MX2008002202A - Method of treating parturient placental mammals in order to reduce maternal and/or utirine exhaustion - Google Patents

Abstract

The present invention relates to a method of facilitating the birth process of placental mammals, especially to a method of reducing delays in the birth process and, thereby, complications resulting there from that may negatively affect the health and wellbeing of the mother and increase the incidence of stillbirths and/or neonatal mortality. According to the present invention delays in parturition that result from maternal and/or uterine exhaustion may be prevented or reduced by the administration of an effective amount of one or more psychomotor stimulants to the parturient mammal prior to and/or during parturition. Said psychomotor stimulant is selected from the group comprising xanthines and amphetamines.

Description

METHOD OF TREATING PLACENTARY MAMMALS PARTURIENTS IN ORDER TO REDUCE MATERNAL AND / OR UTERINE DEPLETION FIELD OF THE INVENTION The present invention concerns the field of births. More particularly, the present invention concerns a method of facilitating the process of birth of placental mammals to reduce complications related to exhaustion during the birth process that can adversely affect the health and well-being of the mother and increase the incidence of stillbirths and / or neo-natal mortality.

BACKGROUND OF THE INVENTION A normal labor process is divided into three stages. Between these stages, the first and second stages are directly involved in the release of the fetus (s). The first stage of labor starts with the beginning of rhythmic uterine contraction and ends with the complete dilation of the cervix. The complete dilation of the cervix marks the beginning of the second stage of labor, which ends immediately after the birth of the neo-born (s). The third stage of labor extends from the birth of the neo-born (s) to the complete expulsion of the placenta. This progress of labor is activated by two types of labor forces. The first force is produced by the involuntary contractions of the uterine muscle. The secondary force is produced by the increase in intra-abdominal pressure through voluntary contractions of the diaphragm and abdominal muscles. These forces cause an increase in intrauterine pressure to provide a critical expulsion force on the fetus. In humans, this primary force should generate pressures of 50 to 60 mm Hg, with contractions of 50 to 60 seconds in duration and taking place at a frequency of every 2 to 3 minutes, The diaphragm and the abdominal muscles in the second stage they should be able to bend the intrauterine pressure in response to the lower support sensations. Exhaustion during labor can lead to the weakening of these primary and / or secondary forces, increasing the duration of labor and eventually results in dystocia (work stoppage). Two forms of exhaustion have been identified: uterine and maternal exhaustion. Uterine exhaustion is also referred to as "secondary uterine inertia", which means that the uterine muscles are fatigued and not they produce significant contractions. Secondary Uterine Inertia (IUS) often occurs with persistent contractions, such as during fetal dystocia. It is also very likely to take place during the release of the last fetuses in a large bait. Maternal depletion refers to the inability to sufficiently increase intrauterine pressure by contractions of the diaphragm and abdominal muscles. Thus, disability can be affected not only by the mothers' physiological state but also by their perception of exertion and exhaustion. Serious health complications may increase in the mother, from exhaustion, during labor. These include retained placenta, hypocalcemia, hypomagnesemia, metritis, and ketosis. These can result in health complications that require medical attention during delivery (for example, forceps or vacuum extraction or cesarean sections) or after delivery (for example, in case of hypocalcemia). In the fetus, serious reductions in respiration can occur as a consequence of exhaustion and numerous clinical studies have correlated prolonged labor duration and dystocia with many undesirable outcomes, which include a higher proportion of infant mortality, neo-natal attacks, and postpartum hemorrhage, mainly as a result of the deprivation of oxygen of the fetus. For example, for some fetuses the umbilical cord is broken before the moment of birth, for example in sows this concerns approximately 20% of the fetuses. If the cord was cut just before birth, is usually of little consequence and the neonate is born healthy. If the parturient mother has had some difficulty releasing or is getting tired, the fetuses are expelled at a slower speed. For fetuses with broken cord, this delay at birth is often fatal when interruptions in blood flow and oxygen deprivation for periods of up to five minutes appear to be tolerated by fetuses, but beyond this, it results in metabolic damage that affects negatively health and may eventually cause them to be born dead (Randall, 1971). Another factor that contributes to reductions in fetal respiration is related to the intensification of uterine contractions when the offspring is being released. Each contraction puts pressure on the umbilical cord and can reduce blood flow to the fetus, thus reducing the amount of oxygen that reaches the unborn. Especially if the birth process tends to be delayed or interrupted due to exhaustion maternal, the unborn fetus can die of suffocation as a result of these contractions and is presented as born dead. Fetuses that have been born alive but have suffered a prolonged reduction in blood flow to the umbilical cord have disrupted metabolism and respiration, including elevated levels of C02 resulting in a decrease in blood pH. Randall (1971) showed that marranitos born with an umbilical blood pH of 7.1 or lower had an evaluation of low viability. In Randall's study, 18.3% of born porcupines had said low blood pH which suggests that dystocia is responsible for a large part of neo-natal mortality (Randall, GC, The relationship of pH and pC02 of arterial blood to viability of neo-native marranitos, Can J. Comp.Med. 1971 Apr. 35 (2): 141-6). For humans and large farm mammals such as horses and cows, exhaustion typically results in human intervention in the birth process. For example, oxytocin, oxytocin analogues, or oxytocin stimulants are injected to stimulate uterine contraction, or the fetus is removed using for example, forceps or vacuum extraction or using a section of caesarean section. In the United Kingdom in humans, 18% of the releases were by cesarean section, while 11.1% required releases with instruments (for example, forceps and vacuum release). Although, more likely, these solutions are the only adequate alternatives given the conditions, mechanical interventions can still have serious implications for the health of the mother and offspring and may be well preventable with appropriate mother support. In addition, oxytocin injections can be dangerous today when the uterus is not properly dilated before administration of the intervention. Oxytocin can cause uterine spasm instead of rhythmic contractions that result in fetal death in the uterus. In the case of animals that have baits, complications resulting from maternal and / or uterine depletion are even less likely to occur, while interventions may be less commonly available, and consequently the proportion of stillbirths is much higher. For example, in sows an estimated 8% of fetuses are stillborn and 12% die shortly after birth. The incidence of unviable pigs (born weak) and aborted pigs (intrapartum deaths) increases with the order of birth and with the duration of delivery. Has been reported that pigs born last in a bait have a 50% chance of being aborted, whereas an 11.8% of perinatal mortality rate was observed in litters born in less than 6 hours, compared to 21.3% of perinatal mortality rate in those baits born in more than 6 hours. The beneficial effect of reducing the intervals of births in stillbirths in sows was demonstrated by Rudloff and Bostedt, who studied the effect of the ß-adrenoreceptor antagonist heart (Suacron) on deliveries in sows. In their study Rudloff and Bostedt showed that intravenous injections of 0.5 mg / 50 kg of body weight of heart reduced the proportion of releases that lasted more than six hours from 14.5 hours to 11.0%, resulting in proportions of stillbirths reduced from 8.3 to 7.1%, less need for external help, decreased the use of oxytocin, and decreased the occurrence of puerperal disorders. [Rudloff PR, Bostedt H., Effect of the beta-blockader heart (Suacron) on parturition in sows. Tierarztl Prax. 1984; 12 (4): 443-449]. The prevention and reduction of exhaustion can provide an interesting tool to reduce the incidence of intrapartum and postpartum morbidity or mortality, to reduce health complications in the mother, resulting from exhaustive work, and / or reduce the need for external help in parturient mammals. The present invention seeks to provide a method of treating mammalian parturients in order to achieve these objectives.SUMMARY OF THE INVENTION The present invention has found that delays in calving as a result of maternal and / or uterine depletion can be reduced by administering an effective amount of one or more psychomotor stimulants to the mammal prior to and / or during childbirth. More particularly, the method of treatment provided by the present invention reduces the symptoms of exhaustion in mammals during labor by administration of one or more psychomotor stimulants selected from xanthines and / or amphetamines immediately before and / or during labor, so that the need for possible traumatic interventions in the birth process is reduced, the total survival rate of newborns during and immediately after the birth process is increasing, and the health complications related to exhaustion in the mother are reduced.

Amphetamines act by releasing mono-amines from nerve terminals in the brain. Nor-adrenaline and dopamine are the most important mediators in this connection, but the release of 5-HT also takes place with some amphetamines. The main pharmacological effects include locomotor stimulation and euphoria and excitation. In addition, amphetamines have peripheral sympathomimetic actions, producing an increase in blood pressure and inhibition of gastrointestinal movement. Xanthines are CNS / psychomotor stimulants. At high concentrations, they may also decrease the possibility of contraction of the bronchial, vascular, and uterine smooth muscles, and stimulate respiration, diuresis, vasodilatation of the coronary and peripheral arteries, cerebral vasoconstriction, and vasodilatation of the cardiac muscle. Some groups have reported the so-called "ergogenic effects" of xanthines that possibly involve modulating effects on the metabolism of carbohydrates and increase the possibility of skeletal muscle contraction. The xanthines thus constitute a class of substances with various pharmacological properties. The use of xanthines to reduce fatigue, that is, improve performance and brain concentration is well known.

Xanthines, especially theophylline, are also used as bronchodilators in severe asthmatic attacks while both caffeine and theophylline are used to prevent apnea in children born prematurely. The psychological effects of xanthines have been the subject of much research and several mechanisms of action have been shown to be involved. Xanthines are adenosine antagonists, a compound that can inhibit both neuronal activity and behavior through direct post-synaptic action on neurons and through presynaptic inhibition that involves the indirect action of neurotransmitter release. Xanthines can also inhibit phosphodiestearases, thus preventing the inactivation of cyclic MFA (adenosine monophosphate) and cyclic MFG (guanosine monophosphate). Elevated levels of cMFA and cMFG affect excitatory neurotransmitters such as norepinephrine and dopamine. Lately, it has been reported that xanthines can modulate the conductance of several ion channels such as Ca2 + and Cl ~ channels. These last two effects of xanthines typically occur at higher concentrations than the first.

Although it is generally conceived that xanthines such as caffeine may affect the results in prolonged exercises there is still much debate about the exact physiological events involved. Numerous studies have examined the effects of xanthines, especially caffeine, on peripheral and central events along the motor trajectory, on metabolism, and on the cardiovascular system both during prolonged extensive exercise and during brief intense exercise. For example, it has been reported that the ingestion of caffeine increases the possibility of skeletal muscle contraction [Tarnopolsky et al .: J. Appl. Physiol. 89: 1719-1724, 2000], alters the muscular sensory processes, and reduces the sensation of strength (which leads to a good disposition) to keep muscle activity close to the maximum longer [Plaskett et al., J. Appl. Physiol. 91: 1535-1544, 2001], increases plasma concentrations of epinephrine (although the metabolic impact of this increase remains uncertain [Jackman et al.; J.

Appl. Physiol. 81 (4): 1658-1663, 1996]), and alters the cardiovascular response to dynamic exercise by increasing regional blood flow [Daniels et al; J. Appl. Physiol 85: 154-159, 1998].

It has been shown that xanthines inhibit uterine contractions stimulated by oxytocin in vitro, in (among others) isolated pregnant myometrium [Berg et al; Am. J. Obstet. Gynecol. 156 (4): 958-962, 1987], [Bird et al .; Am. J. Obstet. Gynecol. 157 (1): 171-177, 1987], [D'Ocom MP; Arch Int. Pharmcodyn Ther. 302: 268-279, 1989], [Savineau et al .; Br., J. Pharmacol. 99 (2): 261-266, 1990]. In addition, theophylline and aminophylline have been tested and used clinically as tocolytic agents because of their inhibitory action on uterine contractions [Lechner .; Z Geburtshilfe Perinatol. 1986 Nov-Dec; 190 (6): 261-5], [Lipschiz J.; Am. J. Obstet. Gynecol. 131: 716-718, 1978]. Lipschitz studied the effects of administering aminophylline (250 mg / for five minutes) by intravenous infusion to women with oxytocin-induced contractions. It was concluded that aminophylline exhibits poor uterine selectivity with an unfavorable cardiovascular / tocolytic relationship, so that this compound was inadequate to delay premature labor. Despite the fact that xanthines have been considered to constitute adequate tocolytics, it was found in the present that they can be used advantageously to prevent and / or reduce delays in deliveries. Without wishing to adopt any theory, the present invention considers the hypothesis that this unexpected finding resides in the fact that for xanthines, the plasma concentration required for effective inhibition of the possibility of contraction of the uterine smooth muscle is substantially higher than that required for stimulation of the psychomotor system so that the unfavorable tocolytic effects of the xanthines are weighted by the unfavorable effects on peripheral and central events along the motor trajectory, on the metabolism and / or on the cardiovascular system.

DESCRIPTION OF THE FIGURE The figure that is included shows the relationship between umbilical blood pH, pC02, and viability in piglets.

DETAILED DECRIPTION OF THE INVENTION Thus, a first aspect of the present invention concerns a method of treating and / or preventing maternal and / or uterine depletion in a placental mammal, said method comprising administering to said mammal an effective amount of one or more psychomotor stimulants selected from the group consisting of xanthines and amphetamines. In this document and in its claims, the verb "to understand" and its conjugations are used in their non-limiting sense to mean that articles that follow the word are included, but articles not specifically mentioned are not excluded. In addition, the reference to an element by the indefinite article "a" "one" does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" usually means "at least one". The terms "uterine exhaustion" and "secondary uterine inertia", which are judged to be synonymous and are used interchangeably in the present, refer to the phenomenon in which the uterine muscles are fatigued and do not produce significant contractions. The term "maternal depletion" as used herein, refers to the phenomenon in which the mother is unable to significantly increase intra-abdominal pressure through voluntary contractions of the diaphragm and abdominal muscles.

The term "maternal dystocia" is also sometimes used to refer to maternal and / or uterine exhaustion. Maternal dystocia is usually defined as "difficulty in releasing or giving birth caused by an abnormality or physical problem in the mother" and should not be confused with "fetal dystocia" (or "support dystocia") which is usually used to refer to a difficult release due to "poor fetal presentation", which by itself can cause uterine and / or maternal exhaustion. As explained above, the application of this method will reduce the incidence of postpartum and intrapartum morbidity or mortality, reduce mother-related health complications resulting from exhaustive labor, and / or reduce the need for external assistance. in parturient mammals. Thus, the present invention also encompasses the use of the method as described herein to reduce the incidence of postpartum and intrapartum morbidity or mortality, reducing health complications in the mother, resulting from exhaustive labor, and / or reducing the need for external help in parturient mammals. The method herein can be used salefully in any placental mammal in need of such treatment. Said mammal can, for example, be selected from humans, primates, equines, cattle, sheep, goats, cervinos, camelids, canines, felines, and pigs. In a first preferred embodiment, the mammal is a human. In another equally preferred embodiment the mammal is not human, more preferably the mammal is a primate, equine, bovine, ovine, caprine, cervino, camelid, canine, feline, or porcine, more preferably an equine, bovine, ovine, or porcine. In yet another preferred embodiment the mammal is a mammal that possesses bait, preferably selected from porcine, ovine, feline or canine. The method of the present invention comprises administering an effective amount of one or more psychomotor stimulants selected from the group consisting of xanthines, and amphetamines. The term "xanthines" is commonly used in the art to refer to xanthine derivatives. Thus, the terms "xanthines" and "xanthine derivatives" are judged to be synonymous and therefore, may be used interchangeably herein. The most abundant and widely used xanthine derivatives are methyl xanthines. Thus, more preferably, according to the invention said xanthines are methyl xanthines. Suitable examples of methyl xanthines include caffeine, theobromine, theophylline, aminophylline, emprophylline, diphiline, pentoxifylline and paraxanthine.

The term "amphetamines" as used herein, refers to amphetamine and a group of compounds with pharmacological properties similar to amphetamines. The term "amphetamines" includes thus, amphetamine, dextroamphetamine, methylphenidate, fenfluramine and methyl amphetamine. The present invention also encompasses the use of salts, complexes and pharmaceutically acceptable and / or edible derivatives of the psychomotor stimulants herein, precursors of the psychomotor stimulants herein that are metabolized to the psychomotor stimulant after administration as well as bio metabolites. -actives of psychomotor stimulants of the present. The edible and / or pharmaceutically acceptable salts may include for example non-toxic acid addition salts formed from the psychomotor stimulant and an organic or inorganic acid recognized in the art as providing pharmaceutically acceptable non-toxic acid addition salts of these compounds , which are formed, for example, theophylline hydrochloride and amphetamine hydrochloride. Since the aqueous solubility of xanthines tends to be low, the reference to xanthines herein also includes derivatives and complexes of the same soluble in water. For example, the term theophylline includes the water-soluble aminophylline compound, which is formed by the combination of theophylline with ethylenediamine (2: 1). Suitable examples of substances that metabolize methamphetamine or amphetamine in the body include amphetaminyl, benzfetamine, clobenzorex, deprenyl, dimethylamphetamine, ethylamphetamine, famprofazone, fencamine, phenethylline, fenproporex, furfenorex, mefenorex, mesocarb, and prenylamine. Theophylline, theobromine, and paraxanthin which, as mentioned above, are psychomotor stimulants themselves, are also metabolites of caffeine. Thus, where the description of a psychomotor stimulant is mentioned, its salts and / or its precursors, and / or bio-active metabolites are also included. According to a preferred embodiment, the psychomotor stimulant herein is a xanthine, preferably a methyl xanthine. Contrary to amphetamines, xanthines do not induce euphoria, patterns of stereotyped behavior or a psychotic state. Xanthines and amphetamines can pass the placental barrier. As mentioned above, several methyl xanthines have been used clinically as tocolytic and adverse side effects with respect to the newly born have not been reported so far. Accordingly, it is particularly preferred to use one or more methyl xanthines according to the method herein. In addition, caffeine, theophylline, and para-xanthine are routinely used in children born (prematurely) as a safe and effective means to treat apnea (eg, Gannon).; Neonatal Netw, 19 (8): 33-36, 2000). The transmission of methyl xanthines from the mother to the offspring should not be considered a risk for the newborn and can now also improve the chances of survival of the newborn. Accordingly, in a particularly preferred embodiment of the present invention the method comprises administering caffeine, theophylline, paraxanthin or mixtures thereof to the parturient mammal. As mentioned herein, xanthines have a variety of pharmacological effects, some of which may contribute advantageously to reduce delays in the birth process and some of which can be described as tocolytic. The hypothesis is considered that different trajectories, that is, different molecular mechanisms, are involved in these different pharmacological effects, that is, antagonistic actions of adenosine and inhibitory effects of phosphodiestearase. In accordance with the present invention it is particularly preferred to use xanthines which are relatively potent adenosine receptor antagonists and / or relatively weak phosphodiesterase inhibitors. Accordingly, according to a preferred embodiment, the psychomotor stimulant is a xanthine selected from the group of caffeine, theophylline, para-xanthine and mixtures thereof. In accordance with a more preferred embodiment, the one or more psychomotor stimulants are selected from caffeine, theophylline and mixtures thereof. The relative potencies of methyl xanthines as found naturally such as caffeine, theophylline and para-xanthine as adenosine receptor antagonists and phosphodiesterase inhibitors can be modulated by replacing the substituent at positions 1-, 3- and 7- thereof. Some of these analogs, therefore, may be particularly suitable for use in the method herein. Caffeine and theophylline analogs which are known to be the most potent adenosine receptor analogues and relatively weak phosphodiesterase inhibitors, include for example, 1, 7- dimethyl-3-propargyl xanthine, 3,7-dimethyl-1-propargyl xanthine and 1, 3, 7- tripropargyl xanthine [Choi et al; Life Sci. 43: 387-98 (1988)]. The use of such analogs is also encompassed by the present invention. According to the invention, the method comprises administering the psychomotor stimulant of the present to said placental mammal in order to reduce maternal and / or uterine exhaustion during delivery. As explained hereinabove, uterine and / or maternal exhaustion becomes particularly relevant towards the end of the first stage (dilation of the cervix) and during the second stage (expulsion of the fetus) from the birth process. Accordingly, it is particularly preferred that the peak plasma levels of the one or more xanthines and / or amphetamines are reached during or immediately after the transition period from the first to the second stage and before the transition from the second to the third stage. stage. Accordingly, in accordance with a preferred embodiment the method comprises administering the one or more psychomotor stimulants during the interval beginning 12 hours before the onset of labor and ending at the time of birth of the fetus. More preferably, the method comprises administering the one or more psychomotor stimulants during the interval between dilation of the cervix and the time of birth of the first neo-nate.

Without wishing to adopt it, it is hypothesized that, due to the pharmacokinetic properties of xanthines, especially caffeine, found in pregnant sows, to administer the effective amount of the one or more xanthines 4 to 10 hours or more, preferably 6 to 8 hours before the The beginning of labor may represent the most preferred and optimal treatment method, as will be illustrated in later examples. However, it will be clear to those skilled in the art, it can be difficult to exactly comply with this optimal, precise regime. Accordingly, other sub-optimal regimes may be applied without departing from the scope of the invention. In accordance with the present invention, "an effective amount" refers to an amount that is sufficient to cause a beneficial therapeutic effect. In the method of the present, said beneficial effect, refers to any physiological and / or psychological effect that leads to the reduction of the delay or interruptions in the birth process. Such physiological and / or psychological effects may involve, for example, the ability of the mother to voluntarily contract the diaphragm and abdominal muscles, the possibility of uterine contraction, and the perception of the mother's effort. Especially in mammals that have baits, the effects of exhaustion can be recognized by the increase in intervals between subsequent births. Those skilled in the art will recognize that the effective amount of the one or more stimulants used in the method herein may vary in accordance with factors such as physiological state., age, and weight of the subject, and the ability of the specific active compound to elicit a desired response in the subject. Thus, dosing regimens can be determined and adjusted by veterinary and medical personnel to provide the optimal therapeutic effect.

In addition, an effective dosage is one in which any of the toxic or detrimental effects of the active compound are weighted by the therapeutically beneficial effects. In accordance with one embodiment of the invention wherein the psychomotor stimulant herein is an amphetamine, the peak plasma concentration does not exceed 1 mM, preferably does not exceed 100 μ. according to a particularly preferred embodiment the plasma concentration ranges from 0.01 mM-1 lmM, preferably from 0.1-100 μ? so that the dosage to be administered ranges from 0.001 to 10 mg / kg for 5 hours, preferably 0.01 to 1 mg / kg for 5 hours, more preferably from 0.05 to 0.5 mg / kg for 5 hours.

In a particularly preferred embodiment, the psychomotor stimulant herein is a xanthine, more preferably a methyl xanthine, and an effective amount is an amount that is sufficient to reach a plasma concentration at which tocolytic effects are weighted by the advantageous effects that they result from cardiovascular stimulation, increasing the contractility of the skeletal muscle and / or stimulation of the central and peripheral psychomotor function. Even more preferably, the effective amount of the one or more methyl xanthines does not exceed an amount necessary to reach the plasma threshold level for physiological effects mediated by the inhibition of phosphodiestearases. Accordingly, in a first preferred embodiment wherein the method of the present invention comprises administering caffeine, it is preferred that the plasma concentration of caffeine and its pharmacologically active metabolites does not exceed 500 μ ?, preferably not exceeding 100 μ. It is even more preferred that said plasma concentration varies from 1 to 50 μ ?. Thus, said method preferably comprises administering caffeine in a dosage of 0.01 to 10 mg / kg of body weight for 12 hours, more preferably 0.05 to 10 mg / kg of body weight, more preferably 0.1 to 7 mg / kg of body weight. Bliss Dosage can be given as either a rapid / immediate release formulation or a slow release / controlled formulation. According to another equally preferred embodiment wherein the method of the present invention comprises administering para-xanthine, the plasma concentration of para-xanthine and its pharmacologically active metabolites does not exceed 500 μ ?. It is even more preferred that said plasma concentration ranged from 1 to 50 μ ?. Thus, said method preferably comprises administering para-xanthine in a dosage of 0.01 to 10 mg / kg of body weight for 12 hours, more preferably 0.05 to 10 mg / kg of body weight, more preferably 0.1-7 mg / kg of weight bodily. In accordance with yet another embodiment, wherein the method of the present invention comprises administering theophylline, the plasma concentrations of theophylline and its pharmacologically active metabolites did not exceed 500 μ ?. It is even more preferred that said plasma concentration varies from 1 to 50 μ ?. Thus, said method preferably comprises administering theophylline at the dosage of 0.01 to 10 mg / kg of body weight for 12 hours, more preferably 0.05 to 10 mg / kg of body weight, more preferably 0.1 to 7 mg / kg of body weight.

According to a particularly preferred embodiment, the method of the present invention comprises the co-administration of one or more additional active ingredients selected from Ca2", Mg2, K +, Zn2 +, Na +, phosphate, sulfate, chloride, vitamin K, vitamin E, nicotinic acid. , carnitine, taurine, and ascorbic acid According to an even more preferred embodiment, the present invention comprises the co-administration of two or more, more preferably three or more and more preferably four or more of said additional active ingredients. The Ca2 +, g2 +, K +, Zn2 +, Na +, phosphate, sulfate and / or chloride are preferably co-administered in the form of their salts, such as NaCl, KC1, MgSO4, CaHP04 and ZnSO4. It was found that the efficiency of the present psychomotor stimulant by reducing the delay in the birth process as a result of uterine and / or maternal exhaustion could be further improved by the co-administration of these additional ingredients. According to a particularly preferred embodiment, the present invention comprises the co-administration of K +, Ca2 + and / or Mg2 +, more preferably the method comprises the co-administration of K ~, Ca2 + and Mg2 +.

Preferably the additional ingredients mentioned above are administered together with the one or more psychomotor stimulants, even more preferably they are administered in an individual preparation. According to a particularly preferred embodiment, the method of the present invention comprises the co-administration of NaCl in an amount of between 0.02 to 20 mg / kg, preferably 0.1 to 10 mg / kg of body weight, KC1 in an amount of 0.02 to 20. mg / kg of body weight, preferably 0.1 to 10 mg / kg of body weight, MgSO4 in an amount of 0.1 to 50 mg / kg, preferably 0.5 to 30 mg / kg of body weight. CaHP04, in an amount of between 0.2 to 250 mg / kg, preferably 1 to 100 mg / kg of body weight. ZnSO4 in an amount of 0.01 to 50 mg / kg, preferably 0.05 to 20 mg / kg of body weight, ascorbic acid in an amount of between 0.002 to 25 mg / kg, preferably 0.01 to 5 mg / kg of body weight, taurine in an amount of between 0.2 to 100 mg / kg, preferably 1 to 50 mg / kg of body weight, carnitine in an amount of 0.01 to 25 mg / kg, preferably 0.05 to 5 mg / kg of body weight, nicotinic acid in an amount between 0.002 to 25 mg / kg, preferably 0.01 to 5 mg / kg of body weight, vitamin E in an amount of between 0.01 to 25 mg / kg, preferably 0.05 to 5 mg / kg and / or vitamin K in an amount between 0.001 to 5 mg / kg, preferably 0.005 to 1 mg / kg of body weight. In addition, the inventors found that the efficiency of the present method can be further improved if the creatinine is administered to the mother in the days preceding delivery. Creatinine is involved in the metabolism of high-energy phosphate, which acts as an "energy regulator" inside the cell. Thus, the energy generated in the form of TFA (5 '- adenosine triphosphate) can be temporarily transferred to creatinine that forms phosphoryl creatinine. Therefore, this energy reserve can be used at the time of high energy demand or when the oxygen supply is reduced. Creatinine thus facilitates intense physical activity to persist longer. Accordingly, in accordance with a particularly preferred embodiment, the method of the present invention comprises loading the mother with creatinine in the days preceding delivery. More particularly, the method of the present invention comprises administering an effective amount of creatinine in the period of 100 days to 1 hour before parturition, more preferably in the period of 50 days to 12 hours before parturition, more preferably in the period of 20 to 1 days before delivery. Preferably the total amount of creatinine administered during said range varies from 0.01 to 100 g / kg, more preferably 0.05 to 50 g / kg, more preferably 0.1 to 10 g / kg. According to an even more preferred embodiment, the method comprises administering creatinine in a dosage regimen of 0.001 to 10 g / kg for 24 hours, more preferably 0.01 to 5 g / kg for 24 hours, more preferably 0.05 to 1 g / kg. for 24 hours during that interval. In accordance with the present invention it is preferred that the one or more psychomotor stimulants and optionally the one or more additional ingredients present, are administered via the oral, buccal, rectal, transdermal, subcutaneous or intravenous route. More preferably the one or more psychomotor stimulants are administered via the oral route. Accordingly, suitable compositions comprising the one or more psychomotor stimulants for use in the method herein may be a solid, a liquid, a paste, or a gel. Solid form preparations include powders, tablets, dispersible granules, capsules, sachets, and suppositories. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, stabilizers, lubricants, suspending agents, binders, energy sources, or tablet dispersing agents, it can also be an encapsulating material. In powders, the carrier is a finely divided solid that is a mixture with the finely divided active component. In tablets and suppositories the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the desired shape and size. The powders, tablets and suppositories preferably contain 0.01% to about 70% of the active component. Suitable carriers are carbohydrates such as lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, or a low melting point wax and the like. Liquid form preparations include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of active compounds can be mentioned as an example of liquid preparations suitable for parenteral administration. The liquid preparations can be formulated in aqueous propylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water, together with a viscous material. Preferably, the formulation is in the form of a paste or a gel, ie a thickened or gelatinized aqueous composition comprising as a carrier a mixture of water and a thickening or gelatinizing agent. Suitable examples of thickening and / or gelling agents include fumed silica, glycerin, hydrocolloid polysaccharides such as carrageenans, alginates, pectins, agar, cellulose and cellulose derivatives, starches, glucan, curdlan, and thickening and / or gelatinising proteins such as gelatin and caseinates. The proportion of water and thickeners used will depend on the specific type of thickeners used and the exact viscosity or gel strength desired. Typically, the carrier will comprise at least 0.1% by weight, preferably at least 0.5% by weight, more preferably at least 1.0% by weight, more preferably at least 2.5% by weight of said thickener and / or gelatinizing agent. The amount of water can vary from 5 - 99.9% by weight based on the total weight of the carrier.

According to a particularly preferred embodiment, the active ingredient of the present invention is provided in a carrier comprising mono-, di- and / or trisaccharides. The mono-di- and trisaccharide, in addition to providing a suitable carrier in admixture with water, can at the same time serve as a source of energy which may further assist the efficiency of the method herein. Typically, in case the carrier comprises mono-, di- and / or trisaccharides, they are incorporated in an amount of at least 1.0% by weight, preferably 2.5% by weight, more preferably 5% by weight, based on the total weight of the carrier In addition, the carrier may comprise additional ingredients such as preservatives, humectants, substances to improve taste or odor, agents for improving texture and / or substances that improve the appearance of the composition. Preferably the active components present, ie the one or more psychomotor stimulants, optionally combined with the additional active ingredients, as well as the creatinine (optional), are provided in preparations in unit dose formulations. In said formulation, the active ingredients are provided in physically discrete units suitable as unit dosage, each unit containing a predetermined amount of said active ingredients. Thus, typically, a composition comprising the active ingredient is divided into unit doses containing fixed and appropriate amounts of said ingredient (s) which are packaged as discrete units. Packaged preparations may contain one or more of these discrete quantities. Suitable examples include tablets or suppositories in a pack of vesicles or liquids, pastes, gels and powders in vials or ampoules or other types of containers. Based on the dosages described hereinbefore, the person skilled in the art will be able to determine appropriate amounts, depending on the (average) body weight of the mammal for which the unit dosage form is provided. According to a particularly preferred embodiment, the composition herein is a nutraceutical. The term "nutraceutical" is commonly used in the art and is usually defined as an "isolated or purified product from food, and generally marketed in medicinal forms not usually associated with food and demonstrated to have a physical benefit or provide protection against chronic diseases. " Caffeine, theophylline, and theobromine They are found naturally and can be found in several plant species. The nutraceuticals of the present may for example comprise extracts of said vegetables. In accordance with a particularly preferred embodiment, the composition of the present invention comprises green tea extract (Camellia sinensis extract), preferably containing at least 1% caffeine. A particularly preferred embodiment concerns a composition in the form of a paste or a gel, said composition comprising 0.01-70% by weight, more preferably 0.05-50% by weight, even more preferably 0.1-20% by weight, of one or more psychomotor stimulants of the present and at least 30% by weight, preferably at least 50% by weight, more preferably at least 80% by weight, and more preferably at least 95% by weight, of a carrier, as described previously in the present. According to a more preferred embodiment, the composition herein further comprises one or more additional ingredients selected from Ca2 ~, Mg2 ~, K +, Zn2 ~, Na +, phosphate, sulfate, chloride, vitamin K, vitamin E, nicotinic acid, carnitine , taurine and ascorbic acid, as defined hereinabove.

Preferably, the aforementioned composition is in a unit dosage form, as explained hereinabove. Thus, typically the present invention is a unit dose comprising at least 10 mg of the one or more psychomotor stimulants, preferably at least 20 mg, more preferably at least 50 mg. An even more preferred embodiment of the present invention concerns a composition as described hereinbefore administration to placental mammals, preferably selected from primates, equines, cattle, sheep, goats, cervinos, camelids, porcine, feline, and canine. Even more preferably the invention concerns a nutraceutical preparation in unit dose formulation for administration to large animals that tend to dystocia such as equines, cattle, sheep, and pigs so that a unit dose comprises the one or more psychomotor stimulants in an amount of at least 100-2000 mg, preferably 200-1500 mg, more preferably 500-1000 mg. Another aspect of the present invention concerns a kit comprising at least one preparation containing a unit dose of the psychomotor stimulant herein as described hereinabove as well as at least one preparation that contain a unit dose of creatinine. Preferably said equipment comprises at least 2, more preferably at least three and more preferably at least preferably at least four of said preparations. Containing a unit dose of creatinine. Such equipment can be conveniently used in a method of facilitating delivery in humans or farm animals as described hereinabove. Another aspect of the present invention concerns a kit comprising at least one preparation containing a unit dose of the psychomotor stimulant herein as described hereinabove, as well as a preparation comprising an active component that can be used for induce labor. The active component that can be used to induce labor is preferably selected from the group consisting of oxytocins, prostaglandins, anti-progestogens, and relaxin. Such equipment can be conveniently used in a method of facilitating delivery in farm animals. It provides the particular advantage that labor can be induced at the moment staff is present to find out that the animals receive the psychomotor stimulant of the present at the exact moment.

The invention will be further illustrated by means of the following non-limiting examples. EXAMPLES Example 1 A nutraceutical composition according to the present invention was prepared in the form of a paste for oral administration, using green tea extract. The nutraceutical was provided in a unit dose form suitable for use in sows having an average body weight of about 250 to 400 kg. Thus, each unit dose comprises 4.0 g of Green Tea extract comprising 10% by weight of caffeine, said extract is mixed uniformly with 41 g of a carrier composition containing, based on the total weight of the carrier, 57% by weight of water, 28% by weight of glycerin, 5% by weight of glucose syrup, and 10% by weight of sorbitol. gS04, CaHP04, KC1 were also incorporated into the composition according to the invention. The unit doses obtained were packed in separate containers and can be used appropriately in accordance with the invention. Unit doses can be administered in portions once or in several during the birthing process.

Another nutraceutical composition according to the invention was prepared in the same manner, except that 1.8 g of a 50% green tea caffeine extract was used instead of 4.0 g of the extract containing 10% by weight of caffeine, so that that each unit dose comprised approximately 900 mg of caffeine instead of 400 mg. Example 2 In commercial swine production, typically 8% by weight of the fetuses are aborted, and 12% of the neo-born piglets die before weaning (SIVA, 2005). Oxygen deprivation during the birth process is a major causal factor for both abortion and neonatal mortality. An indicator for oxygen deprivation is the umbilical pH (blood). This pH is typically 7.4, but after oxygen deprivation the CO 2 accumulates in the blood and tissues resulting in a drop in pH. If this fall is severe enough, it will result in the death of the fetuses. A moderate fall in pH may not be lethal but may inflict enough metabolic damage that affects the health and opportunities of the newborn and thus their chances of survival. The umbilical pH measurements confirmed that the pH falls when the duration of delivery increases. Previous work by Randall (1971) has showed a good correlation between the umbilical pH and the viability of the piglets (Figure 1). The temperature of infrared radiation is another indicator of the metabolic health of a mammal. A strong correlation between infrared temperature and survival opportunities for neo-native pigs has been shown. The infrared temperature was obtained by collecting the piglets at birth, drying them immediately, and measuring the temperature by infrared rays. In a first experiment, 7 sows received a suppository comprising caffeine (1-2 mg / kg body weight, 0 400-600 mg) after the birth of the first piglet in a bait. The health rates of the piglets as described above were compared with those of a control group of 6 piglets. It was found that due to the administration of caffeine to the lechoncillo, the umbilical (blood) pH increased with 0.044 + 0.020 units (P = 0.03) and the radiation temperature increased with 0.60 ± 0.29 ° C (P = 0.4). The range of births among subsequent piglets increased significantly by 9 minutes for each hour in calving (P <0.01) in control sows, while they were not affected by time from the start of labor in sows that received caffeine (numerical increase of 3.6 minutes for each hour in childbirth, P = 0.11). This trial showed that caffeine improved the health indexes in piglets that previously showed to be correlated with the survival of the piglets. Example 3 In a second experiment, 19 sows received 400 mg of caffeine contained in paste for oral ingestion, according to the invention, after the birth of the first piglet while 19 sows served as untreated controls. It was shown that the caffeine administration resulted in an abbreviated time interval between the birth of the first and the tenth piglets in each litter, decreasing from an average of 159 minutes for the controls at 110 minutes for the treated animals. The distributions in the time parameter were significantly different between these two groups of animals, with controls that showed a deviated distribution and strong kurtosis. Practically, some untreated animals released their litter expeditiously and with few problems, but there was a substantial number of mothers for whom the birth became a prolonged process. In the treated animals, a distribution much closer to normal and with a lower mean was observed suggesting that an average delivery proceeded much faster but there were also fewer sows with excessively prolonged deliveries. EXAMPLE 4 Compositions according to the invention, which comprised pure green tea extract or caffeine that was added as such, in amounts sufficient to provide either 470 or 490 mg of caffeine, were administered to 16 pregnant sows (at mid-gestation) . Blood samples were collected pre-administration and at multiple time points post-administration through a vein catheter in the ear so that the uptake of caffeine in the blood (serum) could be modeled. Along with the level of caffeine, the levels of its main metabolites paraxanthin, theophylline, and theobromine were determined. Prior to the administration of the treatment compositions the animals had very low levels of the different methyl xanthines in their blood. The average values were 0.04 mg / 1 for caffeine and theobromine, and 0.01 mg / 1 for theophylline. These data suggest that conventional pig feed contains minimal amounts of methyl xanthines.

After administration of the treatment compositions, a distribution of two caffeine compartments was observed: the first compartment showed a very fast uptake and loss over time, which was considered the hypothesis that represents the uptake of caffeine from the intestines in blood after which it slowly balances with the rest of the body. This set was not modeled. The second compartment exhibited a much slower uptake and decay over time. For the second compartment, the peak blood concentration was observed 8 hours post-administration. This was almost 5 μ? for caffeine and 3 μ? for green tea when 940 mg of caffeine was administered (and half that for the 470 mg dose), suggesting that the different bioavailability between compositions based on green tea and pure caffeine. Based on the assumption that distributed caffeine distributed itself in 60% of the body mass of the animals, the bioavailability was estimated at 44% for caffeine and 28% for green tea, the bioavailability for green tea was equal to approximately 60% of caffeine. It was also found that the average plasma half-life of caffeine was longer than that which had been previously expected. The mean plasma half-life of Caffeine was statistically the same as for all products at approximately 22 hours, which is significantly longer than that reported in literature for non-pregnant sows. Differences in the elimination of caffeine under hormonal influence in other mammalian species, for example during the menstrual cycle, during pregnancy or during hormonal treatment such as contraceptive treatment or hormone replacement therapies, have been previously reported. The observed increase in plasma half-life may therefore, without wishing to adopt this theory, be attributable to hormonal effects. Assuming that the expulsion of the fetuses is the period during which the exhaustion of the parturient sow presents the greatest risk, and that caffeine has its maximum effect during this process, it was concluded that the optimal time of administration of the treatment composition is approximately 6 to 8 hours before the start of labor. Example 5 The treatment method according to the present invention was further tested at the Provini research station in Velddriel, in the Netherlands, between birthing groups. At the Velddriel facilities the deliveries were not attended by veterinary staff and the deliveries were not so actively managed. The proportions of stillbirths and mortality are thus in line with commercial practices. The sows were assigned to treatment based on parity. All, the 27 sows served as controls and 29 were treated in accordance with the present invention when they were expected to hatch in the next 8 hours. The treated sows were administered 900 mg of caffeine contained in a paste for oral ingestion, according to the invention. The control sows had 0.89 stillbirths per dead bait (without identification of the cause) or were euthanized for being slightly weak after calving. In contrast, in the treated group 0.31 piglets per bait were aborted and 0.48 piglets per bait died or were euthanized because they were weak after calving. In order to assess whether caffeine was transferred from the mother to the piglets, blood samples were collected from several piglets at birth and samples of colostrum were taken. Analysis of these samples showed that caffeine was transferred to the piglet in utero and also via colostrum. The concentrations found were dependent on the time in relation to dosing the treatment composition. For piglets at birth, they were "roughly" a quarter of the concentration in the mother at the time point, and in milk were "roughly" one sixth of the concentration in the mother at the time point. The observed values were in the range of 0.1 to 1.5 mg / 1. Example 6 The treatment method according to the present invention was further tested in a well-managed farm in Bieganow, Poland. In these facilities the deliveries were attended by veterinary personnel and the deliveries were actively managed. As a result, the proportions of stillbirths were extremely low (0.33 piglets per litter or 3% of the piglets). On this farm, 89 sows, which included a calving group, were available for the test. These sows were assigned to receive either a paste containing 900 g of caffeine according to the invention or no treatment, based on parity, body condition, and historical results. The treatment composition was orally administered to the selected sows when they were expected to hatch in the next 8 hours.

Probably, as a result of this active management there were no significant statistical differences in stillbirths between the two treatment groups. However, there was a higher proportion of care (26%) in the control group than in the treated group (18%). In the control group, seven sows required postpartum medical care (one of which died) while no sow required medical care in the control group. It was observed that the treated group consumed more post-partum food. This is probably the result of the birthing process that had been less stressed. The increase was 14% on the first day postpartum and 10% for the first five days postpartum. At weaning, the pigs in the treated pigs were 9% heavier than the controls, more likely as a result of this increase in food intake compared to the control group.

Claims (14)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore the content of the following is claimed as property: CLAIMS

1. - Use of a psychomotor stimulant characterized in that it is selected from the group consisting of xanthines and amphetamines in the manufacture of a composition for use in a method of treating or preventing uterine and / or maternal exhaustion in a parturient mammal.

2. Use according to claim 1, characterized in that the psychomotor stimulant is selected from caffeine, theobromine, theophylline, paraxanthin, aminophylline, emprophylline, amphetamine, methylphenidate, fenfluramine, methyl amphetamine, and mixtures thereof, preferably caffeine. , theophylline, paraxanthine and mixtures thereof.

3. Use according to claim 1 or 2, characterized in that the psychomotor stimulant is selected from caffeine, theophylline and mixtures thereof.

4. - Use according to any one of the preceding claims, characterized in that the The method comprises administering said psychomotor stimulant to said mammal during the interval beginning 12 hours prior to the start of labor and ending at the time of the birth of the last fetus.

5. Use according to any one of the preceding claims, characterized in that the method comprises the administration of an effective amount of creatinine in the period from 100 days to 1 hour before delivery.

6. - Use according to any one of the preceding claims, characterized in that the method comprises oral, buccal, rectal, transdermal, subcutaneous, or intravenous administration of the composition, preferably oral administration.

7. - Use according to any one of the preceding claims, characterized in that the mammal is a human.

8. Use according to any one of the preceding claims, characterized in that the mammal is a primate, equine, bovine, ovine, caprine, cervino, camelid, feline, canine or porcine.

9. - Use according to any one of claims 1 to 5, characterized in that the mammal is not a human mammal, preferably a mammal that have bait such as a pig, sheep, feline, or canine.

10. Use according to any one of the preceding claims, characterized in that the method comprises the co-administration of one or more additional ingredients selected from Ca2", Mg2, K1, Zn2, Na, phosphate, sulfate, chloride, Vitamin K , Vitamin E, nicotinic acid, carnitine, taurine and ascorbic acid

11. - A composition in the form of a paste or a gel, said composition is characterized in that it comprises 0.1 to 20% by weight of one or more psychomotor stimulants selected from xanthines and amphetamines and at least 30% by weight of a carrier comprising a mixture of water and a thickening and / or gelatinizing agent

12. The composition according to claim 11, characterized in that it additionally comprises one or more additional active ingredients. selected from Ca2 ~, Mg2", K +, Zn2 +, Na +, phosphate, sulfate, chloride, Vitamin K, Vitamin E, nicotinic acid, carnitine, taurine, and ascorbic acid; and a carrier comprising a mixture of water and a sugar.

13. - A device characterized in that it comprises at least one preparation that contains a unit dose of a psychomotor stimulant selected from the group of xanthines and amphetamines and at least one preparation comprising an active component selected from the group consisting of oxytocins, prostaglandins, anti-progesterones and relaxin.

14. A team characterized in that it comprises at least one preparation containing a unit dose of a psychomotor stimulant selected from the group consisting of xanthines and amphetamines and at least one preparation containing a unit dose of creatine.