Evaluation of the comparative influence of magnesium sulfate single and combination with ritodrine hydrochloride in the prevention of preterm delivery / Avaliação da influência comparativa de sulfato de magnésio único e combinação com cloridrato de ritodrina na prevenção de parto prematuro

This project was designedto explore the effects of ritodrine hydrochloride combined with magnesium sulfate in the prevention of preterm delivery of patients with threatened premature birth. 128 cases of threatened premature birth were randomly divided into two groups according to the number table method. The control group was treated with magnesium sulfate, while the study group was treated with ritodrine hydrochloride combined with magnesium sulfate. The data (p > 0.05) was analyzed using SPSS 18.0 and was subjected to Chi-square and t-test. The onset time and prolonged gestation time of the study group were shorter than those of the control group (p < 0.05). There was no difference in the incidence of myocardial ischemia between the study group and the control group (p > 0.05). The heart rate per minute of the study group was higher than that of the control group (p < 0.05). There was no difference in blood pressure between the study group and the control group. Nevertheless, the neurological function, pregnancy outcome, and neonatal status of the group were better than those of the control group (p < 0.05).(AU)

Este projeto foi desenvolvido para explorar os efeitos do cloridrato de ritodrina combinado com sulfato de magnésio na prevenção do parto prematuro de pacientes com risco de nascimento prematuro. 128 casos de nascimento prematuro ameaçado foram divididos aleatoriamente em dois grupos, de acordo com o método da tabela numérica. O grupo de controle foi tratado com sulfato de magnésio, enquanto o grupo de estudo foi tratado com cloridrato de ritodrina combinado com sulfato de magnésio. Os dados (p > 0,05) foram analisados pelo SPSS 18.0 e submetidos ao teste do qui-quadrado e ao teste t. O tempo de início e o tempo prolongado de gestação do grupo de estudo foram menores que os do grupo de controle (p < 0,05). Não houve diferença na incidência de isquemia miocárdica entre o grupo de estudo e o grupo de controle (p > 0,05). A frequência cardíaca por minuto do grupo de estudo foi superior à do grupo controle (p < 0,05). Não houve diferença na pressão arterial entre o grupo de estudo e o grupo de controle. No entanto, a função neurológica, o resultado da gravidez e o status neonatal do grupo foram melhores do que os do grupo de controle (p < 0,05).(AU)

The Synergic In Vitro Tocolytic Effect of Nifedipine Plus Ritodrine on Human Myometrial Contractility.

Many pharmacological agents have been investigated to manage preterm labor; we postulate that a combination of tocolytic drugs may achieve a better effect in the prevention of uterine contractions without dose-dependent adverse effects. The aim of this study was to evaluate the inhibitory effect of dual combinations of tocolytics in vitro. Human myometrium was obtained during elective cesarean sections (term without labor; n = 40). Myometrial strips were placed in organ baths for the measurement of isometric tension. Contractile activity was induced by oxytocin (10-8 mol/L), then a concentration-response curve to single or dual combinations of tocolytics was started. All studied tocolytics (nifedipine, ritodrine, nitroglycerin, atosiban, and NS-1619), when used alone, significantly inhibited myometrial contractions. When combined, nifedipine plus ritodrine produced a significantly greater inhibition of contractility than each drug alone in the midrange of concentrations. The combination of nifedipine plus nitroglycerin or nifedipine plus atosiban produced a significantly greater inhibition than nitroglycerin or atosiban alone but not greater than nifedipine. The combination of nifedipine plus NS-1619 (Ca+2-activated K+ [BKCa] channel opener) reduced the inhibitory effect of each drug. We concluded that a selected combination of tocolytics (nifedipine plus ritodrine) produced a significantly greater inhibitory effect on contractility than each drug alone at intermediate concentrations. Thus, specific combinations of tocolytics with different intracellular signaling pathways may have a synergic effect constituting a provocative new option for preterm labor treatment.

Sperm transport and retention at the fertilization site is orchestrated by a chemical guidance and oviduct movement.

In mammals, only a few spermatozoa arrive at the fertilization site. During the last step in the journey to the egg, apart from their self-propulsion, spermatozoa may be assisted by oviduct movement and/or a guidance mechanism. The proportion of rabbit spermatozoa that arrive at the fertilization site was determined under in vivo conditions, in which either the ovulation products (secreting chemoattractants) and/or the oviduct movement (causing the displacement of the oviductal fluid) was inhibited. When only one of these components was inhibited, sperm transport to the fertilization site was partially reduced. However, when both the ovulation products and the oviduct movement were inhibited, almost no spermatozoa arrived at the fertilization site. The results suggest that spermatozoa are transported to and retained at the fertilization site by the combined action of a chemical guidance and the oviduct movement. A working model is proposed to explain how these two mechanisms may operate to transport spermatozoa to the fertilization site, probably as an evolutionary adaptation to maximize the chance of fertilizing an egg.

Nifedipino versus ritodrina en la amenaza de parto pretérmino / Nefidipine versus ritodrine in threatened preterm labor

OBJETIVO: Comparar la eficacia, tolerancia y seguridad del nifedipino con la ritodrina, en la amenaza del parto pretérmino. MATERIAL Y MËTODOS: ensayo clínico aleatorio que, entre los años 1998 y 1999, estudió 70 mujeres con gestación única a quienes se les distribuyó al azar en 2 grupos de 35 pacientes, para ser tratadas con ritodrina o nifedipino. LUGAR: Hospital Sergio E Bernales de Collique, hospital docente. RESULTADOS: El tiempo de prolongación de la gestación fue de 13,3 más menos 9,8 días para ritodrina y nifedipino, respectivamente. Los pesos del recién nacido fueron 2259 más menos 805 g para ritodrina y 2392 más menos 828 g para nifedipino (p=NS). El 94 por ciento de pacientes tratados con ritodrina tuvo uno o más efectos colaterales, mientras sólo 28,5 por ciento del grupo nifedipino tuvo molestias (p=0,00001). Fueron efectos colaterales producidos por ritodrina taquicardia materna y fetal, temblores, cefalea, palpitaciones, mareos; el nifedipino produjo hipotensión, cefalea y mareos. CONCLUSION: En el tratamiento de la amenaza de parto pretérmino, el nifedipino es tan efectivo como la ritodrina y está asociado a mucho menos efectos colaterales.

OBJETIVE: To compare efficacy, tolerance and safety nifedipine with ritodrine in the treatment of preterm labor. DESIGN: Randomized clinical essay. SETTING: “Sergio E Bernales” Hospital teaching hospital. MATERIAL AND METHODS: Between 1998 and 1999 70 women with single pregnancy were randomly assigned to two 35 patients groups to be treated with either nifedipine or ritodrine. RESULTS: Gestation was prolonged 13.25 more less 9,8 days with ritodrine and 16,9 more less 10,4 days with nifedipine. Gestational age at birth were respectively 34,9 more less 3,8 weeks and 35,3 more less weeks with ritodrine and nifedipine; newborn weights were 2259 more less 805 g for ritodrine and 2392 more less 828 g for nifedipine (p=NS). One or more collateral effects were found 94 per cent of patients trated with ritodrine (maternal and fetal tachycardia, shakings, palpitations, headache, vertigo) and only in 28,5 per cent in the nefidipine group, including hypotension, dizziness and headache (p=0,00001). CONCLUSION: Nifedipine is as effective as ritodrine in the treatment of preterm labor, but is associated to less collateral effects.

Antibiotic treatment in preterm labor and intact membranes: a randomized, double-blinded, placebo-controlled trial.

Although an association between microbial invasion of amniotic cavity and preterm birth has been extensively demonstrated, there is conflicting evidence regarding the benefits of antibiotic therapy in patients with preterm labor and intact membranes. We attempted to assess the efficacy of amoxicillin and erythromycin on pregnancy outcome in those patients. A randomized, double-blinded, placebo-controlled trial was designed and implemented. A total of 196 patients with singleton pregnancies and preterm labor with intact membranes (22-36 weeks) were randomly allocated to receive either antibiotics or placebo, plus adjunctive parenteral tocolysis, and 173 patients (antibiotics group n = 83 vs. placebo group n = 90) completed the treatment. The overall prevalence of microbial invasion of the amniotic cavity was 5.2% (9/173). No significant difference between both groups was found in maternal outcomes, including duration of randomization-to-delivery interval, frequency of preterm delivery, and frequency of clinical chorioamnionitis and endometritis. Rate of cesarean section was significantly higher in the placebo group (28% vs. 12%). Regarding neonatal outcome, no significant difference was detected between both groups in neonatal death, respiratory distress syndrome, proven sepsis, and birthweight. Suspected sepsis was significantly more frequent in the placebo group (6/90 vs. 0/78). The results of this trial indicate that amoxicillin and erythromycin do not prolong pregnancy in patients with preterm labor and intact membranes. A significant reduction in the rate of cesarean section was observed in patients receiving antibiotics. A significant reduction in the rate of neonatal suspected sepsis was also demonstrated.

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women.

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.

Pharmacokinetics of ritodrine administered intravenously: recommendations for changes in the current regimen.

We define the pharmacokinetics of ritodrine in 13 pregnant women who received the drug intravenously. With constant infusion of 50 micrograms/minute, steady state ritodrine concentrations reached 28 +/- 11 ng/ml (SD) with a range of 15 to 45 ng/ml. This wide variation is a result of differences in plasma clearance, which ranged from 1.0 to 3.3 L/min, mean 1.94 +/- 0.71 L/min. The apparent volume of distribution was 6.95 +/- 3.54 L/kg, indicating that ritodrine is extensively bound to extravascular tissue. When an infusion of ritodrine is stopped, plasma concentrations fall rapidly initially with a distribution half-life of 5.9 +/- 6.0 minutes. After the initial rapid fall, plasma concentrations decrease more slowly with a mean disposition half-life of 156 +/- 51 minutes. On the basis of the pharmacokinetic parameters defined, we recommend that the current infusion regimen for ritodrine be changed. The infusion rate of ritodrine should start at 50 micrograms/minute rather than 100 micrograms/minute. The maximal infusion rate of 350 micrograms/minute should be increased and once labor is inhibited, the infusion rate should be reduced.

Pharmacokinetics of orally administered ritodrine.

The oral dosing regimen for ritodrine was based in large part on kinetic data obtained in nonpregnant subjects. There are limited kinetic data after oral administration of ritodrine in pregnancy. The purpose of the present study was to compare ritodrine kinetics in pregnant and nonpregnant women, evaluate the effect of feeding on ritodrine absorption in pregnant women, and determine if the plasma concentration of ritodrine is proportional to the dose administered in nonpregnant women. Plasma concentrations after a single 20 mg dose of ritodrine were significantly greater in fasting nonpregnant women than in fasting pregnant women. The area under the concentration time curve was 1372 +/- 385 and 1001 +/- 257 ng/ml/min, respectively. In pregnant women ingesting 20 mg of ritodrine, plasma concentrations were not significantly different in the fed or fasted state; plasma concentrations peaked at 11 ng/ml and were less than 3 ng/ml within 4 hours. In nonpregnant subjects the concentration of ritodrine in plasma was proportional to the dose. After ingestion of 10, 20, or 30 mg of ritodrine, the area under the curve was 751 +/- 253, 1372 +/- 385, and 2148 +/- 571 ng/ml/min, respectively. These data indicate that ritodrine concentrations in pregnant women after a 20 mg oral dose are low. Increases in dosage will probably result in proportional increases in plasma concentration. The maximal dose of ritodrine recommended for prevention of recurrent preterm labor should be increased.

Ventricular septal thickness and cardiac function in neonates after in utero ritodrine exposure.

Cardiac septal hypertrophy occurs after in utero ritodrine exposure. To assess the effect of septal hypertrophy on cardiac function we obtained M-mode echocardiograms on day 1 of life in 41 infants exposed to ritodrine and 22 control infants matched for gestational age. Mean duration of ritodrine exposure was 16.2 +/- 13.2 days (range 1 to 49 days). Disproportionate septal hypertrophy (DSH) was defined as an interventricular septal thickness/posterior wall thickness ratio (ST/PW) of greater than 1.3. Infants exposed to ritodrine in utero had DSH and increased right systolic time intervals compared with control values (P less than 0.05). A subgroup, those infants exposed for 2 weeks or longer, had not only DSH but also an absolute increase in septal thickness compared with control infants and infants exposed to ritodrine for less than 2 weeks. ST/PW correlated well with the duration of ritodrine exposure (r = 0.96); the longer the exposure the thicker the septum. Although all echocardiographic changes lasted for less than 3 months, we have no information regarding the effect on the fetus of maternal ritodrine exposure for longer than 7 weeks. Until such information is available, cardiac evaluation is recommended in neonates exposed to ritodrine in utero for longer than 7 weeks.

Mechanisms of beta sympathomimetic action on neonatal glucose homeostasis in the lamb.

Beta sympathomimetic drugs are used clinically to inhibit premature labor. Significant alterations in glucose homeostasis have been documented in both mother and offspring. To determine the mechanism(s) of beta sympathomimetic drugs on neonatal glucose homeostasis, ritodrine hydrochloride was infused in a newborn term lamb model of glucose kinetics by a crossover design. There was a progressive rise in plasma glucose concentration and plasma insulin concentration during ritodrine hydrochloride infusion compared with the control (saline) infusion. The rise in plasma glucose concentration was associated with a progressive rise in Ra (rate of appearance, production) and Rd (rate of disappearance, utilization). The ritodrine hydrochloride-infused animals had a progressive rise in [insulin/glucose] compared with our prior studies in the newborn lamb, suggesting direct stimulation of pancreatic beta cell secretion. In the neonatal lamb, beta sympathomimetic drugs directly stimulate both hepatic glucose production and pancreatic beta cell secretion. These effects explain, in part, why infants of mothers infused with ritodrine hydrochloride may evidence alterations in neonatal glucose homeostasis.

Effects of maternal ritodrine administration on neonatal renal function.

Because of its effects on the cardiovascular and renin-angiotensin systems and on fluid and electrolyte homeostasis, maternal administration of ritodrine to inhibit preterm labor may cause significant alterations in renal function in the newborn infant. We determined inulin clearance, plasma renin activity, urinary arginine vasopressin excretion, and serum and urine electrolyte concentrations and osmolalities at 12 to 36 hours of life and at 6 days of life in 15 infants whose mothers had received ritodrine and in 15 infants whose mothers did not (control infants). At the time of each study, plasma ritodrine concentrations were obtained in the infants whose mothers received ritodrine. The infants whose mothers had received ritodrine had significantly lower inulin clearances and higher plasma renin activity and urinary arginine vasopressin excretion on day 1 but not on day 6. Gestational age was inversely correlated with plasma ritodrine concentration, plasma renin activity, and urinary arginine vasopressin excretion. There were no overt clinical signs of renal failure in any of the infants, and no differences in serum and urine electrolyte values, osmolality, fractional sodium excretion, or urine flow rate were observed between the groups.