**6. Tocolytic action of oxytocin antagonists**

Since the most recognized signs of preterm labor are uterine contractions, the main method for postponement of preterm labor is currently the pharmacological inhibition of uterine contractions. The inhibition of myometrial contractions is called tocolysis, and a drug administered to that end is referred to as a tocolytic agent. The aim of tocolytic agents is to maintain pregnancy for 24-48 hours, to allow the beneficial effects of corticosteroids administration to take place (reduced risk of perinatal death, neonatal respiratory distress syndrome, etc), usually after 18 hours, and also to permit safe transfer of the mother to a center with neonatal intensive care facilities. There are several tocolytics agents, such as ritodrine (a beta-receptor agonist), calcium-channel blockers, nitric oxide donors (as glyceryl trinitrate), and COX-2 inhibitors such as indomethacin (Simhan and Caritis, 2007).

Selective human oxytocin receptor antagonists, such as atosiban and barusiban have also been synthesized as tocolytic agents for the management of preterm labor. Atosiban, an oxytocin analog (1-Deamino-2-D-Tyr-(O-ethyl)-4-Thr-8-ornoxytocin), is based on modification of amino acids in the structure of oxytocin at positions 1, 2, 4 and 8, thus being a competitive inhibitor of the OTR that blocks OT binding. It is also a mixed vasopressin V1a/OT antagonist that results in the incidence of related unwanted effects. Vasopressin V1a receptors (V1aR) expression are also present in myometrium.

The onset of uterine relaxation after atosiban administration is fast. Atosiban is given intravenously as shown in Table 1 and the total dose should preferably not exceed 330 mg.

oxytocin infusion. However, oxytocin is normally secreted in pulses, this pulsatile secretion likely being a mechanism that prevents desensitization from occurring. This might explain why in women in labor, induction of labor requires significantly lower doses of oxytocin when oxytocin is administered in pulses, compared with continuous oxytocin infusion

The widespread distribution of OTR has led to the development of OTR agonist molecules that could be used as pharmacological tools (agents used experimentally to study the functions of oxytocin and its receptor) or as potential drugs for the management of obstetric disorders and neuropsychiatric diseases, including anxiety-related disorders, autism and schizophrenia. OTR agonists may be peptide (such as [Thr4]OT, [HO1][Thr4]OT, [Thr4,Gly7]OT and [HO1][Thr4,Gly7]OT) or non-peptide molecules (such as WAY-267464 and other compounds) (Borthwick, 2006; Manning et al., 2008). WAY-267464 exerts

Clinically, synthetic oxytocin is used for labor induction and augmentation and the treatment of postpartum hemorrhage. Carbetocin, a synthetic oxytocin analog, is also indicated for prevention of uterine atony after delivery by cesarean section in spinal or epidural anesthesia. It also has the advantage of longer half life than oxytocin (4-10 times) and it is administered in a single dose, intramuscularly or intravenously, compared to

Since the most recognized signs of preterm labor are uterine contractions, the main method for postponement of preterm labor is currently the pharmacological inhibition of uterine contractions. The inhibition of myometrial contractions is called tocolysis, and a drug administered to that end is referred to as a tocolytic agent. The aim of tocolytic agents is to maintain pregnancy for 24-48 hours, to allow the beneficial effects of corticosteroids administration to take place (reduced risk of perinatal death, neonatal respiratory distress syndrome, etc), usually after 18 hours, and also to permit safe transfer of the mother to a center with neonatal intensive care facilities. There are several tocolytics agents, such as ritodrine (a beta-receptor agonist), calcium-channel blockers, nitric oxide donors (as glyceryl trinitrate), and COX-2 inhibitors such as indomethacin

Selective human oxytocin receptor antagonists, such as atosiban and barusiban have also been synthesized as tocolytic agents for the management of preterm labor. Atosiban, an oxytocin analog (1-Deamino-2-D-Tyr-(O-ethyl)-4-Thr-8-ornoxytocin), is based on modification of amino acids in the structure of oxytocin at positions 1, 2, 4 and 8, thus being a competitive inhibitor of the OTR that blocks OT binding. It is also a mixed vasopressin V1a/OT antagonist that results in the incidence of related unwanted effects. Vasopressin

The onset of uterine relaxation after atosiban administration is fast. Atosiban is given intravenously as shown in Table 1 and the total dose should preferably not exceed 330 mg.

V1a receptors (V1aR) expression are also present in myometrium.

**5. Experimental or clinical use of oxytocin agonists** 

oxytocin continuous infusion (Rath, 2009).

(Simhan and Caritis, 2007).

**6. Tocolytic action of oxytocin antagonists** 

oxytocinergic actions, such as anxiolytic effects, in mice (Ring et al., 2010).

(Dawood, 1995).


**Side effects:** Nausea, vomiting, hyperglycemia, headaches, dizziness, tachycardia, hot flushes, hypotension, injection site reactions, pruritis, rush, pyrexia, insomnia

Table 1. Dose, method of administration, and side effects of atosiban.

Clinically, atosiban, which requires continuous intravenous administration, is as effective as β2-adrenergic agonists, but without producing their adverse effects. Subcutaneously administered after a period of preterm labor, atosiban given as maintenance therapy was not shown to be associated with a reduction of the incidence of preterm birth nor with any improvement of neonatal outcome. In a study in which a total of 513 women were randomized to receive either atosiban or placebo administered with a subcutaneous infusion pump in order to prevent recurrence of preterm birth, atosiban compared to placebo did not reduce the incidence of preterm birth before 37 weeks (RR 0.89; 95% CI 0.71 to 1.12), 32 weeks (RR 0.85; 95% CI 0.47 to 1.55), or 28 weeks (RR 0.75; 95% CI 0.28 to 2.01). Outcomes were also similar for both groups with respect to birth weight, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, and intraventricular hemorrhage (Papatsonis et al., 2009).

In Europe and other countries atosiban is the only oxytocin/vasopressin antagonist used today for preterm delivery. However, this does not apply to the USA where the Food and Drug Administration has not granted approval of the drug as a tocolytic because of sufficient lack of evidence as to its efficacy and improvement of neonatal outcomes.

Clinical studies have determined that atosiban is safer than beta-receptor agonists. A large study (Worldwide Atosiban versus Beta-agonists Study Group, 2001) demonstrated that atosiban was comparable in clinical effectiveness to conventional beta-agonist therapy (ritodrine, salbutamol or terbutaline), but was better tolerated and was associated with fewer maternal cardiovascular side effects (ClinicalTrials.gov, 2001). Atosiban is also safer than calcium channel blockers. Meanwhile, clinical studies have shown nifedipine to be equally effective as atosiban, although the maternal side effects were significantly more common among women allocated to nifedipine rather than atosiban (Al-Omari et al., 2006). Cyclooxygenase inhibitors act as tocolytics by inhibiting prostaglandins production but also present significant side effects (King et al., 2005). Conversely, evidence is as yet not strong enough for recommendation of the use of nitric oxide donors as inhibitors of preterm delivery (Duckitt and Thornton, 2002). Nevertheless, atosiban has not been proven to be superior in terms of neonatal outcome, concerns having been expressed in other studies (Papatsonis et al., 2005).

Atosiban's limited bioavailability—which necessitates parenteral administration and hospitalization—together with its low affinity for OTR and the binding to V1a receptors that causes side effects, have led to endeavors for the identification of new peptide and nonpeptide oxytocin antagonists for the management of preterm labor. While many such substances have been discovered, these drugs are still being evaluated at the experimental level and clinical studies in most cases have ceased or have been completed unsuccessfully (Manning et al., 2008). These compounds are either peptide or non-peptide molecules.

Oxytocin and Myometrial Contractility in Labor 249

atosiban's effect ceased within 1.5–3 hours. For long-term treatment, continuous high-dose infusions of barusiban (150 μg/kg/h) or the beta-2 agonist fenoterol (3 μg/kg/h) were administered. Barusiban reduced uterine activity in response to daily OT challenge and

Although barusiban suppresses oxytocin-induced preterm labor in non-human primates, in a recent study it was no more effective than placebo in terminating preterm labor in pregnant women at between 34+0-35+6 weeks of gestation. This study was conducted at 21 participating centers with subjects from six different European countries. Participants were randomly assigned to receive a single intravenous bolus dose of 0.3, 1, 3, or 10 mg barusiban or placebo (acetate buffer). The percentage of women who did not deliver within 48 hours was not significantly different between the placebo group and any of the barusiban groups (*P* = 0.21-0.84). No significant decreases in the number of uterine contractions compared with placebo were registered. All doses of barusiban were well tolerated and there were no adverse events that would lead to withdrawal from the study. Finally, there was no statistically significant difference in maternal or neonatal adverse effect between the placebo

The lack of peptide antagonists characterized by oral bioavailability have led researchers to seek an effective non-peptide oxytocin antagonist. The non-peptide oxytocin antagonist 2' methyl-1',3'-oxazol-4'-yl morpholine amide derivative 74 (GSK221149A or retosiban) when administered orally or intravenously produced a dose-dependent decrease in oxytocininduced uterine contractions in rats, after either single or multiple dosing for 4 days. In addition, spontaneous uterine contractions in late-term pregnant rats (at 19–21 days gestation) were significantly reduced by intravenous administration of GSK221149A at a dose of 0.3 mg/kg. In vitro experiments using Chinese hamster ovary (CHO) cell membranes expressing human OT receptors or human V1a, V1b, or V2 receptors, and human endothelial kidney (HEK) cells expressing rat oxytocin receptors showed that GSK221149A also has a higher affinity for human and rat oxytocin receptors than for V1a and V2 receptors (McCafferty et al., 2007). GSK221149A is over 15-fold more potent compared to atosiban for the OTR (Borthwick and Liddle, 2011). GSK221149A is on a Phase ll Clinical trial described as "A randomized, double-blind, placebo-controlled, dose ranging study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK221149A administered intravenously and to investigate the pharmacokinetics of GSK221149A administered orally to healthy, pregnant females with uncomplicated pre-term labor between 30+0 and 356 weeks' gestation" . The estimated date for study completion was June 2011 and no results have so far been published. Another non-peptide molecule, 1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl) butyramido) bicyclo[2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4(2methylphenyl) piperazine, known as L-368,899, was shown to be a potent OT antagonist that inhibits spontaneous nocturnal uterine contractions in pregnant rhesus monkeys. L-368,899 also blocked OTstimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey (Pettibone et al., 1995). The pharmacokinetics and oral bioavailability, however, were suboptimal, and further clinical evaluation was not undertaken (Freidinger and Pettibone, 1997). L-368,899 is moreover brain penetrant. In a study, the non-peptide OT antagonist L-368,899 was accumulated when injected intravenously in four male monkeys in limbic brain areas. This antagonist when injected iv in one adult female monkey altered maternal and sexual behavior (Boccia et al., 2007).

prolonged pregnancy more effectively than fenoterol (Reinheimer, 2007).

and barusiban groups (Thornton et al., 2009).

The OT antagonists shown in Table 2 bind for both oxytocin and AVP receptors. However, limitations exist, these being: a) there are major differences among them with regard to their selectivity for a specific OT receptor; b) selectivity also varies according to the AVP receptor (V1a, V1b, V2); c) there are striking differences among species as to both receptors' affinity for a given antagonist; and d) specification as to receptors' affinity varies in the literature according to the experimental method used.


Table 2. OT antagonists with tocolytic action and AVP receptor binding

The V2 and V1a peptide antagonist d(CH2)5[Tyr(Me)2]AVP (known as Manning compound) is a potent OT antagonist in vitro and in vivo (Chan et al., 1996). d(CH2)5[Tyr(Me)2]AVP is also a mixed V1a/OT antagonist for human VP and OT receptors.

Several others highly selective OT peptidic antagonists have been designed and synthesized. These include d(CH2)5[Tyr(Me)2]OVT, desGly–NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT (which is about 18 times more potent as an OT antagonist in the rat than as a V1a antagonist) and desGly–NH2,d(CH2)5[D-Tyr2,Thr4]OVT (which is 95 times more potent as an OT antagonist in the rat than as a V1a antagonist). Moreover, the peptide d(CH2)5,[D-Thi2,Thr4,Tyr–NH2 9 ]OVT is a very selective oxytocin antagonist while being a very weak V1a antagonist, as is also desGly–NH2,d(CH2)5 [D-Trp2, Thr4, Dap5]OVT in the rat. On the other hand, there are between species striking differences in the affinity of most antagonists for OT and AVP receptors. The first peptide above, d(CH2)5[Tyr(Me)2]OVT, is 5 times more potent as an V1a antagonist than as a OT antagonist in the rat, whereas in humans it is about 9 times more potent as an OT antagonist than as a V1a antagonist. d(CH2)5,[D-Thi2,Thr4,Tyr–NH29Tyr–NH29(Pierzynski

Some of the new peptide OT/VP antagonists have higher affinity for human receptor than the peptide atosiban, which, as noted, is the only antagonist used today in Europe. These new peptides are desGly–NH2,d(CH2)5[D-2-Nal2,Thr4]OVT, desGly–NH2,d(CH2)5[2- Nal2,Thr4]OVT, d(CH2)5[D-2-Nal2,Thr4,Tyr–NH29 ]OVT, and d(CH2)5[2-Nal2, Thr4, Tyr–NH2 9 ]OVT. These four peptides may be candidates as potential tocolytic agents for the prevention of preterm labor (Manning et al., 2008).

Barusiban is a selective peptide oxytocin antagonist that exerts a high affinity for the human oxytocin receptor On the contrary, it displays low affinity for the vasopressin (V1a) receptor. It possesses greater potency and a longer duration of action than atosiban. Contractility studies with isolated human myometrium have revealed that barusiban inhibits oxytocininduced myometrial contractions of both preterm and term myometrium, this action being at least as potent as that of atosiban (Pierzynski et al., 2004). In a study with eight pregnant monkeys, following induction of stable contractions by OT, barusiban or atosiban were administered. Barusiban's duration of action was generally longer than 13–15 hours, while

The OT antagonists shown in Table 2 bind for both oxytocin and AVP receptors. However, limitations exist, these being: a) there are major differences among them with regard to their selectivity for a specific OT receptor; b) selectivity also varies according to the AVP receptor (V1a, V1b, V2); c) there are striking differences among species as to both receptors' affinity for a given antagonist; and d) specification as to receptors' affinity varies in the literature

The V2 and V1a peptide antagonist d(CH2)5[Tyr(Me)2]AVP (known as Manning compound) is a potent OT antagonist in vitro and in vivo (Chan et al., 1996). d(CH2)5[Tyr(Me)2]AVP is

Several others highly selective OT peptidic antagonists have been designed and synthesized. These include d(CH2)5[Tyr(Me)2]OVT, desGly–NH2,d(CH2)5[Tyr(Me)2,Thr4]OVT (which is about 18 times more potent as an OT antagonist in the rat than as a V1a antagonist) and desGly–NH2,d(CH2)5[D-Tyr2,Thr4]OVT (which is 95 times more potent as an OT antagonist in the rat than as a V1a antagonist). Moreover, the peptide d(CH2)5,[D-Thi2,Thr4,Tyr–NH29 ]OVT is a very selective oxytocin antagonist while being a very weak V1a antagonist, as is also desGly–NH2,d(CH2)5 [D-Trp2, Thr4, Dap5]OVT in the rat. On the other hand, there are between species striking differences in the affinity of most antagonists for OT and AVP receptors. The first peptide above, d(CH2)5[Tyr(Me)2]OVT, is 5 times more potent as an V1a antagonist than as a OT antagonist in the rat, whereas in humans it is about 9 times more

Some of the new peptide OT/VP antagonists have higher affinity for human receptor than the peptide atosiban, which, as noted, is the only antagonist used today in Europe. These new peptides are desGly–NH2,d(CH2)5[D-2-Nal2,Thr4]OVT, desGly–NH2,d(CH2)5[2- Nal2,Thr4]OVT, d(CH2)5[D-2-Nal2,Thr4,Tyr–NH29 ]OVT, and d(CH2)5[2-Nal2, Thr4, Tyr–NH29 ]OVT. These four peptides may be candidates as potential tocolytic agents for the

Barusiban is a selective peptide oxytocin antagonist that exerts a high affinity for the human oxytocin receptor On the contrary, it displays low affinity for the vasopressin (V1a) receptor. It possesses greater potency and a longer duration of action than atosiban. Contractility studies with isolated human myometrium have revealed that barusiban inhibits oxytocininduced myometrial contractions of both preterm and term myometrium, this action being at least as potent as that of atosiban (Pierzynski et al., 2004). In a study with eight pregnant monkeys, following induction of stable contractions by OT, barusiban or atosiban were administered. Barusiban's duration of action was generally longer than 13–15 hours, while

**I. Peptide** Atosiban Yes

Table 2. OT antagonists with tocolytic action and AVP receptor binding

also a mixed V1a/OT antagonist for human VP and OT receptors.

potent as an OT antagonist than as a V1a antagonist.

prevention of preterm labor (Manning et al., 2008).

 **Oxytocin antagonists OT and AVP receptor** 

FE 200 400 (Barusiban) Yes

GSK221149A (Retosiban) Yes SSR-126768A Yes L-368,899 Yes

**binding** 

according to the experimental method used.

**II. Non-peptide**

atosiban's effect ceased within 1.5–3 hours. For long-term treatment, continuous high-dose infusions of barusiban (150 μg/kg/h) or the beta-2 agonist fenoterol (3 μg/kg/h) were administered. Barusiban reduced uterine activity in response to daily OT challenge and prolonged pregnancy more effectively than fenoterol (Reinheimer, 2007).

Although barusiban suppresses oxytocin-induced preterm labor in non-human primates, in a recent study it was no more effective than placebo in terminating preterm labor in pregnant women at between 34+0-35+6 weeks of gestation. This study was conducted at 21 participating centers with subjects from six different European countries. Participants were randomly assigned to receive a single intravenous bolus dose of 0.3, 1, 3, or 10 mg barusiban or placebo (acetate buffer). The percentage of women who did not deliver within 48 hours was not significantly different between the placebo group and any of the barusiban groups (*P* = 0.21-0.84). No significant decreases in the number of uterine contractions compared with placebo were registered. All doses of barusiban were well tolerated and there were no adverse events that would lead to withdrawal from the study. Finally, there was no statistically significant difference in maternal or neonatal adverse effect between the placebo and barusiban groups (Thornton et al., 2009).

The lack of peptide antagonists characterized by oral bioavailability have led researchers to seek an effective non-peptide oxytocin antagonist. The non-peptide oxytocin antagonist 2' methyl-1',3'-oxazol-4'-yl morpholine amide derivative 74 (GSK221149A or retosiban) when administered orally or intravenously produced a dose-dependent decrease in oxytocininduced uterine contractions in rats, after either single or multiple dosing for 4 days. In addition, spontaneous uterine contractions in late-term pregnant rats (at 19–21 days gestation) were significantly reduced by intravenous administration of GSK221149A at a dose of 0.3 mg/kg. In vitro experiments using Chinese hamster ovary (CHO) cell membranes expressing human OT receptors or human V1a, V1b, or V2 receptors, and human endothelial kidney (HEK) cells expressing rat oxytocin receptors showed that GSK221149A also has a higher affinity for human and rat oxytocin receptors than for V1a and V2 receptors (McCafferty et al., 2007). GSK221149A is over 15-fold more potent compared to atosiban for the OTR (Borthwick and Liddle, 2011). GSK221149A is on a Phase ll Clinical trial described as "A randomized, double-blind, placebo-controlled, dose ranging study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of GSK221149A administered intravenously and to investigate the pharmacokinetics of GSK221149A administered orally to healthy, pregnant females with uncomplicated pre-term labor between 30+0 and 356 weeks' gestation" . The estimated date for study completion was June 2011 and no results have so far been published.

Another non-peptide molecule, 1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl) butyramido) bicyclo[2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4(2methylphenyl) piperazine, known as L-368,899, was shown to be a potent OT antagonist that inhibits spontaneous nocturnal uterine contractions in pregnant rhesus monkeys. L-368,899 also blocked OTstimulated uterine activity in postpartum women with a potency similar to that in the pregnant rhesus monkey (Pettibone et al., 1995). The pharmacokinetics and oral bioavailability, however, were suboptimal, and further clinical evaluation was not undertaken (Freidinger and Pettibone, 1997). L-368,899 is moreover brain penetrant. In a study, the non-peptide OT antagonist L-368,899 was accumulated when injected intravenously in four male monkeys in limbic brain areas. This antagonist when injected iv in one adult female monkey altered maternal and sexual behavior (Boccia et al., 2007).

Oxytocin and Myometrial Contractility in Labor 251

GSK221149A (retosiban) are some other OTR antagonists demonstrating tocolytic properties

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tocolytics for preterm labor. J Pharmacol Exp Ther, Vol. 277 (2): 999-1003. ClinicalTrials.gov. The Safety, Tolerability And Metabolism Of GSK221149A, In Pregnant

Conti, F., Sertic, S., Reversi, A. &Chini, B. (2009). Intracellular trafficking of the human

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Decaux, G., Soupart, A. & Vassart, G. (2008). Non-peptide arginine-vasopressin antagonists:

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**8. References** 

WAY-162720 is another high-affinity, potent, and selective non-peptide antagonist of the OTR. WAY-162720 also penetrates the brain and is a tool for studies of OT on the CNS effects. In one study, the effects of OT on both the behavioral and autonomic parameters of the anxiety response in male mice were examined. Oxytocin showed an anxiolytic-like effect comparable to those observed with the reference anxiolytic alprazolam. The administration of WAY-162720 fully reversed the effects of centrally administered OT (Ring et al., 2006).

The non-peptide SSR-126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl) -3 methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, hydrochloride) produced a competitive antagonistic effect against OT in rat myometrial strips, while after oral administration in conscious pregnant rats in labor it significantly delayed parturition, in a manner similar to ritodrine. The onset of its action was rapid and the duration was still observed 24h after treatment. In experiments performed in human uterine sections in term pregnancies, SSR-126768A inhibited the response to OT and this effect was observed in a concentration-dependent manner (Serradeil-Le et al., 2004).

Relcovaptan, a vasopressin (V1a) receptor antagonist, was reported to inhibit uterine contractions in women with preterm labor, thus indicating a role for V1a receptors (Steinwall et al., 2005). In a study including 18 women with preterm labor between 32–36 weeks, 12 patients received at random a single oral dose of 400 mg relcovaptan and 6 patients received placebo; uterine contractions were monitored up to 6h after administration. Relcovaptan inhibited uterine contractions and the decrease in the frequency of contractions was significantly higher than the frequency in the placebo-treated group. It has also shown positive initial results when used against Raynaud's disease and dysmenorrhea, although it has not yet been approved for clinical use (Decaux et al., 2008). When relcovaptan was given orally once a day for 7 days in patients with Raynaud's disease, it showed favorable effects compared with placebo on finger systolic pressure and temperature recovery after cold immersion, without inducing side effects (Hayoz et al., 2000). Relcovaptan is administered orally 100 mg or 300 mg daily in women suffering from primary dysmenorrhoea, from 4 hours up to a maximum of 3 days before the onset of bleeding and/or menstrual pain. After the start of dysmenorrhea (defined as the onset of vaginal bleeding or the onset of pain, whichever occurred first), treatment was prolonged for up to 3 days. Relcovaptan showed a therapeutic effect in the prevention of dysmenorrhea (Brouard et al., 2000). Relcovaptan also produced significant neuroprotective actions and reduced ischemic brain edema in an embolic model of stroke in rats when given immediately or 1 hour after middle cerebral artery occlusion, but not when administered at 3 hours after middle cerebral artery occlusion (Shuaib et al., 2002).

As our knowledge on OT/OTR system expands, the development and use of different OTR antagonists becomes an increasingly promising field in the management of preterm labor.

### **7. Conclusion**

OT exerts its myometrial and other actions through a transmembrane receptor that belongs to the G- protein coupled receptor superfamily. Various peptide and non-peptide antagonists have been developed in order to be used as potential tocolytic agents or as research tools in assessing different OT functions. Atosiban is at present the only available OTR antagonist used as a tocolytic agent. Barusiban, L-368,899, SSR-126768A, and GSK221149A (retosiban) are some other OTR antagonists demonstrating tocolytic properties when tested, but have not so far been approved for clinical use.

#### **8. References**

250 From Preconception to Postpartum

WAY-162720 is another high-affinity, potent, and selective non-peptide antagonist of the OTR. WAY-162720 also penetrates the brain and is a tool for studies of OT on the CNS effects. In one study, the effects of OT on both the behavioral and autonomic parameters of the anxiety response in male mice were examined. Oxytocin showed an anxiolytic-like effect comparable to those observed with the reference anxiolytic alprazolam. The administration of WAY-162720 fully reversed the effects of centrally administered OT (Ring et al., 2006).

The non-peptide SSR-126768A (4-Chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl) -3-

hydrochloride) produced a competitive antagonistic effect against OT in rat myometrial strips, while after oral administration in conscious pregnant rats in labor it significantly delayed parturition, in a manner similar to ritodrine. The onset of its action was rapid and the duration was still observed 24h after treatment. In experiments performed in human uterine sections in term pregnancies, SSR-126768A inhibited the response to OT and this

Relcovaptan, a vasopressin (V1a) receptor antagonist, was reported to inhibit uterine contractions in women with preterm labor, thus indicating a role for V1a receptors (Steinwall et al., 2005). In a study including 18 women with preterm labor between 32–36 weeks, 12 patients received at random a single oral dose of 400 mg relcovaptan and 6 patients received placebo; uterine contractions were monitored up to 6h after administration. Relcovaptan inhibited uterine contractions and the decrease in the frequency of contractions was significantly higher than the frequency in the placebo-treated group. It has also shown positive initial results when used against Raynaud's disease and dysmenorrhea, although it has not yet been approved for clinical use (Decaux et al., 2008). When relcovaptan was given orally once a day for 7 days in patients with Raynaud's disease, it showed favorable effects compared with placebo on finger systolic pressure and temperature recovery after cold immersion, without inducing side effects (Hayoz et al., 2000). Relcovaptan is administered orally 100 mg or 300 mg daily in women suffering from primary dysmenorrhoea, from 4 hours up to a maximum of 3 days before the onset of bleeding and/or menstrual pain. After the start of dysmenorrhea (defined as the onset of vaginal bleeding or the onset of pain, whichever occurred first), treatment was prolonged for up to 3 days. Relcovaptan showed a therapeutic effect in the prevention of dysmenorrhea (Brouard et al., 2000). Relcovaptan also produced significant neuroprotective actions and reduced ischemic brain edema in an embolic model of stroke in rats when given immediately or 1 hour after middle cerebral artery occlusion, but not when administered at

al.,

As our knowledge on OT/OTR system expands, the development and use of different OTR antagonists becomes an increasingly promising field in the management of preterm labor.

OT exerts its myometrial and other actions through a transmembrane receptor that belongs to the G- protein coupled receptor superfamily. Various peptide and non-peptide antagonists have been developed in order to be used as potential tocolytic agents or as research tools in assessing different OT functions. Atosiban is at present the only available OTR antagonist used as a tocolytic agent. Barusiban, L-368,899, SSR-126768A, and

methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide,

effect was observed in a concentration-dependent manner (Serradeil-Le et al., 2004).

3 hours after middle cerebral artery occlusion (Shuaib et al., 2002).

**7. Conclusion** 


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**16** 

*1Nigeria* 

*2United Kingdom* 

**Operative Vaginal Deliveries in** 

Sunday E. Adaji1 and Charles A. Ameh2

**Contemporary Obstetric Practice** 

*2Liverpool School of Tropical Medicine, Pembroke Place, Liverpool,* 

*1Ahmadu Bello University and Ahmadu Bello University Teaching Hospital, Zaria,* 

The expectation of every pregnant woman is to undergo a spontaneous vaginal delivery with minimal or no resort to operative procedures at the end of pregnancy. For the majority of women this expectation becomes a reality. For some however, assistance is required either in the form of caesarean sections or operative vaginal procedures in order to avert adverse maternal and fetal outcomes. Assisting laboring women to deliver vaginally using specialized instruments is a practice that dates back several centuries. Forceps and ventouse are the most popular of the operative vaginal procedures with comprehensive documentation of their development and use in the lay and medical media. Procedures like symphysiotomy and destructive operations to remove a dead fetus are probably now materials for the waste bins of medical history. However some still argue for a place for them in modern obstetric practices especially in low income countries where the indications

Instrumental vaginal delivery is a key element of essential obstetric care, scaling up its use in resource poor countries through training and supply of appropriate equipment is likely to contribute significantly to reduced maternal and newborn morbidity/mortality(Ameh and

'If the head advances, no matter how slowly, no interference unless the child be dead

The obstetrical forceps is probably the earliest instrument designed to assist vaginal delivery. Behind its design, invention and evolvement lies florid and interesting history

for their use may still be found (Maharaj and Moodley, 2002).

~A summary of the guidelines for the use forceps in Smellie's time

**1. Introduction** 

Weeks, 2009).

**2. The obstetrical forceps** 

'Use the forceps sparingly –

'Use only on the most urgent occasions

'Where they save one they murder many'

'Head on the perineum for 6 hours

