Effectiveness and Safety of Isoxsuprine Hydrochloride as Tocolytic Agent in Arresting Active/Threatened Preterm Labor and Its Role in Maintenance Tocolysis: A Prospective, Open-Label Study.

OBJECTIVE: The aim of the study is to obtain insights on the short and long-term safety and effectiveness of isoxsuprine hydrochloride as a tocolytic agent in the management of PTL. STUDY DESIGN: In this prospective, single-center, noncomparative study, patients (with preterm labor at gestational age of 24-37 weeks) were administered intravenous (IV) infusion of 40-mg isoxsuprine hydrochloride until uterine quiescence, followed by intramuscular (IM) injection of isoxsuprine hydrochloride 10 mg/4-hourly for first 24 hours and maintained with retard 40-mg sustained release capsule (two times a day) till the time of delivery or 37 completed weeks of pregnancy. RESULTS: All patients (n = 50) achieved successful tocolysis in 24 hours and 48 hours postadministration of isoxsuprine hydrochloride (IV/IM/oral). Mean (±SD) gestation age at the time of delivery was 39.8 ± 2.1 weeks, with latency period of 58.5 ± 18.7 days. Pregnancy outcomes were normal in all the patients and no congenital anomaly/fetal infection was reported. Mean (±SD) fetal birth weight was 2.7 ± 0.3 kg; mean (±SD) Apgar score at 1 and 5 minutes were 7.5 ± 0.6 and 9.2 ± 0.4, respectively. Maternal tachycardia and vomiting (8.0% each) were the commonly reported adverse drug reactions, which were resolved with dose adjustment. CONCLUSION: Isoxsuprine was found to be an effective and well-tolerated tocolytic agent in arresting PTL, in turn resulting in the overall improvement in maternal and perinatal outcomes.

Catalytic activity and structural changes of catalase in the presence of Levothyroxine and Isoxsuprine hydrochloride.

Two drugs that pregnant women (with hypothyroidism) may use during pregnancy include Isoxsuprine hydrochloride (ISO) and levothyroxine (LEV); ISO to reduce uterine contractions and LEV for the treatment of hypothyroidism. In the current work, we explored the mechanism of binding affinity between the above drugs and antioxidant enzyme Bovine Liver Catalase (BLC). The experimental results confirmed that both drugs could bind with BLC to form drug-BLC complexes but LEV showed a higher binding affinity toward enzyme. The binding constants of LEV-and ISO-BLC were 0.42 × 105 and 0.13 × 104 M-1 at 310 K, respectively. LEV enhanced the catalase activity but the enzymatic activity of BLC reduced gradually in the presence of ISO. Both drugs were able to induce conformational changes in the BLC structure. The results of the molecular docking investigations confirmed the experimental data and showed that the main binding forces in the LEV-BLC and ISO-BLC systems were hydrogen bond and hydrophobic force. The best binding site of both drugs on BLC is located at a cavity among the wrapping domain, N-Terminal arm, and ß-barrel.

Fetal ductus arteriosus constriction and closure: analysis of the causes and perinatal outcome related to 45 consecutive cases.

OBJECTIVE: The aim of this study was to analyze the causes and perinatal outcome related to fetal ductus arteriosus constriction or closure at a single center over a 26-year period. METHODS: This was a retrospective analysis of 45 consecutive cases of constriction (n = 41) and closure (n = 4) from 1987 through 2013. Patients were divided into Group A (maternal use of non-steroidal anti-inflammatory drugs (NSAID), n = 29), Group B (idiopathic, n = 8), and Group C (other drugs not previously described, n = 8). RESULTS: The median gestational age at diagnosis was 34 weeks (range, 27-38), mean systolic and diastolic velocity in the ductus arteriosus was 2.01 ± 0.66 m/s and 0.71 ± 0.46 m/s, respectively. Among the 29 cases of NSAIDs, 27.5% (8/29) have taken a single day use and 75% multiple days/doses. Right ventricular dilatation was present in 82.2% of the fetuses, tricuspid insufficiency in 86.6%, and heart failure in 22.2%. Neonatal persistent pulmonary hypertension occurred in 17.7% of the patients. Late follow-up showed all 43 survivors alive and healthy with only two deaths from unrelated causes. CONCLUSIONS: The results of this study indicate that clinically significant ductal constriction may follow maternal exposure to single doses of NSAIDs. Unknown causes or other new substances were also described, such as naphazoline, fluoxetine, isoxsuprine, caffeine and pesticides. Echocardiographic diagnosis of ductal constriction led to an active medical approach that resulted in low morbidity of this group of patients.

Atosiban versus betamimetics in the treatment of preterm labour in Italy: clinical and economic importance of side-effects.

The aim of this study was to determine the cost effectiveness of atosiban compared to betamimetics in the treatment of preterm labour within the Italian setting. A systematic literature review identified randomised controlled trials (RCTs) comparing atosiban with betamimetics. Meta-analysis of nine RCTs determined that atosiban and betamimetics had similar efficacy in delaying preterm birth by at least 48 h (p=0.910). Use of atosiban was associated with significantly fewer adverse events (p<0.008). Results demonstrate that atosiban is cost-saving versus ritodrine or isoxuprine. Atosiban cost savings are €657 per patient from the National Health Service payer's perspective; €299 at 18 h of tocolysis to €189 at 48 h from the hospital's perspective. The respective values versus isoxuprine were €303 and €199. From the combined perspective, using atosiban versus ritodrine saved from €425 to €316; and versus isoxuprine from €429 to €326. Owing to its superior safety profile, atosiban is cost-saving versus betamimetics in the treatment of preterm labour in Italy from the payer's, hospital's and combined perspectives. With the approximate 40,000 annual preterm births in Italy the annual savings could be in excess of €13 million for the payer or €3.8-6.2 million for the hospitals.

Tocólisis con clorhidrato de isoxuprina o nifedipina en la amenaza de parto pretérmino / Tocolysis with isoxuprine hydrochloride or nifedipine in preterm labor

Comparar la eficacia del clorhidrato de isoxuprina o la nifedipina en la tocólisis de la amenaza de parto pretérmino. Se seleccionaron 82 pacientes con edad gestacional entre 24 y 34 semanas y diagnóstico de amenaza de parto pretérmino. Las pacientes se dividieron al azar en 2 grupos para recibir clorhidrato de isoxuprina (grupo A) o nifedipina (grupo B). Se determinaron el tiempo de cese de las contracciones, tensión arterial materna, concentraciones de glucosa y efectos adversos maternos. Maternidad "Dr. Nerio Belloso", Hospital Central "Dr. Urquinaona", Maracaibo. Estado Zulia. Se logró una tocólisis efectiva en las primeras 24 horas en 61,0 por ciento y 70,7 por ciento de las pacientes del grupo A y B, respectivamente (P = ns). Después de 7 días de tratamiento, 36,6 por ciento de las pacientes en el grupo A y 31,7 por ciento de las pacientes en el grupo B aun permanecían sin contracciones (P = ns). Se logró un retraso del parto hasta las 34 semanas o más en 26,8 por ciento y 29,3 por ciento de las pacientes de los grupos A y B, respectivamente. En el grupo de pacientes tratadas con clorhidrato de isoxuprina se observó un aumento significativo de las concentraciones séricas de glucosa (P < 0,001). Los efectos adversos maternos fueron significativamente más frecuentes en el grupo de clorhidrato de isoxuprina después de 2 y 24 horas de tratamiento (P < 0,05). La nifedipina es igual de efectiva que el clorhidrato de isoxuprina en la tocólisis de la amenaza de parto pretérmino y produce menos efectos adversos

To compare the efficacy of isoxuprine clorhidrate or nifedipine in tocolysis of threatened preterm labor. 82 patients with a gestational age between 24 and 34 weeks and threatened preterm labor diagnosis were selected. Patients were randomly divided in 2 groups to receive isoxuprine clorhidrate (group A) or nifedipine (group B). Time of cease of contractions, maternal blood pressure, glucose concentrations and maternal adverse effects were determined. Maternidad "Dr. Nerio Belloso", Hospital Central "Dr. Urquinaona", Maracaibo. Estado Zulia. An effective tocolysis was obtained within 24 hours in 61.0 percent and 70.7 percent for patients in group A and B, respectively (P = ns). After 7 days of treatment, 36.6 percent of patients in group A and 31,7 percent of patients in group B were still without contractions (P = ns). A delay in labor till 34 weeks or more was made in 26.8. percent and 29.3 percent of patients in group A and B, respectively. In the group of patients treated with isoxuprine clorhidrate a significant raise of glucose concentrations was observed (P < 0.001). Maternal adverse effects were significant more frequent in isoxuprine clorhidrate group after 2 and 24 hours of treatment (P < 0,05). Nifedipine has a similar effectivity than isoxuprine clorhidrate for tocolysis in threatened preterm labor and produces less adverse effects

Pharmacokinetics of isoxsuprine hydrochloride administered orally and intramuscularly to female healthy volunteers.

Isoxsuprine (1-(4-hydroxyphenyl)-2-(1-methyl-2-phenoxyethylamino)-1-propanol, CAS 395-28-8) is a peripheral vasodilator that also stimulates beta-adrenergic receptors. It causes a direct relaxation of vascular and uterine smooth muscles and produces positive inotropic and chronotropic effects. It is widely used to arrest premature labour and miscarriage. The aim of this trial was to investigate the pharmacokinetics of isoxsuprine hydrochloride administered orally to healthy young female volunteers as an extended-release formulation at the doses of 30, 60 and 90 mg compared to 10 mg by i.m. route. A randomised, crossover, four-period, multisequence, single-dose design was adopted. Plasma and urine concentrations of free and total isoxsuprine were evaluated by tandem mass spectrometry that reached a low quantification limit of 1 ng/ml. From plasma concentrations Cmax, tmax, AUC(0-t), AUC(0-infinity), t1/2 and Vd and from urine concentration CUE(0-24h) were evaluated by the non-compartmental model. The free drug was present only in plasma after i.m. route, whereas total isoxsuprine, namely the drug after an enzymatic hydrolysis of the conjugate form, was detected in all plasma and urine samples. The distribution volume of the free drug proved to be 2.5 times higher than that of total isoxsuprine, which indicates a good penetration of the free drug into tissue compartments. Oral absorption was evaluated from the p.o./i.m. percentualized ratio of AUC and CUE and proved to be on average around 51%, being linearly correlated with the three doses administered. The oral absorption proved to be sustained as expected from the zero-order kinetics of the drug release from the core of the extended-release formulation. This has justified different values of half-life that was on average 2.2 h after the i.m. route and around 10 h after the three oral doses. After isoxsuprine administration, both oral and i.m. routes, the heart rate increased from baseline during the 9 h monitoring period. This was an expected finding attributable to the stimulating activity of beta-adrenergic receptors. The tolerability of isoxsuprine proved to be very good with all the four administrations performed.

Ritodrine and isoxsuprine in management of preterm labor.

INTRODUCTION: Preterm delivery is an important cause of perinatal morbidity and mortality. To decrease the medical and economical impact of preterm delivery, tocolytic agents are available among which isoxsuprine and ritodrine are widely used in Nepal. The study on efficacy of ritodrine and isosuprine has not been done yet in Nepelese women. So to observe on efficacy and safety of Ritodrine and Isoxsuprine, this study was conducted. METHODS: A prospective observational study was conducted with an aim to assess the efficacy and safety of Isoxsuprine 10 mg orally eight hourly versus Ritodrine 10 mg initially infused intravenously along with 5% dextrose at the rate of 10 drops per minute with an increase of 5-10 drops every 30 minutes for 24 hours and then given oral at 5-10 mg eight hourly, in patient with preterm labor requiring uterine tocolysis. RESULTS: This study found that Ritodrine is more effective and safer than Isoxsuprine in suppressing preterm labor. The failure rate of Isoxsuprine and Ritodrine were 22.22% and 6.5% respectively. The maternal side effects including cardiac side effects were significantly higher in Isoxsuprine. The cardiac side effects caused by Ritodrine can be controlled by adjusting the drip rate. Though Isoxsuprine seems more economical than Ritodrine, it is lesser cost effective to patients due to its higher failure rate, that results in added expenses in terms of increased morbidity and mortality. CONCLUSIONS: Hence, Ritodrine is superior to Isoxsuprine as it is more efficacious in managing preterm labor and increasing fetal maturity. Also the adverse effects of Ritodrine are less than those of Isoxsuprine which result in better patient compliance and cost effectiveness.

A comparative study between nifedipine and isoxsuprine in the suppression of preterm labour.

Preterm labour and delivery remains a major cause of perinatal morbidity and mortality. Numerous drugs and interventions have been used to prevent and inhibit preterm labour but none have been found to be completely effective with the choice being further limited by troublesome side effects. This study compares in a prospective and randomised design the efficacy and safety of the calcium antagonist Nifedipine with the beta mimetic Isoxsuprine. 81.25% of patients receiving Nifedipine and 70% of those receiving Isoxsuprine achieved successful tocolysis. The mean prolongation of pregnancy with Nifedipine was 25+/-19.85 days and with Isoxsuprine it was 19.18+/-17.82 days. Maternal side effects were similar in both groups with hypotension and tachycardia being the commonest. Discontinuation rates were also similar with pulmonary oedema and severe hypotension being the reasons for foregoing tocolysis. It can be concluded that Nifedipine is a safe and effective alternative to Isoxsuprine for suppressing preterm labour.

Therapeutic effects of high-dose isoxsuprine in the management of mixed-type impotence.

OBJECTIVES: To determine the effectiveness and safety of high-dose isoxsuprine for the treatment of mixed-type erectile dysfunction. METHODS: Forty-four patients who had vasculogenic impotence diagnosed on the basis of their sexual history, physical examination, laboratory analysis, polysomnographic recording of nocturnal erections, and dynamic color Doppler sonography of the cavernosal arteries were entered into a randomized, double-blind, placebo-controlled, crossover comparison of a placebo with high-dose isoxsuprine hydrochloride (60 mg/day orally). The treatment consisted of two 30-day courses. After a 14-day washout period, the patients who initially received the placebo for 30 days switched to isoxsuprine hydrochloride for 30 days and vice versa. Erectile function, ejaculation, interest in sex, and physical examination findings were investigated before treatment and at the end of each drug period. RESULTS: Thirty-six patients (82%) completed the entire treatment schedule. Positive clinical results (complete and partial responses) were obtained in 6 men (16.6%) at the end of the isoxsuprine phase and in 7 men (19.4%) after the placebo period. The statistical analysis disclosed no significant difference when isoxsuprine was compared with placebo (P >0.05). Significant drug-related adverse effects occurred in the isoxsuprine group and treatment was discontinued in 2 patients. CONCLUSIONS: Isoxsuprine is no better than placebo as a first-line treatment for mixed-type erectile dysfunction.

[Magnesium oxide and tocolysis. Our clinical experience and comparison with beta-mimetic (isoxusprine) therapy]. / Ossido di magnesio e tocolisi. Considerazioni in base alla nostra esperienza clinica e confronto con la terapia beta-mimetica (isossisuprina).

The authors propose the use of oral Magnesium Oxide in the quantity of 200 mg every 3-4 hours for the tocolytic treatment of the pre-term pain, once intravenous tocolysis has decreased or stopped uterine activity (since it has considerably more rapid effect). This treatment constitutes a valid alternative to the use of Beta Mimetic agents in all cases where their use is contraindicated. In the present study, we followed one heterogeneous group of 130 patients, suffering from premature labor hospitalized in our department. After decreasing the uterine contractions by intravenous isossuprine, sixty patients were subsequently treated with magnesium Oxide, fifty with oral isossisuprine, twenty with a simple antispasmodic and the remaining constituted the control group. The percentage of pre-term births has been almost the same in the first two groups (around 17%). The percentage of the patients who exhibited side effects of Beta Mimetic was 30-40%, against 2% of the patients treated with Magnesium Oxide. The intensity of the symptoms was however so slight in the patients treated with Magnesium Oxide, that it failed to disturb the compliance of the patients which allowed to continue the therapy for the necessary period.

Outcome of very-low-birth-weight infants exposed to beta-sympathomimetics in utero.

In this study we examined neonatal and early childhood outcomes after intrauterine exposure to beta-sympathomimetic agents on infants with birth weights less than or equal to 1500 gm. The hospital courses and anthropomorphic, developmental, and neurologic development of 201 infants exposed to one or more beta-sympathomimetic agents (isoxsuprine, 33; ritodrine, 70; terbutaline, 43; combination, 55) were analyzed and compared with those of 130 control infants of similar birth weight. One hundred and seventy-seven infants had follow-up to 1 year of age, 101 to age 3, and 58 to age 4. When treatments consisting of a single beta-sympathomimetic or no treatment were compared, there were no statistically significant overall differences found in growth and development or in most of the short-term measures of infant well-being. However, significant overall differences with no evidence of confounding by time-related effects were found for the following; mortality, none greater than terbutaline; maximum positive inspiratory pressure when respiratory distress syndrome was present, none greater than terbutaline; neonatal trauma, terbutaline greater than ritodrine. Other differences were found in conjunction with evidence of time-related confounding, or within specific time intervals. It should be noted that these differences are not necessarily due to effects of the different treatments, as the data are observational.

Transient electrocardiographic changes suggesting myocardial ischaemia in newborn infants following tocolysis with beta-sympathomimetics.

Serial electrocardiograms (ECGs) were studied prospectively in 80 apparently healthy newborn infants; 30 infants exposed in utero to prolonged tocolytic therapy (21 to ritodrine and 9 to isoxsuprine) and 50 infants non-exposed in utero to drugs (control group) matched for gestational age, Apgar score, and birth weight. Duration of exposure to tocolysis was at least 30 days (30-180 days) with an oral dosage of 10 mg 3 times daily. ECGs were graded for changes suggestive of ischaemia using the arbitrary grading system described by Jedeikin et al. In all infants with ECG features of myocardial ischaemia, serum creatine-phosphokinase iso-enzyme (CK-MB) activity was measured. Six out of 21 infants to ritodrine and six out of nine infants exposed to isoxsuprine showed a degree of ECG ischaemia which persisted for several weeks. No control infant presented grade 2 or 3 ECG changes after the 5th day of life. The results of this study seem to show that prolonged tocolytic therapy with beta-sympathomimetics has side-effects on the fetal myocardium and suggest that this treatment be reserved only for selective cases and/or for short periods of time.

Hemodynamic observations on pulmonary edema associated with a beta-mimetic agent. A report of two cases.

Pulmonary edema associated with the use of beta agonists in the treatment of preterm labor is a major risk of tocolytic therapy. The data obtained from echocardiographic and hemodynamic evaluation in one such case and echocardiography in another differ markedly from those in two previously published reports. Specifically, the pulmonary capillary wedge pressure became elevated, and both patients failed to improve with oxygen therapy and positional changes only. Left ventricular dysfunction was ruled out as the possible cause since the left ventricular structure and function were normal on echocardiography. The heart failure was probably the result of increased preload, giving rise to increased end diastolic pressure and hence pulmonary edema. Diuretic therapy is very important in this situation.

Pulmonary edema associated with isoxsuprine therapy.

A 0.5% incidence of pulmonary edema was observed when the records of 1,407 patients treated with parenteral isoxsuprine over a 7-year interval were reviewed. Drug infusion rates were within the normal range in the seven affected patients. Discontinuation of therapy, oxygenation, and the administration of diuretics with or without digoxin were successful in reversing the process in all cases. Anemia, multiple gestation, and excessive intravenous fluids were identified as possible risk factors.

Association between ruptured membranes, tocolytic therapy, and respiratory distress syndrome.

Two hundred ninety-seven patients from the placebo group of the National Institutes of Health Collaborative Study on Antenatal Steroid Therapy for prevention of respiratory distress syndrome were selected for analysis to investigate a possible association between premature rupture of the membranes, tocolytic therapy, and respiratory distress syndrome. Both premature rupture of the membranes and tocolytic therapy with isoxsuprine were individually associated with a lowered incidence of respiratory distress syndrome. However, when present together, their protective effect was not additive and resulted in a higher incidence of respiratory distress syndrome. It is suggested that the use of tocolytic therapy with beta-adrenergic agents be restricted to patients with intact membranes.