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PubMed1985

The neurohypophysial hormones of the egg-laying mammals: identification of arginine vasopressin in the platypus (Ornithorhynchus anatinus).

Two neurohypophysial peptides have been purified from acetone desiccated posterior pituitary glands of the platypus (Ornithorhynchus anatinus) by molecular sieving and high-pressure liquid chromatography. A single pressor peptide, having an amino acid composition and a chromatographic retention time identical to those of arginine vasopressin, has been identified. A single oxytocic peptide has been isolated that ressembles oxytocin by its chromatographic retention time, but lack of material has prevented to obtain a correct amino acid composition. The pressor peptide is roughly four times more abundant than the oxytocic peptide. Neurohypophysial hormones of platypus seem similar to those of echidna, the other living prototherian, and to those of most placental mammals.

Amino Acids↗
PubMed2002

Uterine compression sutures: surgical management of postpartum hemorrhage.

BACKGROUND: It has been estimated that worldwide, over 125,000 women die of postpartum hemorrhage each year. The traditional management of this condition includes the use of oxytocics, such as oxytocin, ergometrine, and prostaglandins, before proceeding to ligation of the internal iliac arteries and even hysterectomy. The B-Lynch technique is a surgical procedure that may be used to arrest postpartum hemorrhage resulting from uterine atony. CASES: This paper describes simple modifications of this technique that make this procedure less complex to perform. Three clinical case scenarios illustrate the context in which the sutures may be used. CONCLUSION: Compression sutures placed into the postpartum uterus may provide a simple first surgical step to control bleeding when routine oxytocic measures have failed. We suggest that the technique we have described is a simple procedure and should be tried before more complex interventions are used.

Adult↗
PubMed2003

Is the intrapartum biophysical profile useful?

OBJECTIVE: To assess the role of biophysical profile (BPP) during normal labor. The secondary goal was to assess the effect of oxytocics, regional anesthesia, and ruptured membranes on fetal behavior during labor. METHODS: The BPP (according to the Manning criteria) was performed prospectively in 100 normal, singleton pregnancies in active labor. To evaluate its role in the prediction of cesarean delivery and admission to the neonatal intensive care unit (NICU), statistical analysis included chi2 and Fisher exact tests for frequency analyses and t tests for comparisons of continuous data. RESULTS: At the mean cervical dilatation of 5.2+/-1.4 cm, 73 women had a BPP score of at least 8/10, 16 had 6/10, six had 4/10, and five had 2/10. The BPP was not influenced by use of oxytocics, prostaglandins, or epidural anesthesia. Fetal breathing (95% versus 71%; P=.002) and gross fetal movements (98% versus 84%; P=.04) decreased with rupture of amniotic membranes. A BPP score of 6/10 or less in labor was associated with a relative risk (RR) for cesarean delivery of 8.00 (95% confidence interval [CI] 2.4, 26.5). Cessation of any ultrasound component of BPP significantly increased the risk of cesarean delivery and admission to the (NICU) (RR=29; 95% CI 2.73, 308.66). In the multivariable analysis, however, fetal movements and amniotic fluid volume were most important in predicting the need for cesarean delivery. CONCLUSION: Fetal heart rate monitoring alone did not predict the need for cesarean delivery or neonatal outcome, whereas the BPP did. Biophysical profile could prove to be a clinically useful adjunctive tool in the assessment of fetal well-being in labor.

Adult↗
PubMed2003

Uterine compression sutures as an alternative to hysterectomy for severe postpartum hemorrhage.

OBJECTIVE: To assess the use of B-Lynch type uterine compression sutures as an alternative to hysterectomy for severe postpartum hemorrhage (PPH) due to uterine atony. METHODS: The use of uterine compression sutures for severe postpartum hemorrhage was reviewed over a 30-month period (January 2000 June 2002) in a tertiary obstetric unit. RESULTS: In 7 cases of uterine atony at the time of Caesarean section, which were unresponsive to all oxytocic agents, a B-Lynch type compression suture was used before resorting to hysterectomy. In 6 of the 7 women, the bleeding was controlled with the suture, while the other required hysterectomy. CONCLUSION: At the time of writing there were 6 reports in the literature involving a total of 20 women who were successfully treated with this type of compression suture for severe atonic PPH. Our review adds 7 cases and found that the B-Lynch compression suture is easy to apply and should be considered in cases of severe atonic PPH when oxytocic agents fail, and before resorting to hysterectomy.

Adult↗
PubMed1989

Solid-phase synthesis of 16 potent (selective and nonselective) in vivo antagonists of oxytocin.

We describe the synthesis and some pharmacological properties of 16 new in vivo antagonists of oxytocin. These are based on modifications of three peptides: A, B, and C. A is our previously reported potent and selective antagonist of the vasopressor (V1 receptor) responses to arginine-vasopressin (AVP)/weak oxytocin antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid), 2-O-methyltyrosine]arginine-vasopressin (d(CH2)5[Tyr(Me)2]AVP. B reported here, the Ile3 analogue of A, is d(CH2)5[Tyr(Me)2]AVT (5 below) and C is our previously reported potent nonselective oxytocin antagonist/AVP V1 antagonist, [1-(beta-mercapto-beta,beta-pentamethylenepropionic acid),2-O- methyltyrosine,8-ornithine]vasotocin (d(CH2)5[Tyr(Me)2]OVT). The following substitutions and deletions, alone or in combination, were employed in A, B, and C: 1-deaminopenicillamine (dP); D-Tyr(Alk)2 (where Alk = Me or Et), D-Phe2; Val4, Thr4; delta 3-Pro7; Lys8, Cit8; desGly9, desGly-NH2(9), Ala-NH2(9); Leu-NH2(9); Arg-NH2(9). The 16 new analogues are (1) d(CH2)5[D-Tyr(Me)2]AVP, (2) d(CH2)5[D-Tyr(Me)2, Val4,delta 3-Pro7]AVP, (3) d(CH2)5[D-Tyr-(Et)2, Val4,Lys8]VP, (4) d(CH2)5[D-Tyr(Et)2,Val4,Cit8]VP, (5) d(CH2)5[Tyr(Me)2]AVT, (6) d(CH2)5[Tyr(Me)2,Lys8]VT, (7) dP[Tyr(Me)2]AVT, (8) dP[Tyr(Me)2,Val4]AVT, (9) d(CH2)5[D-Tyr(Me)2, Val4]AVT, (10) d(CH2)5[D-Phe2,Val4]AVT, (11) d(CH2)5[Tyr(Me)2,Thr4]OVT, (12) d(CH2)5[Tyr(Me)2,Thr4,Ala-NH2(9)]OVT, (13) d(CH2)5[Tyr(Me)2,Thr4,Leu-NH2(9)]OVT, (14) d(CH2)5[Tyr(Me)2,Thr4,Arg-NH2(9)]OVT, (15) desGly-NH2(9),d(CH2)5[Tyr(Me)2,Thr4]OVT, (16) desGly9,d(CH2)5[Tyr(Me)2,Thr4]OVT. 1-4 are analogues of A, 5-10 are analogues of B, and 11-16 are analogues of C. Their protected precursors were synthesized either entirely by the solid-phase method or by a combination of solid-phase and solution methods (1 + 8 or 8 + 1 couplings). All analogues were tested in rats for agonistic and antagonistic activities in oxytocic (in vitro, without and with Mg2+, and in vivo) assays as well as by antidiuretic and vasopressor assays. All analogues exhibit potent oxytocic antagonism in vitro and in vivo. With an in vitro pA2 (in the absence of Mg2+) = 9.12 +/- 0.09, dP[Tyr(Me)2]AVT is (7) one of the most potent in vitro oxytocin antagonists reported to date. Fifteen of these analogues (all but 6) appear as potent or more potent in vivo oxytocin antagonists than C (pA2 = 7.37 +/- 0.17). Analogues 1-9 and 14 are potent AVP V1 antagonists. Their anti-V1 pA2 values range from 7.92 to 8.45. They are thus nonselective oxytocin antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1978

Design of potent antagonists of the vasopressor response to arginine-vasopressin.

As part of a program in which we are attempting to design and synthesize antagonists of the vasopressor response to arginine-vasopressin (AVP), [1-deaminopenicillamine]arginine-vasopressin (dPAVP), [2-O-methyl)tyrosine]-arginine-vasopressin [Tyr(Me)AVP], and [1-deaminopenicillamine,2-(O-methyl)tyrosine]arginine-vasopressin [dPTyr(Me)AVP] were synthesized by the solid-phase method and assayed for vasopressor, antidiuretic, and oxytocic activities. Tyr(Me)AVP has a vasopressor potency of 9.7 +/- 0.5 units/mg and an antidiuretic potency of 386 +/- 36 units/mg. These values are 2.5 and 120%, respectively, of the corresponding potencies of AVP. The analogue is an antagonist of the in vitro response to oxytocin (pA2 = 7.44 +/- 0.12). dPAVP has an antivasopressor pA2 of 7.45 +/- 0.11. Its antidiuretic potency is 42.2 +/- 2 units/mg, 2.5% that of its parent, 1-[deamino]arginine-vasopressin (dAVP). It is an antagonist of the in vitro response to oxytocin (pA2 value = 6.93 +/- 0.10). dPTyr(Me)AVP has an antivasopressor pA2 of 7.96 +/- 0.05 and an antidiuretic potency of 3.5 +/- 0.5 units/mg. It is also an antagonist of the in vitro oxytocic response to oxytocin (pA2 value = 7.61 +/- 0.14). It is thus one of the most potent vasopressor antagonists reported to date.

Animals↗
PubMed1977

[1-deaminopenicillamine,4-valine]-8-D-arginine-vasopressin, a highly potent inhibitor of the vasopressor response to arginine-vasopressin.

In attempting to design an antagonist of the antidiuretic response to arginine-vasopressin (AVP) [1-deaminopenicillamine,4-valine,8-D-arginine]vasopressin (dPVDAVP) was synthesized by the solid-phase method and assayed for antidiuretic, vasopressor, and oxytocic activities. dPVDAVP has an antidiuretic potency of 123 +/- 22 units/mg, one-tenth that of its parent [deamino,4-valine,8-D-arginine]vasopressin (dVDAVP). Like dVDAVP its antidiuretic effect in conscious diabetes insipidus rats is greatly prolonged when compared to AVP. dPVDAVP causes a prolonged inhibition of vasopressor responses to AVP but not to norepinephrine or angiotensin II. It has an antivasopressor pA2 value of 7.82 +/- 0.05 when tested against AVP. Thus the penicillamine substitution at position 1 in dVDAVP increased its antivasopressor activity sixfold (dVDAVP has a pA2 value of 7.03 +/- 0.11). dPVDAVP is thus the most potent vasopressor antagonist yet reported. dPVDAVP was also found to be a potent inhibitor of the in vitro oxytocic response to oxytocin (pA2 value = 7.23 +/- 0.04). dPVDAVP with its potent and specific ability to antagonize the vasopressor effects of AVP should be a useful pharmacological tool with which to explore the possible participation of AVP's potent vasoconstrictor properties in cardiovascular regulation in physiological and pathological states.

Animals↗
PubMed1975

Synthesis and some pharmacological properties of (3-beta-(2-thienyl)-L-alanine)-8-lysine-vasopressin.

[3-beta-(2-Thienyl)-L-alanine]-8-lysine-vasopressin was synthesized by solution techniques. The partially protected heptapeptide Boc-Cys(Ec)-Tyr-Thi-Gln-Asn-Cys(Ec)-Pro (1) was synthesized in a stepwise manner using the active ester method or the dicyclohexylcarbodiimide (DCC) coupling technique mediated by 1-hydroxybenzotriazole (HBt). The protected nonapeptide amide Boc-Cys(Ec)-Tyr-Thi-Gin-Asn-Cys(Ec)-Pro-Lys(Coc)-Gly-NH2 (2) was prepared by coupling 1 with Lys(Coc)-Gly-NH2 using DCC-HBt. From 2, [3-thienylalanine]-8-lysine-vasopressin was obtained by removing the Boc-protecting groups with trifluoroacetic acid and ethylcarbamoyl (Ec) protecting groups in refluxing liquid NH3 followed by oxidative cyclization in H2O-MeOH using ICH2CH2I. Purification was effected by partition chromatography followed by gel filtration. The highly purified product possesses activities in the oxytocic, avian vasodepressor, rat pressor, and antidiuretic assays of 19.0 +/- 0.5, 87 +/- 4, 243 +/- 5, and 332 +/- 32 units/mg, respectively. Thus [3-thienylalanine]-8-lysine-vasopressin has higher oxytocic, avian vasodepressor, and antidiuretic potencies than does 8-lysine-vasopressin, whereas its pressor potency is about the same as or slightly lower than that of 8-lysine-vasopressin.

Alanine↗
PubMed1977

Biologically active macromolecular forms of oxytocin. [8-Lysine]oxytocin as a suitable ligand.

[8-Lysine]oxytocin was synthesized on a solid support and possessed an oxytocic activity of 100 +/- 6 units mumol on the isolated rat uterus. The epsilon-carbamoyl, epsilon-3-carboxypropionyl and epsilon-3-carboxybutryl derivatives were prepared and had uterotonic activities of 400, 55 and 50 units/mumol respectively. [8-Lysine]oxytocin was coupled unambiguously through the epsilon-amino group to the carboxyl groups of carboxymethylated dextrans or epsilon-3-carboxypropionly-gelatin. The macromolecular oxytocins were water-soluble and retained signigicant oxytocic activity. [8-Lysine]oxytocin should prove a useful ligand for affinity chromatography of oxytocin-binding proteins.

Animals↗
PubMed1992

Alterations in uterine contractility during the oviposition cycle in domestic hens.

1. The potencies of several neurohypophysial hormones were examined at different times during the oviposition cycle in an in vitro fowl oxytocic assay. 2. Uterine tissues were removed 2 h before (-2h-OP), immediately after (0h-OP) and 5 h after (+5h-OP) spontaneous oviposition. In addition, uterine tissue was removed immediately after oviposition was induced, by administering prostaglandin E2 2 h before an expected oviposition (Induced-OP). 3. The rank order of oxytocic potencies for the peptides was arginine vasotocin = vasopressin greater than oxytocin greater than mesotocin. The sensitivity of the uterus to the hormones was 0h-OP = Induced-OP greater than -2h-OP = +5-OP. 4. These results suggest that uterine sensitivity to neurohypophysial hormones changes during the oviposition cycle in domestic fowls.

Animals↗
PubMed2003

Comparison of midwifery-led and consultant-led maternity care for low risk deliveries in Nepal.

OBJECTIVE: To evaluate Nepal's first independent midwifery unit, the Patan Hospital Birthing Centre (BC), as a model for training and service provision for low risk deliveries. Specifically, to compare its efficacy with that of an adjacent Consultant-led Maternity Unit (CMU). METHODS: Unpaired comparison of delivery procedures and outcomes at the Patan Hospital, Lalitpur. The sample was 988 women (550 at BC, 438 at CMU). Women judged to be at low risk of complications were enrolled at delivery at each facility. Information was collected by standardized interviews and record review. Main outcome measures were incidence of complications of labour, technical procedures and access to postnatal care and family planning services. RESULTS: Artificial rupture of membranes was more likely to be performed at the BC (RR 1.26, 95% CI 1.10-1.44). Augmentation of labour with oxytocin was less likely to be performed (RR 0.26, 95% CI 0.20-0.33), as was episiotomy (RR 0.64, 95% CI 0.57-0.72). The incidence of oxytocic augmentation was high at the CMU (205/438: 46.9%). The incidence of moderately or thickly meconium-stained liquor was lower at the BC than at the CMU (RR 0.62, 95% CI 0.43-0.91), a finding that was associated with oxytocic augmentation of labour. No significant differences were found for duration or complications of labour, mode of delivery, birth weight, neonatal Apgar score or admission to the special care baby unit. Women delivering at the BC were more likely to attend both postnatal (RR 1.33, 95% CI 1.18-1.51) and family planning clinics (RR 1.85, 95% CI 1.44-2.38). CONCLUSIONS: After appropriate screening, intrapartum care for low risk deliveries is effectively provided by midwives. The Birthing Centre model should be considered throughout the developing world, particularly as a site for training of skilled attendants.

Birthing Centers↗
PubMed1980

Synthesis, pharmacological, conformational, and dynamic studies of the potent hormone antagonists [1-penicillamine, 4-threonine]-oxytocin and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin. Conformational and dynamic considerations in the design of antagonists.

The solid phase synthesis of [1-penicillamine, 4-threonine]-oxytocin and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin is reported. The two compounds have no in vitro milk ejecting activity and no in vivo or in vitro oxytocic activity, but both are potent antagonists in these three assay systems. In the in vitro oxytocic assay, [1-penicillamine, 4-threonine]- and [1-penicillamine, 2-phenylalanine, 4-threonine]-oxytocin have pA2 values of 7.55 +/- 0.04 and 7.67 +/- 0.02, respectively, and both inhibit the uterine contractile response to oxytocin in nonpregnant and pregnant rats. [1-Penicillamine, 2-phenylalanine, 4-threonine]-oxytocin has a weak antipressor activity and at high doses, consistently caused a weak and transient fall in blood pressure in the rat. Carbon-13 nuclear magnetic resonance chemical shift parameters and spin-lattice relaxation times (T1) indicate that these two new oxytocin antagonists have very similar conformation and dynamic properties to oxytocin inhibitors which have previously been examined. These results are discussed in terms of conformational and dynamic models of oxytocin antagonism at the uterus. It is suggested that conformational restrictions at the 2- and 4-positions of penicillamine-1 analogues of oxytocin are important to antagonist activity and potency.

Amino Acid Sequence↗
PubMed1997

Influence of L-naphthylalanine in position 3 of AVP and its analogues on their pharmacological properties.

We describe the synthesis and pharmacological properties of two series of analogues: one which consists of three peptides having L-1-naphthylalanine in position 3 and the second composed of analogues substituted in position 3 with L-2-naphthylalanine. All peptides were tested in bioassays for pressor and antidiuretic activities. We also checked the uterotonic activity in vitro. We observed that the activity of counterparts in both series is, in two cases, strikingly different. One of the new analogues, [(L-2-Nal)3,(D-Arg)8]VP is among the most potent antagonists of the vasopressor response to AVP. Moreover, it is the first potent V1 antagonist devoid of antiuterotonic activity. This analogue was designed without modification of position 1, which was previously thought to be essential for substantial pressor antagonism. Two other peptides, [Mpa1;(L-2-Nal)3;(D-Arg)8]VP and [Mpa1,(L-1-Nal)3,D-Arg)8]VP, are highly potent V2 agonists. The second analogue is highly selective. With the exception of [(L-2-Nal)3]AVP, which showed weak antioxytocic activity, (L-Nal)3 modification resulted in the almost complete removal of interaction of our analogues with oxytocic receptors in vitro. Our results suggest that position 3 in AVP and its analogues is important not only for binding and recognition as previously though, but also for pressor, antidiuretic and uterotonic activities. We also assume that the hindering effect caused by bulky naphthyl moiety has a significant impact on the bioactive conformations of molecules which contain Nal residue, and can thus influence their interaction with V1, V2 and oxytocic receptors.

Animals↗
PubMed1996

A prospective cohort study of oxytocin plus ergometrine compared with oxytocin alone for prevention of postpartum haemorrhage.

OBJECTIVE: To determine the safety and efficacy of intramuscular oxytocin plus ergometrine compared to intravenous oxytocin for prevention of postpartum haemorrhage, and the significance of administration at the end of the second stage of labour compared with that after the third stage. DESIGN: A prospective cohort study. SETTING: A university affiliated tertiary medical centre. PARTICIPANTS: Two thousand one hundred and eighty-nine women delivering singletons during 40 consecutive weeks. MAIN OUTCOME MEASURES: Postpartum haemorrhage (> 500 ml), prolonged third stage (> 30 min), retained placenta (> 60 min), elevated blood pressure (systolic > 150 mmHg, diastolic > 100 mmHg). RESULTS: The rate of postpartum haemorrhage was not significantly different for oxytocin-ergometrine compared with oxytocin, when administered at the end of the second stage of labour (odds ratio 1.10, 95% confidence interval (CI) 0.75-1.61) or after the third stage (odds ratio 0.95, 95% CI 0.68-1.34). The patients receiving oxytocics at the end of the second stage of labour had significantly lower rates of postpartum haemorrhage, for both oxytocin-ergometrine (odds ratio 0.69, 95% CI 0.49-0.98) and oxytocin (odds ratio 0.60, 95% CI 0.41-0.87), compared with those treated after the third stage. CONCLUSION: Administration of oxytocin alone is as effective as the use of oxytocin plus ergometrine in the prevention of postpartum haemorrhage, but associated with a significantly lower rate of unpleasant maternal side effects. Oxytocics administered after delivery of the fetal head compared with after the placental expulsion are associated with a significantly lower rate of postpartum haemorrhage.

Adult↗
PubMed1976

Comparison of intravenous oxytocin and prostaglandin E2 for accelerating labour.

In a prospective study of 52 consecutive women who required acceleration of labour intravenous prostaglandin E2 (PGE2) was used as the oxytocic agent. These mothers were matched for age, parity, height, gestational age, initial cervical dilatation, and station and position of the fetal head with 52 women whose labours were accelerated with oxytocin; both drugs were equally effective. Acceleration to delivery intervals, second-stage durations, the number of assisted deliveries, and Apgar scores were similar regardless of the oxytocic used. Although PGE2 compares well with oxytocin, it offers no further advantages and is more expensive and less well tried than oxytocin.

Adolescent↗
PubMed1975

Identification of high risk labours by labour nomogram.

The labour stencil representing the expected cervimetric progress of normal labour was used in 741 consecutive spontaneous labours to identify high-risk labours which needed oxytocic stimulation. Uterine contractions were stimulated if progress extended two hours past the nomogram, which resulted in shorter labours, fewer instrumental deliveries and caesarean sections, and babies with higher Apgar scores than in those dysfunctional labours which were not stimulated. According to the protocol used 36% of primigravid and 13% of multigravid labours needed acceleration. The remaining patients did not need any oxytocic interference during the first stage. This selection of patients is important to prevent a major obstetric advance being abused and discredited at a time when the profession and public are questioning the safety of active labour.

Anesthesia, Epidural↗
PubMed1975

Isolation and some observations of the properties of a bovine neurohypophysial milk-ejecting factor.

A substance possessing milk-ejecting activity has been isolated from an acetone powder preparation of bovine posterior pituitary glands by Sephadex G-25 chromatography of the neurophysin-neurohypophysial hormone complex. While the material possessed an oxytocic activity of 2.8 IU/mg as measured on the isolated rat uterus, the milk-ejecting activity was more than three fold greater, 9.6 IU/mg. The peptide had an antidiuretic activity of 0.133 IU/mg and a pressor activity of 0.083 IU/mg. Neither the uterine-stimulating action nor the pressor activity was destroyed by incubating the peptide with 0.01 M sodium thioglycollate at 65 degrees C for 5 min. The oxytocic activity was antagonized neither by 1.4 X 10(-6) M atropine nor 3.3 X 10(-7) M phenoxybenzamine.

Amino Acids↗
PubMed1985

A novel type of vasopressin receptor on anterior pituitary corticotrophs?

Suspensions of rat anterior pituitary cells were exposed to corticotropin-releasing factor (CRF) (5 nM) and various neurohormones (0.002-1000 nM). CRF-induced secretion of ACTH was doubled by 0.1 nM arginine vasopressin (AVP), 0.2 nM arginine vasotocin, 1 nM oxytocin, 10 nM angiotensin II, and 100 nM noradrenalin; vasoactive intestinal peptide had no effect at 0.2-200 nM. CRF potentiation by AVP was also observed at lower concentrations of CRF. Since AVP appeared to be the most potent modulator of CRF-induced ACTH secretion, potentiation was further tested with specific antidiuretic and oxytocic agonists. Potentiation was clearly related to pressor biological activity, less so to antidiuretic, and hardly at all to oxytocic activities. However, even at 200 nM, the antipressor antagonists dPTyr(Me)AVP and d(CH2)5Tyr(Me)AVP had no effect on potentiation by AVP. The lack of antagonism was partly due to the agonistic effects of the antagonists on the pituitary gland, an effect not observed within vascular tissue. The results thus suggest that anterior pituitary vasopressin receptors resemble, but are not identical to, V1 (pressor and hepatic), do not resemble the V2 (renal), and might be classified as V3 (pituitary) receptors.

Adrenocorticotropic Hormone↗