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PubMed1999

An investigation of position 3 in arginine vasopressin with aliphatic, aromatic, conformationally-restricted, polar and charged amino acids.

We report the solid-phase synthesis and some pharmacological properties of 23 new analogs of arginine vasopressin (AVP) which have the Phe3 residue replaced by a broad variety of amino acids. Peptides 1-9 have at position 3: (1) the mixed aromatic/aliphatic amino acid thienylalanine (Thi) and the aliphatic amino acids; (2) cyclohexylalanine (Cha); (3) norleucine (Nle); (4) Leu; (5) norvaline (Nva); (6) Val; (7) alpha-aminobutyric acid (Abu); (8) Ala; (9) Gly. Peptides 10-23 have at position 3: the aromatic amino acids, (10) homophenylalanine (Hphe): (11) Tyr; (12) Trp; (13) 2-naphthylalanine (2-Nal); the conformationally-restricted amino acids (14) Pro; (15) 2-aminotetraline-2-carboxylic acid (Atc); the polar amino acids (16) Ser; (17) Thr; (18) Gln; and the charged amino acids (19) Asp; (20) Glu; (21) Arg; (22) Lys; (23) Orn. All 23 new peptides were evaluated for agonistic and, where appropriate, antagonistic activities in in vivo antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays and in in vitro (no Mg2+) oxytocic assays. The corresponding potencies (units/mg) in these assays for AVP are: 323+/-16; 369+/-6 and 13.9+/-0.5. Peptides 1-9 exhibit the following potencies (units/mg) in these three assays: (1) 379+/-14; 360+/-9; 36.2+/-1.9; (2) 294+/-21: 73.4+/-2.7; 0.33+/-0.02; (3) 249+/-28; 84.6+/-4.3; 4.72+/-0.16; (4) 229+19; 21.4+/-0.6; 2.1+/-0.2; (5) 134+/-5; 31.2+/-0.9; 28.4+/-0.2; (6) 114+/-9; 45.3+2.3; 11.3+/-1.6; (7) 86.7+/-2.5; 4.29+/-0.13; 0.45+/-0.03; (8) 15.5+/-1.5; 0.16+/-0.01; approximately 0.02: (9) 3.76+/-0.03; < 0.02; in vitro oxytocic agonism was not detected. These data show that the aliphatic amino acids Cha, Nle, Leu, Nva and Val are well-tolerated at position 3 in AVP with retention of surprisingly high levels of antidiuretic activity. Peptides 2-9 exhibit significant gains in both antidiuretic/vasopressor (A/P) and antidiuretic/oxytocic (A/O) selectivities relative to AVP. [Thi3]AVP appears to be a more potent antidiuretic and oxytocic agonist than AVP and is equipotent with AVP as a vasopressor agonist. The antidiuretic potencies of peptides 10-23 exhibit drastic losses relative to AVP. They range from a low of 0.018+/-0.001 units/mg for the Lys3 analog (peptide 22) to a high of 24.6+/-4.6 units,mg for the Hphe3 analog (peptide 10). Their vasopressor potencies are also drastically reduced. These range from a low of < 0.002 units/mg for peptide 22 to a high of 8.99+0.44 units/mg for the Atc3 analog (peptide 15). Peptides 10-23 exhibit negligible or undetectable in vitro oxytocic agonism. The findings on peptides 10-23 show that position 3 in AVP is highly intolerant of changes with aromatic, conformationally-restricted, polar and charged amino acids. Furthermore, these findings are in striking contrast to our recent discovery that position 3 in the potent V2/V1a/OT antagonist d(CH2)5D-Tyr(Et)2VAVP tolerates a broad latitude of structural change at position 3 with many of the same amino acids, to give excellent retention of antagonistic potencies. The data on peptides 1-4 offer promising clues to the design of more potent and selective AVP V2 agonists.

Alanine↗
PubMedDate not supplied

An exploration of the effects of L- and D-tetrahydroisoquinoline-3-carboxylic acid substitutions at positions 2, 3 and 7 in cyclic and linear antagonists of vasopressin and oxytocin and at position 3 in arginine vasopressin.

We have investigated the effects of mono-substitutions with the conformationally restricted amino acid, 1,2,3,4 tetrahydroisoquinoline-3-carboxylic acid (Tic) at position 3 in arginine vasopressin (AVP), at positions 2, 3 and 7 in potent non-selective cyclic AVP V2/V1a antagonists, in potent and selective cyclic and linear AVP V1a antagonists, in a potent and selective oxytocin antagonist and in a new potent linear oxytocin antagonist Phaa-D-Tyr(Me)-Ile-Val-Asn-Orn-Pro-Orn-NH2 (10). We report here the solid-phase synthesis of peptide 10 together with the following Tic-substituted peptides: 1. [Tic3]AVP: 2. dICH2)5[D-TIc2]VAVP: 3, d(CH2)5[D-Tyr(Et)2Tic3]VAVP: 4, d(CH2)5[Tic2Ala-NH2(9)]AVP: 5. d(CH2)5[Tyr]Me)2.Tic3,Ala-NH2(9)]AVP: 6. d(CH2)5 [Tyr(Me)2,Tic7]AVP: 7, Phaa-D-Tyr(Me)-Phe-Gln-Asn-Lys-Tic-Arg-NH2: 8, desGly-NH2,d[CH2]5[Tic2,Thr4]OVT: 9. desGly-NH2d(CH2)5[Tyr(Me)2Thr4, Tic7[OVT; 11, Phaa-D-Tic-Ile-Val-Asn-Orn-Pro-Orn-NH2, using previously described methods. The protected precursors were synthesized by the solid-phase method, cleaved, purified and deblocked with sodium in liquid ammonia to give the free peptides 1-11 which were purified by methods previously described. Peptides 1-11 were examined for agonistic and antagonistic potency in oxytocic (in vitro, without Mg2+) and AVP antidiuretic (V2-receptor) and vasopressor (V1a-receptor) assays. Tic3 substitution in AVP led to drastic losses of V2, V1a and oxytocic agonistic activities in peptide 1, L- and D-Tic2 substitutions led to drastic losses of anti-V2/anti-V1a and anti-oxytocic potencies in peptides 2, 4, 8 and 11 (peptide 2 retained substantial anti-oxytocic potency; pA2 = 7.25 +/- 0.025). Whereas Tic3 substitution in the selective V1a antagonist d(CH2)5[Tyr(Me)2,Ala-NH2(9)]AVP(C) led to a drastic reduction in anti-V1a potency (from anti-V1a pA2 8.75 to 6.37 for peptide 5, remarkably, Tic3 substitution in the V2/V1a antagonist d(CH2)5(D-Tyr(Et)2]VAVP(B) led to full retention of anti-V2 potency and a 95% reduction in anti-V1a potency. With an anti-V2 pA2 = 7.69 +/- 0.05 and anti-V1a pA2 = 6.95 +/- 0.03. d(CH2)5[D-Tyr(Et)2, Tic3]VAVP exhibits a 13-fold gain in anti-V2/anti-V1a selectivity compared to (B). Tic7 substitutions are very well tolerated in peptides 6, 7 and 9 with excellent retention of the characteristic potencies of the parent peptides. The findings on the effects of Tic3 substitutions reported here may provide promising leads to the design of more selective and possibly orally active V2 antagonists for use as pharmacological tools and as therapeutic clinical agents for the treatment of the syndrome of the inappropriate secretion of antidiuretic hormone (SIADH).

Amino Acid Sequence↗
PubMed1975

The action of amantadine on the rat uterus: its interaction with oxytocin and the effects of several ionic modifications of the medium.

The influence of amantadine on the contractile responses of the rat uterus to oxytocin in the presence of several ionic modifications of the external medium was studied both in situ and in vivo. Oxytocic effects of amantadine were observed in vivo (1 and 5 mg/kg), and in vitro (9.3 times 10-7 M to 2.8 times 10-6 M); possible competitive partial potentiation of the contractile effect of oxytocin was also observed. Amantadine, 9.35 times 10-6, 1.3 times 10-5 and 1.8 times 10-5 M, significantly reduced oxytocic activity. Calcium ions antagonized the oxytocic and antioxytocic effects of amantadine. Excess K+ and the presence of Mg2+ ions (1.8 mM/l and 1.08 mM/l respectively) reversed the antioxytocic effect of amantadine. Propranolol also reversed the antioxytocic effect of amantadine. It is postulated that the oxytocic effect of amantadine may be related to antagonism of calcium; antioxytocic activity may be explained by stabilization of the resting cell membrane, inhibiting ionic flow, and also by its catecholamine-liberating activity.

Amantadine↗
PubMed1979

Oxytocin treatment in twin pregnancy labour.

A continuous series of 483 twin deliveries was studied. In 30% of cases, intravenous oxytocic treatment was given for labour induction or to accelerate the first stage. In 13% of twin deliveries this treatment was applied only after the first twin's birth. In the group perfused during cervix dilatation, foetal mortality rate was significantly lower than in the nontreated group. In order to understand the reason(s) for this difference, the following factors were studied in relation to oxytocic treatment: parity, obstetrical complications, second stage duration, abnormal presentations, obstetrical maneuvers, and birth weight. Contrasting with mortality data, Apgar scores of first twins were significantly lower in the oxytocin-treated group. In summary, several variables indirectly linked to oxytocic treatment could have favoured or hampered foetal outcome in the treated group. Therefore, it is difficult to ascertain if the use of oxytocics is helpful in twin pregnancy management. In the majority of cases, however, it may at least be considered harmless.

Apgar Score↗
PubMed1983

Pharmacological, conformational and dynamic properties of cycloleucine-2 analogues of oxytocin and [1-penicillamine]oxytocin.

The solid phase syntheses of [2-cycloleucine] oxytocin and [1-penicillamine, 2-cycloleucine] oxytocin are reported. [1-Penicillamine, 2-cycloleucine] oxytocin is an oxytocin antagonist exhibiting no in vitro oxytocic activity. In the in vitro oxytocic assay, [1-penicillamine, 2-cycloleucine] oxytocin has a pA2 value of 6.70 +/- 0.08. [2-Cycloleucine]-oxytocin is a full oxytocin agonist exhibiting 4.9 +/- 0.5 U/mg of oxytocic activity. Neither compound possesses any measurable agonist or antagonist activity in the rat pressor assay. Carbon-13 nuclear magnetic resonance chemical shift parameters and spin-lattice relaxation times (T1) of the antagonist, [1-penicillamine, 2-cycloleucine] oxytocin, indicate that the antagonist exhibits similar conformational and dynamic properties as other oxytocin inhibitors previously studied. The carbon-13 nuclear magnetic resonance shift parameters and spin-lattice relaxation times (T1) of the oxytocin agonist, [2-cycloleucine] oxytocin, indicate that the agonist exhibits similar conformational and dynamic properties as oxytocin. These results are discussed in terms of the different receptor requirements for agonist and antagonist activities. It appears that there are different structural and conformational requirements at the 2-position for oxytocic agonist and antagonist activities.

Animals↗
PubMed2003

Effect of 2,5-dimethylpyrazine on uterine contraction in late stage of pregnant female rats.

Effect of 2,5-dimethylpyrazine (2,5-DMP) on oxytocic agent-induced late pregnant uterine contraction in female rats was studied. Oxytocic agents induced-hypercontraction in the late phase of pregnant uterine movements were inhibited by administration of 2,5-DMP. The inhibition of uterine contraction was obtained more strengthening by presence of a low dose of ritodrine hydrochloride than 2,5-DMP alone. These results suggests that 2,5-DMP has an inhibitory action on uterine hypercontraction induced by oxytocic agent through the beta2-adrenoceptor in the pregnant uterus and supports the applicability of relaxing drugs for oxytocic agent-induced accidents.

Animals↗
PubMed1975

Studies on pharmacological and biochemical properties of deamino-dicarba-[GLY-7]-oxytocin (Y-5350).

Pharmacological and biochemical properties were investigated on deamino-dicarba-[Gly-7]-oxytocin (Y-5350). This is a newly developed compound, in which the disulfide bond and [Pro-7] of deamino-oxytocin are substituted by an ethylene linkage and glycine respectively. Bioassayed Y-5350 exhibited 202.6 u/mg of oxytocic activity, 4.6 u/mg of avian depressor activity, 441.2 u/mg of rat milk-ejecting activity and 0.02 u/mg of rat antidiuretic activity, however, adepressor activity was also evident in rats. In particular, the diuration of antidiuretic activity was short. Moreover, the oxytocic activity in pregnant rats and rabbits was weak in comparison with oxytocin. Cumulative dose-response studies were carried out on the isolated rat uterus using van Dyke-Hasting solution. The intrinsic activity was the same level as that of oxytocin, and the pD2 value was 8.62. Oxytocic activity was much enhanced by the existence of 0.5 or 2mM magnesium ion in vitro. However, the agreement between in vivo and in vitro oxytocic activity was not complete when assay was carried out in the prescence of 2 mM magnesium ion. Oxytocin was inactivated by the serum of pregnant women. In the experiment using rats, oxytocin was also destroyed by the extracts of uterus, kidney and liver. In contrast, Y-5350 was not destroyed by any of the enzyme solutions mentioned above.

Animals↗
PubMed1977

Design of neurohypophyseal peptides that exhibit selective agonistic and antagonistic properties.

Within the spectrum of the characteristic pharmacological activities (oxytocic (O), milk-ejecting (ME), antidiuretic (A), pressor (P) associated with the known natural and synthetic analogs of oxytocin and vasopressin it is possible to discern patterns of selectivity of these types: 1) interpeptide-like (a) O/A, (b) O/P; 2) intraoxytocin-like (a) O/ME; (b) ME/O; 3) intravasopressinlike (a) A/P, (b) P/A. Consideration of structural modifications of oxytocin or vasopressin, which individually or in combination give rise to peptides possessing enhanced selectivity of a given type, can in some cases provide a rational basis for the design of peptides with even greater selectivity. [1-Deamino-4-valine-8-D-arginine]vasopressin, the most highly specific antidiuretic peptide known to date, was designed in this fashion. By contrast, intraoxytocin-like selectivity, is manifested to only a minor degree in all peptides studied to date. Enhanced interpeptide-like selectivity of the type 1a (O/A; O/P) is readily attainable by specific single substitutions at positions 4 or 7 in oxtocin. Substitution of threonine in the 4 position of the oxytocic antagonist [1-deaminopenicillamine]oxytocin brought about a threefold enhancement in oxytocic inhibitory activity. Thus [1-deaminopenicillamine-4-threonine]oxytocin (dPTOT) is the most potent antagonist of the in vitro oxytocic response to oxytocin known to date. Thus analysis of the pharmacological data from over 300 analogs of oxytocin and vasopressin allows the delineation of those structural modifications that can optimize selectivities. The potential and limitations of this approach for the design of peptides possessing desired agonistic or antagonistic selectivity for potential clinical use and for studies on oxytocin and vasopressin receptors is discussed.

Animals↗
PubMed1980

Effect of prostaglandin E2 and its metabolites on lower segment myometrium in vitro.

The spontaneous activity of pregnant human lower segment myometrium has been studied in vitro using strips removed at cesarean section. Contractions were measured isometrically. During the 4-h experiments there was in increase in amplitude and decrease in frequency of contractions in control preparations. Prostaglandin F2 alpha (PGF2 alpha), its metabolites and prostaglandin E2 (PGE2) have been shown to be oxytocic in vivo, but there are no published data on the oxytocic effect of PGE2 metabolites. The effect on contractile activity of adding either PGE2 or one of its initial metabolites (15-keto-PGE2, 13,14-dihydro-15-keto-PGE2 or 13,14-dihydro-PGE2) or prostaglandin A2 (PGA2) to the tissue baths has been tested. No significant or consistent change in contractility was observed after the addition of any of the compounds tested. This probably indicates an inherent difference in the response of different portions of the uterine muscle, and cannot be taken to exclude activity in the intact uterus, particularly since PGE2 is a well-known oxytocic agent in vivo. The difficulty of working with this type of preparation is stressed, since there is wide variation in contractility as well as a constantly changing pattern.

Dinoprostone↗
PubMed1996

The prevention of post partum haemorrhage: optimising routine management of the third stage of labour.

This paper concerns itself with the use of oxytocic therapy as part of the routine management of the third stage of labour. It attempts to answer three different questions: (1) do oxytocics reduce the risk of post partum haemorrhage (PPH) when used during the routine management of the third stage of labour? (2) does the clinical package of active management reduce the risk of PPH (3) which is the best oxytocic to use during routine active management of the third stage? It attempts to answer these questions by presenting the evidence from formal meta-analytical reviews of the randomised controlled trials of the pertinent intervention and by presenting the results of the two trials that were undertaken as a result of the hypotheses which were generated from the formal reviews.

Australia↗
PubMed1999

Double-blind comparison of carbetocin versus oxytocin in prevention of uterine atony after cesarean section.

OBJECTIVE: The goal of this study was to compare carbetocin, a long-acting oxytocin analog, with oxytocin in the prevention of uterine atony after cesarean section. STUDY DESIGN: We enrolled 694 patients undergoing elective cesarean section in a Canadian multicenter, double-blind, randomized clinical trial. We compared the effect of a single 100 microg dose of carbetocin with that of a standard 8-hour infusion of oxytocin. The primary outcome was the proportion of patients requiring additional oxytocic intervention for uterine atony. A variable sample size, sequential design was used. RESULTS: The overall oxytocic intervention rate was 7.4%. The odds of treatment failure requiring oxytocic intervention was 2.03 (95% confidence interval 1.1 to 2.8) times higher in the oxytocin group compared with the carbetocin group, respectively, 32 of 318 (10.1%) versus 15 of 317 (4.7%), P <.05. CONCLUSIONS: Carbetocin, a new drug for the prevention of uterine atony, appears to be more effective than a continuous infusion of oxytocin and has a similar safety profile.

Adult↗
PubMed2000

Phytochemical and pharmacological studies on Monechma ciliatum.

The leaves of Monechma ciliatum were found to contain alkaloids, glycosides, proteins, tannins and saponins. The hot methanol extract (HME) of the leaves, previously found to have potent oxytocic effect in various species was fractionated in various solvents and the fractions analysed chemically and also assayed on the rat uterus in an attempt to identify the chemical constituents present and in particular the oxytocic principle. Positive reaction with ninhydrin spray suggests that the oxytocic constituent is an amino acidic derivative.

Animals↗
PubMed1985

[Blood loss and nausea during legal abortion].

The efficiency of oxytocic drugs in therapeutic abortion was studied in 113 women who were randomly assigned to either a control group (n = 44) receiving no oxytocic drugs, a group (n = 36) receiving 0.2 mg ergometrine by slow intravenous injection, or a group (n = 33) given 5 units oxytocin in a intravenous infusion throughout the procedure. The three groups were comparable with regard to the age of patients, the age of pregnancies and parity. The surgical procedure was the same in all three groups and carried out by the same surgeon. General anaesthesia was obtained with an infusion of 500 mg methohexitone and 500 micrograms fentanyl in 500 ml isotonic dextrose solution at a rate of 3 ml X min-1. The anaesthetic requirements were 2.94 +/- 0.80 micrograms X kg-1 fentanyl and 2.94 +/- 0,80 mg X kg-1 methohexitone. The criteria studied were the blood loss as measured by the volume aspired, the presence or absence of nausea and vomiting after the procedure, the age of pregnancy and the total amount of anaesthetic drugs given. No correlation was found between the amount of anaesthetic drugs given and the frequency of nausea and vomiting, and between the amount of blood lost (r = 0.287; ddl = 111; alpha = 17.322). The study did not, therefore, confirm the reputation of oxytocic drugs in reducing the bleeding. It seemed that, in therapeutic abortion, spontaneous uterine contraction was sufficient to control the bleeding. But a significant correlation was found between the amount of blood lost and the age of the pregnancy (r = 0.399; ddl = 111; alpha less than 1%).

Abortion, Legal↗
PubMed1995

Prevention of postpartum haemorrhage.

Primary prevention of PPH is advocated at all levels of obstetric care. This implies active management of the third stage of labour also at the first and most peripheral levels of obstetric care. Active management includes the use of an oxytocic, early cord clamping and active delivery of the placenta. The oxytocic drug of choice at this moment is oxytocin 5 IU given intramuscularly. Women with high-risk factors for PPH (polyhydramnios, previous complications in third stage, APH or multiple pregnancies) should be delivered in hospital. Timely antepartum referral is necessary. In these women, prevention and anticipatory management includes the availability of intravenous treatment, as well as active management with an oxytocic. Evidence for the effectiveness of active management of the third stage of labour in women at low risk of PPH is not yet available. Whether women delivering at home with easy accessibility to hospital, or those at low risk delivering in hospital, should be actively managed remains controversial, and such an approach is not supported by us until a clinical trial in this particular group of women has shown the effectiveness of the active management.

Female↗
PubMed2001

A multicentre randomized controlled trial of oral misoprostol and i.m. syntometrine in the management of the third stage of labour.

Postpartum haemorrhage accounts for nearly 28% of maternal mortality in developing countries. Syntometrine is an effective and commonly used oxytocic in preventing postpartum haemorrhage, but it requires a controlled storage environment and i.m. administration. Misoprostol is an orally active uterotonic agent. A total of 2058 patients having a singleton pregnancy, low risk for postpartum haemorrhage and vaginal delivery were randomized to receive either 1 ml syntometrine or 600 microgram misoprostol for the management of the third stage of labour. There were no significant differences between the two groups in the mean blood loss, the incidence of postpartum haemorrhage and the fall in haemoglobin concentration. The need for additional oxytocic injection was significantly higher in the misoprostol group [relative risk (RR) 1.62, 95% confidence interval (CI) 1.34-1.96], but that of manual removal of placenta was reduced (RR 0.29, 95% CI 0.09-0.87). Shivering and transient pyrexia were more common in the misoprostol group. Oral misoprostol might be used in the management of the third stage, especially in situations where the use of syntometrine is contraindicated and facilities for storage and parenteral administration of oxytocics are limited.

Administration, Oral↗
PubMed1998

A randomised placebo controlled trial of oral misoprostol in the third stage of labour.

OBJECTIVE: To compare oral misoprostol 400 microg with placebo in the routine management of the third stage of labour. DESIGN: A double-blind placebo controlled trial. Setting The labour ward of an academic hospital in Johannesburg, South Africa with 7000 deliveries per annum. PARTICIPANTS: Low-risk women expected to deliver vaginally. METHODS: Women in labour were randomly allocated to receive either misoprostol 400 microg orally or placebo after the birth. Conventional oxytocics were given immediately if blood loss was thought to be more than usual. Postpartum blood loss in the first hour was measured by collection in a special flat plastic bedpan. Side effects were recorded. MAIN OUTCOME MEASURES: Measured blood loss > or = 1000 ml within the first hour after birth. Use of additional oxytocics. RESULTS: The groups were well matched. Measured blood loss > or = 1000 ml occurred in 15/250 (6%) after misoprostol and 23/250 (9%) after placebo (relative risk 0.65; 95% confidence interval 0.35-1.22). The difference may have been reduced by the greater use of conventional oxytocics in the placebo group, which was statistically significant for intravenous oxytocin infusion (2.8% vs 8.4%, relative risk 0.33, 95% confidence interval 0.14-0.77). Shivering was more common in the misoprostol group (19% vs 5%, relative risk 3.69; 95% confidence interval 2.05-6.64). CONCLUSIONS: Shivering has been shown in this study to be a specific side effect of misoprostol administered orally in the puerperium. No serious side effects were noted. Misoprostol shows promise as a method of preventing postpartum haemorrhage. Because of the potential benefits for childbearing women, particularly those in developing countries, further research to determine its effects with greater certainty should be expedited.

Administration, Oral↗
PubMed1966

The formation of peptides with uterine activity from ovine, human and bovine growth hormones and from bovine and ovine lactogenic hormones.

1. Both starch gel and disk electrophoresis demonstrated stepwise degradation of acidic preparations of human and bovine growth hormones and of ovine and bovine lactogenic hormones in solution at pH 9.0-10.0. This developed in 1-3 weeks in refrigerated solutions and in 5-16 hr on incubation at 37 degrees C. Increasing acidity accompanied degradation.2. Oxytocic activity, initially absent, developed in these same solutions of hormones during stepwise degradation and appeared to be associated with a single phase of degradation.3. Storage in solution at pH 9.5 generated oxytocic activity in an initially basic preparation of ovine growth hormone. The uterine action was attributable to a small amount of acidic material with electrophoretic properties very similar to those of the oxytocic fractions formed during stepwise degradation of the acidic preparations of growth and lactogenic hormones.4. Prolonged storage of all these hormones at pH 9.0-10.0 resulted in the formation of acidic substances of low molecular weight which ran close to the buffer front and were dialysable (14 hr) through membranes which permitted the passage of nonapeptides in 6-8 hr.5. alpha-Chymotrypsin very rapidly generated uterine stimulant action in freshly prepared solutions of human growth and bovine lactogenic hormones at pH 9.5.6. All the hormone samples used proved capable of hydrolysing purified ox haemoglobin, urea-denatured, at pH 9.5.

Animals↗
PubMed1988

The Bristol third stage trial: active versus physiological management of third stage of labour.

OBJECTIVE: To compare the effects on fetal and maternal morbidity of routine active management of third stage of labour and expectant (physiological) management, in particular to determine whether active management reduced incidence of postpartum haemorrhage. DESIGN: Randomised trial of active versus physiological management. Women entered trial on admission to labour ward with allocation revealed just before vaginal delivery. Five months into trial high rate of postpartum haemorrhage in physiological group (16.5% v 3.8%) prompted modification of protocol to exclude more women and allow those allocated to physiological group who needed some active management to be switched to fully active management. Sample size of 3900 was planned, but even after protocol modification a planned interim analysis after first 1500 deliveries showed continuing high postpartum haemorrhage rate in physiological group and study was stopped. SETTING: Maternity hospital. PARTICIPANTS: Of 4709 women delivered from 1 January 1986 to 31 January 1987, 1695 were admitted to trial and allocated randomly to physiological (849) or active (846) management. Reasons for exclusion were: refusal, antepartum haemorrhage, cardiac disease, breech presentation, multiple pregnancy, intrauterine death, and, after May 1986, ritodrine given two hours before delivery, anticoagulant treatment, and any condition needing a particular management of third stage. INTERVENTIONS: All but six women allocated to active management actually received it, having prophylactic oxytocic, cord clamping before placental delivery, and cord traction; whereas just under half those allocated to physiological management achieved it. A fifth of physiological group received prophylactic oxytocic, two fifths underwent cord traction and just over half clamping of the cord before placental delivery. ENDPOINT: Reduction in incidence of postpartum haemorrhage from 7.5% under physiological management to 5.0% under active management. MEASUREMENTS AND MAIN RESULTS: Incidence of postpartum haemorrhage was 5.9% in active management group and 17.9% in physiological group (odds ratio 3.13; 95% confidence interval 2.3 to 4.2), a contrast reflected in other indices of blood loss. In physiological group third stage was longer (median 15 min v 5 min) and more women needed therapeutic oxytocics (29.7% v 6.4%). Apgar scores at one and five minutes and incidence of neonatal respiratory problems were not significantly different between groups. Babies in physiological group weighed mean of 85 g more than those in active group. When women allocated to and receiving active management (840) were compared with those who actually received physiological management (403) active management still produced lower rate of postpartum haemorrhage (odds ratio 2.4;95% CI1.6 to 3.7). CONCLUSIONS: Policy of active management practised in this trial reduces incidence of postpartum haemorrhage, shortens third stage, and results in reduced neonatal packed cell volume.

Breast Feeding↗