taste of the tablets and a high incidence of nausea and vomiting indicated that buccal prostaglandins had no advantages over other methods of administering oxytocic agents.

Administration, Oral↗
PubMed1985

Myometrial activity in first trimester human pregnancy after Epostane therapy. Effect of intravenous oxytocin.

The effect on myometrial activity of Epostane, a competitive inhibitor of the 3 beta-hydroxy steroid dehydrogenase enzyme system (3 beta-HSD) has been studied in 20 women awaiting termination of pregnancy. The women were randomly allocated by a double-blind procedure into two groups. In the Epostane-treated group there were significant falls in serum progesterone and oestradiol concentrations after 3 days of treatment. The placebo-treated group showed a small but significant decline in serum progesterone concentration. Insertion of an intrauterine balloon catheter for pressure measurements produced significantly greater uterine activity in the Epostane-treated group. The oxytocin response was variable and there was no significant difference between the two groups. A small rise in the peripheral plasma concentration of a prostaglandin F2 alpha metabolite (PGFM) was observed in the placebo group following oxytocin injection. There was a significant inverse correlation between post treatment progesterone values and uterine activity. Epostane appears to sensitize the myometrium to endogenous oxytocics and this probably results from progesterone 'withdrawal'. This effect may prove useful in potentiating the action of exogenous myometrial stimulants, such as prostaglandins, and may have a role in the termination of early pregnancy.

3-Hydroxysteroid Dehydrogenases↗
PubMed1993

Measurement of uterine activity in labour--clinical aspects.

Intra-uterine pressure measurement remains the most objective way of measuring uterine activity in labour, and in this respect is superior to clinical assessment or external tocography. However there is little evidence to show that improving the assessment of uterine activity in labour is associated with an improvement in the outcome of labour for mother or fetus. It seems logical that use of intra-uterine pressure monitoring will provide additional safety in women with a scarred uterus, breech presentation, high parity, or apparent failure of response to induction or augmentation of labour with the usual dose rates of oxytocics, but this has not been established by appropriately sized clinical trials. Further research to establish the role of uterine activity measurement in labour is urgently needed.

Breech Presentation↗
PubMed1993

The effect of early labour, maternal analgesia and fetal acidosis on fetal plasma oxytocin concentrations.

OBJECTIVE: To determine the effect of early labour, maternal analgesia and fetal hypoxia on circulating fetal oxytocin concentrations. DESIGN: Prospective observational study. SETTING: Delivery suite in a District General Hospital. SUBJECTS: Fifty women at term who did not require oxytocin administration or more than one form of analgesia. Study groups: vaginal delivery with (1) no analgesia, (2) pethidine, or (3) epidural analgesia. Caesarean section under regional analgesia (4) prior to, and (5) after the onset of labour. INTERVENTIONS: Samples of blood were collected from the umbilical artery (UA) and umbilical vein (UV) immediately after fetal delivery prior to placental separation or oxytocic administration. MAIN OUTCOME MEASURES: Plasma oxytocin (OT) concentration, umbilical vein pH, cystine aminopeptidase activity. RESULTS: The geometric mean UA-OT was significantly greater than UV-OT in all groups and was not altered by pethidine; however, epidural administration increased the UA-UV difference. The UA-UV difference at caesarean section was not significantly altered by the onset of labour. There was no correlation between UV pH and UA-UV plasma oxytocin. Cystine aminopeptidase activity was not detectable in UA and UV plasma. CONCLUSIONS: Fetal OT production is increased by epidural but not by pethidine analgesia. It is not influenced by the onset of labour or fetal hypoxia.

Acidosis↗
PubMed1997

Routine oxytocin in the third stage of labour: a placebo controlled randomised trial.

OBJECTIVE: To compare intravenous oxytocin administration (Partocon 10 IU) with saline solution in the management of postpartum haemorrhage in the third stage of labour. DESIGN: A double-blind, randomised controlled trial involving 1000 parturients with singleton fetuses in cephalic presentation and undergoing vaginal delivery, randomly allocated to treatment with oxytocin (n = 513) or 0.9% saline solution (n = 487). SETTING: Labour ward at a central county hospital. MAIN OUTCOME MEASURES: Mean blood loss (total, and before and after placenta delivery); frequencies of blood loss > 800 mL, need of additional oxytocic treatment, postpartum haemoglobin < 10 g/dL; and duration of postpartum hospitalisation. RESULTS: As compared with saline solution, oxytocin administration was associated with significant reduction in mean total blood loss (407 versus 527 mL), and in frequencies of postpartum haemorrhage > 800 mL (8.8% versus 5.2%), additional treatment with metylergometrine (7.8% versus 13.8%), and postpartum Hb < 10 g/dL (9.7% versus 15.2%), and a nonsignificant increase in the frequency of manual placenta removal (3.5% versus 2.3%). There was no group difference in the mean duration of postpartum hospitalisation (4.6 versus 4.5 days, respectively). CONCLUSIONS: Administration of intravenous oxytocin in the third stage of labour is associated with an approximately 22% reduction in mean blood loss, and approximately 40% reductions in frequencies of postpartum haemorrhage (> 500 mL or > 800 mL) and of postpartum haemoglobin < 10 g/dL. Identification of risk groups for oxytocin treatment does not seem worthwhile. Oxytocin is a cheap atoxic drug and should be given routinely after vaginal delivery.

Adult↗
PubMed1959

The fate of oxytocin in male and female rats.

A method for quantitative extraction of oxytocin from blood is described. The disappearance of injected oxytocin from the circulation in rats was shown to depend upon its uptake in the kidneys and in organs of the splanchnic vascular area. In lactating rats there was uptake by an additional organ or tissue, probably the mammary gland. In animals without kidneys or lactating mammary glands and with no circulation in the splanchnic area oxytocin was distributed into a volume greater than the extracellular fluid volume, and after equilibration the concentration in plasma did not change significantly. During severe haemorrhage increased amounts of antidiuretic activity were detected in blood when there was no significant increase in oxytocic activity.

Animals↗
PubMed1959

The extraction of human urinary kinin (substance Z) and its relation to the plasma kinins.

Human urinary kinin (substance Z) has been extracted by modifications of the methods previously described by Gomes (1955) and Jensen (1958). The separation of two oxytocic fractions from such extracts by paper pulp chromatography (Walaszek, 1957; Jensen, 1958) could not be confirmed. Substance Z could not be distinguished from kallidin, bradykinin or glass-activated kinin by parallel quantitative assays, thus confirming that these four substances are very closely related.

Biological Assay↗
PubMed1960

Assay of lysergic acid diethylamide and its passage from blood into the perfused cerebral ventricles.

On the isolated rat uterus, lysergic acid diethylamide had an oxytocic action in a concentration of 2x10(-8); in smaller concentrations (10(-9) to 10(-10)), which had no stimulating effect of their own, it potentiated acetylcholine-induced contractions. This potentiating effect was made the basis for assaying minute amounts of lysergic acid diethylamide. The method was used to assay this substance in plasma of cats during its intravenous infusion at a rate of 10 mug./min./kg. During these infusions 0.4 to 2 ng./min. of lysergic acid diethylamide passed into the cerebral ventricles perfused with a salt solution of a composition resembling that of cerebrospinal fluid.

Acetylcholine↗