TOCOLYSIS IN VETERINARY REPRODUCTION

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Application of tocolytic drugs in veterinary obstetrics for correction of dystocias, caesarean section, fetotomy and postponement of parturition.

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Tocolysis in Veterinary Reproduction A post graduate credit seminar on Speaker: DHIREN B.BHOI Reg.No.-04-00303-07 VOBG-900 Major Guide: Dr. V. K. Sharma Minor Guide: Dr. J. N. Mistry

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DEFINITION Reduced uterine contractions following administration of myometrial relaxing agents: Tocolytic drugs. Tocolysis is a Greek derivative; tokos = childbirth or labor lysis = dissolution

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These drugs emerged for human use and gradually linked with animal medicine. TOCOLYTIC DRUGS: GENERAL CONCEPT Innes and Nicherson, 1975; Putnam et al., 1985 Smooth muscles innervated by the sympathetic nervous system: a and ß receptors a receptors:- Muscular contractions ß receptors:- Relaxation ß1:confined to heart and small intestine ß2:vascular smooth muscle, myometrium, bronchial tree

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So, drugs that produce this effect are termed uterine myorelaxants, tocolytic drugs or simply tocolytics. Stimulation of ß2 receptor cause bronchodilation, relaxation of the uterus and vasodilation in most species. Zerobin and Kondig,1980

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DRUGS USED AS TOCOLYTICS ß-sympathomimetics – e.g. Isoxsuprine, Ritodrine, Terbutaline, salbutamol, Orciprenaline, Fenoterol, Clenbuterol, Meluadrine Tartrate, KUR-1246. Calcium antagonists – e.g. Nifedipine, Verapamil, Nicardipine, Nitrendipine. Oxytocin antagonists – e.g. Atosiban and all Beta-sympathomimetics. Prostaglandin antagonists – e.g. Indomethacin Other agents – e.g. glyceryl trinitrate, Extracts of Bryophyllum pinnatum, omega-3 long chain Polyunsaturates and Magnesium sulfate. Norwitz et al., 1999

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Kauppila et al., 1978, Schenken et al., 1980 Subsequently new agents invented that stimulate ß2 receptors and used as tocolytics without side effects, Ritodrine Salbutamol, Terbutaline, Clenbuterol, Orciprenaline. For examples Isoxsuprine lactate was 1st agents to be used for treatment of labor. ß-SYMPATHOMIMETICS Tocolytic agents Vamerzani et al., 1996, Garg et al., 2004

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Major side effects: Cardiovascular complications COMMERCIALLY AVAILABLE TOCOLYTIC DRUGS

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MECHANISM OF ACTION Drug administration Adenyle cyclase activation ATP cAMP (www.Drug.com) Drug transportation through carrier protein or diffused osmosis; within 10-15 min. Protein kinese stimulation Protein phosphorilation Intracellular calcium sequesterization Deminished contractile protein activity Uterine myometrial relaxation

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PHARMACOKINETICS Unknown in ruminants Entire intestine in monogastric animal PH affects the absorption Higher/lower PH:- Reduce absorption Neutral PH:- Increase absorption (Smith, 1998) Peak plasma level occurs within 1-3 hr after oral dose. (Morgan, 1990) Phase: I; Oxidation, Reduction, Hydrolysis Phase: II; Conjugation Milk, Urine and feaces Urine:-Clenbuterol in bovine. (Smith and Paulson, 1997) Absorption Distribution Metabolism Excretion Clenbuterol: Dave et al, 1998 Terbutaline: Melanie et al, 2007

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Threatened abortion / Preterm labour Controlled calving / Nocturnal delivery To reduce neonatal morbidity and mortality in dystocia. To aid obstetrical operations; cesarean section and fetotomy Treatment of uterine prolapse Embryo biotechnology CLINICAL USE OF TOCOLYTIC DRUGS

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Incidence of premature labor in animals is around 5–7 %. Gaspar et al.., 2005; King et al., 2008 Statistics indicate that preterm birth is the leading factor causing neonatal morbidity and mortality in animals. Haram et al., 2003, Tucker and McGuire 2004 PRETERM LABOUR / THRETENED ABORTION

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300 µg, Clenbuterol, i/m, injected in a cow for the treatment of premature labour. The treatment induced inhibition of uterine contractions without any side effects. Albeck, 1981 Clinical trial Progesterone therapy is generally advocated for the treatment of premature labour, but it has some adverse effects: When labour pain has reached to its maximum amplitudes, the drug does not work or ineffective. It prolongs gestation length, when administered during advanced pregnancy, as a result, chances of dystocia increases due to additional weight gain of the fetus.

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Tocolytic effects of KUR-1246 & Ritodrine hydrochloride on Oxytocin-Induced Uterine Contraction in Pregnant Sheep. Kiguchi et al., 2002 Efficacy is adjudged on: Cardiovascular parameters of dam. : General metabolism of dam and fetus.

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Experimental trial Effect of Meluadrine tartrate and ritodrine hydrochloride on maternal systolic, diastolic and mean blood pressure in pregnant goats. Matsuda et al., 2002

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Effect of Clenbuterol and Nifedipine on xylazine-induced alterations in the frequency of uterine contractions, 5 min-1 in adult goats. Perez et al., 1997

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Bovine , Ovine & Porcine Prediction of calving time Physical signs:-slackening of sacrosciatic ligament, relaxation of perineum and vulva, distension of udder, vaginal mucous discharge are difficult to quantify and their development in relation to calving varied considerably. Body temperature :-Too variable to be used in prediction of parturition time (either side of 38.9? C). Ewbank, 1963 Using PGF2a / Corticosteroids:- More incidence of retained placenta (Lewing, 1985) Tocolysis:- Prediction of calving time CONTROLLED CALVING / NOCTURNAL DELIVERY

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Probability (%) of cow calving within a specified period in relation to plasma progesterone concentration. Parker et al., 1988

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300 µg, i/m, Clenbuterol suppressed uterine contractions and delay parturition in cattle on an average 5 - 8 hrs without any ill effect on cow or calf, expulsion of placenta and fertility of cow. Ballarini et al., 1978 Clenbuterol was employed to regulate the calving time (i.e. to avert night calving) by suppressing the uterine contractions. A dose of 300µg, i.m, arrested uterine contractions for about 5 hr, in 95 cows without obvious harmful effect. Ballarini, 1978 Terbutaline,5mg/kg, i/m, has potential as a tocolytic drug to delay parturition and for various bovine obstetrical maneuver. Melanie et al., 2007

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FACTORS AFFECTING TOCOLYSIS Stage of labour Parity of animal Cervical dilatation & fetal position Pelvic area of dam

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18 cross bred cows used in a trial and found that duration of delaying calving in the first stage of labour was much more compare with the second stage of labour. Vamerzani et al., 1996 Once cervix is fully dilated or fetal feet are passing into cervical area Clenbuterol will only delay labour for maximum of a few hours. Arbeiter and Holler, 1980

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Zerobin and Kundig, 1980 Clinical observations of Clenbuterol on nocturnal delivery 300 µg, Clenbuterol Hydrochloride, i/v, was used to postponed parturition in cows.

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Clenbuterol 300µg, i/m, was used in heifers for postponement of parturition. Influence of Clenbuterol on the length (minutes) of stage-I of parturition in heifers with large and small pelvic areas. Putnam et al., 1985

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Influence of Clenbuterol on the length (Minutes) of stage-II of Parturition in heifers with large and small pelvic areas. Putnam et al., 1985

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Clenbuterol 300 µg, i/m is useful to postpone the parturition at different stages in cows. Greene, 1981 During Clenbuterol treatment in cows, the duration of tocolysis depends on the position of the fetus at the time of treatment, being longest at the beginning of the labour process (Stage-I). Greene, 1981

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Clenbuterol treatment in ewes effectively resulted in to delayed parturition for at least 10 hr. in most ewes. Plant and Bowler, 1988 Clenbuterol, 240 µg, i/m, abolished uterine motoricity for 8-10 hrs suspending overnight lambing in 91% of ewes subjected to trial. Delatour and Roizard, 1979 OVINE Nifedipine 80 µg/kg, i/v given to sheep and found that it delayed the parturition for 6-7 hours. Parez et al., 1997 Clenbuterol, 6 ml, i/m given to ewes to delay lambing for 7 hours. Hirst et al., 2005

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Clenbuterol had been used in 13 pigs for postponement of parturition at dose rate of 150 µg, i/v (Planipart). Interruption of parturition Nocturnal delivery Suitable for all the phases of farrowing, Interrupts labour for several hours, Results into unhindered farrowing without affecting piglet vitality. PORCINE Zerobin and Kundig, 1980

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Zerobin and Kundig, 1980

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DYSTOCIA

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ADVANTAGES OF TOCOLYSIS IN OBSTETRICAL MANEUVER Less requirement of epidural anaesthesia Easy and correct diagnosis of obstetrical defects Facilitated obstetrical maneuvers Repositioning of head and neck deviations. Corrections of malpresentations and malpostures Repulsion and rotation of fetus Correction of forelimb retension, hock flexion, and breech presentation Low incidence of retained placenta (Menard, 1994) Low incidence of genital prolapse (Albeck, 1981)

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REQUIREMENT OF EPIDURAL ANAESTHESIA 300 µg, i/m, Clenbuterol given to cows in dystocia cases Menard, 1994

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Results of Clenbuterol, i/v, 0.6-0.8 µg/kg body wt. before 15-20 min of obstetrical corrections in cow. Menard, 1994

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Incidence of retension of placenta was lower in dystocia cases treated with Clenbuterol compared to non-treated cows. Influence of Clenbuterol treatment on Retension of placenta Menard, 1994

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CAESAREAN SECTION Advantages Facilitate veterinarians’ work. Easy extraperitoneal lifting of the uterus. (Hassett and Sloss, 1984) No risk of anaesthetic induced recumbancy. Impermeable closure of uterine muscles. (Horvath and Bacsfay, 1981) Easy suturing of uterus and no incidence of ROP. (DeNooij, 1984) Prevent post operative adhesions. Reduce mortality of dam and calf. (Menard and Diaz, 1987)

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Cows treated with Clenbuterol 0.6 µg/kg body wt. 15-30 min prior to caesarean, then good proportion of exteriorization was noticed than in the non-treated animals. Menard and Diaz, 1987

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The incidence of retension of placenta and loss of cows and calf also noticed very less in caesarean performed in cows using Clenbuterol, 0.6 µg/kg body wt. Menard and Diaz, 1987 Good plane of uterine relaxation observed in cows affected with dystocia treated with 5 mg/kg, i/v, terbutaline. Melanie et al., 2007

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Uterine Exteriorization Total animals Exteriorization achieved No response Treatment Group Control Group 66 90% 59 10% 7 60% 40 40% 26 66 10 ml Isoxsuprine, i/m, given in cows during caesarean section Ahlers and Anderson, 1967

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A cesarean section performed in a Berkshire saw treated with 6 ml Isoxsuprine, i/m, a good uterine relaxation was noticed and uterus could be easily exteriorized. Narasimhan and Thangaraj, 1969 Very good uterine relaxation, improved ease of manipulation and exteriorization of uterus was noticed during Caesarean performed in Sheep (n=3) using Clenbuterol, 0.8 µg/kg b. wt. Menard and Diaz, 1987 Sheep Pig

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FETOTOMY

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UTERINE PROLAPSE

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Rajasekaran et al., 1980 Seven cases of bovine uterine prolapse were treated with uterine relaxant Isoxsuprine with varying doses from 30-100 µg i/m, according to size of the animal and good results were achieved.

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UTERINE TORSION

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Recipients received 300µg Clenbuterol, i/m, 30-90 min. prior to Embryo transfer. Pregnancy rates varied from 19-56 % in Clenbuterol treated cases. The results indicate no improvement in pregnancy rates. But treatment resulted into a relaxant effect on uterine myometrium. Wenkoff, 1986 Clenbuterol used to relax non-pregnant uterus & increased pregnancy rates in cattle recipients undergoing surgical embryo transfer. Coulthard, 1982 EMBRYO TRANSFER Surgical method Non-surgical method

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In a field trial, Clenbuterol, 364 µg (10 ml) was given by i/m, immediately following the embryo transfer in cattle, Recipient Pregnancy Rate Barnes and First, 1985

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The effects of Planipart (Clenbuterol), Duvadilan (Isoxsuprine) and Aerolin (Salbutamol) were tested on pregnancy rates of cows receiving the embryos transferred by non - surgical method. Gregory et al., 1986

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Total 300 µg Clenbuterol given i/m to cattle recipients at the time of ovarian palpation, 30 - 180 min. prior to embryo transfer had effectively improved pregnancy rate after surgical embryo transfer. Surgical Embryo Transfer Maplotoft et al., 1986 Non-surgical Embryo Transfer

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Among the ß-sympathomimetic drugs used in reproduction, only Clenbuterol and Isoxsuprine have been used widely in clinical management of obstetrical disorders apart from embryo biotechnology with encouraging post therapeutic results. CONCLUSIONS The efficacy of these drugs is mostly assessed clinically and pharmacokinetic of each needs to be studied in detail to ensure wide use with awareness of adverse effects of drug metabolites, if any.

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