Effects of tocolytic drugs (isoxsuprine hydrochloride) during the implantation period in pregnant sheep.

In this study, the effects of isoxsuprine hydrochloride applied 14 and 15 days after insemination in Anatolian Merino Sheep on lamb yield and some blood parameters were investigated. The research was conducted during the breeding season and 54 ewes inseminated on the same day were used. The ewes were assigned to three groups. Group I: For the placebo effect, physiological saline was injected on the 14th day into half of the control group and on the 15th day into the other half after insemination (n=18). Group II: Tocolytic drug was injected on the 14th day after insemination (n=18). Grop III: Tocolytic drug was injected on the 15th day after insemination (n=18). As the tocolytic drug, isoxsuprine hydrochloride (HCl) 3 ml (Utelax, Sanovel, Türki̇ye) was used intramuscularly. The number of pregnant and viviparous ewes, single and multiple birth ewes, lambs per viviparous ewes were determined as reproductive parameters. Blood progesterone, cortisol and calcium concentration were determined. As a result, it was determined that the single application of isoxsuprine hydrochloride (3 ml) in the implantation period did not have a positive or negative effect on reproductive parameters, and did not change the blood progesterone, calcium and cortisol concentration in ewes.

Topical Isoxsuprine in experimentally induced hypertrophic scar in rabbits.

Hypertrophic scars are pathological scars which result from exaggerated skin proliferation following a wound and injury. Although many theories have been implicated for keloidogenesis, the precise pathophysiological cause is still masked. Different treatment strategies have been tried in their management, but there is no satisfactory option for treating hypertrophic scar currently; moreover the standard steroid therapy is associated with numerous local side effects, and there is a need for researches in new treatment options. The aim of this study is to evaluate the role of topical isoxsuprine in experimentally induced hypertrophic scar in rabbits. In the current experimental study, 40 healthy male albino rabbits between 12 and 14 months of age were studied. These rabbits were categorized into five groups: healthy animal group (n = 8), hypertrophic scar without treatment (n = 8), hypertrophic scar treated with triamcinolone acetonide gel (n = 8), and hypertrophic scar treated with isoxsuprine gel (n = 8). Histological assessment of skin biopsy, including the conventional hematoxylin and eosin stain, and immunohistochemistry for transforming the growth factor beta 1 level (TGF-ß1) and collagen 3 alpha1 (COLIIIαI) in skin tissue was done. The immunohistochemical score of TGF-ß and collagen III was highest in group 2 (hypertrophic scar without treatment), followed by group 3 (hypertrophic scar treated with triamcinolone acetonide gel) and group 4 (hypertrophic scar treated with isoxsuprine gel) - no significant difference between them since p > 0.05, and then by group 1 (healthy control group). Regarding histopathological scores of inflammation, the scar height, and scar index, the scores were highest in was highest in group 2 (hypertrophic scar without treatment), followed by group 3 (hypertrophic scar treated with triamcinolone acetonide gel) and group 4 (hypertrophic scar treated with isoxsuprine gel) - no significant difference between them since p > 0.05, with the exception of index of scar, and then by group 1 (healthy control group). It was concluded that isouxoprine in a topical formulation greatly reduced inflammation and scar formation in deep wounds in a manner comparable to that seen with triamcinolone.

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.

Comparing the predictability of different chemometric models over UV-spectral data of isoxsuprine and its toxic photothermal degradation products.

Isoxsuprine (ISX) is widely used for cerebral and peripheral vascular diseases. A comparative study was held among different multivariate calibration models for selective determination of a complex mixture of Isoxsuprine and four of its toxic photothermal degradation products that impair kidney and liver functions. The Partial Least Squares (PLS) and Artificial Neural Network (ANN) models were applied on the specific spectrum and on selected wavelengths using genetic algorithm (GA) technique as an efficient variable selection tool. The effect of GA on the model construction and performance was evaluated. The multilevel multifactor experimental design was adopted for the construction of the calibration set. Optimized parameters were used for the development of the different models. The performances of the developed models were assessed by predicting the concentration of eight different mixtures composing the validation set. Results were compared to one another and to the official method using one-way ANOVA statistical test to assure the validity of the constructed models. The lower chance of overfitting offered by ANN minimized the RMSEP relative to the PLS. On the other hand, the application of GA prior to model implementation affected the number of latent variables the prediction ability of both PLS and ANN models. The validated models were successfully applied as stability indicating assay methods for the selective determination of ISX and its photothermal degradation products in ISX raw material and market formulations.

Vasodilation Elicited by Isoxsuprine, Identified by High-Throughput Virtual Screening of Compound Libraries, Involves Activation of the NO/cGMP and H2S/KATP Pathways and Blockade of α1-Adrenoceptors and Calcium Channels.

Recently, our research group demonstrated that uvaol and ursolic acid increase NO and H2S production in aortic tissue. Molecular docking studies showed that both compounds bind with high affinity to endothelial NO synthase (eNOS) and cystathionine gamma-lyase (CSE). The aim of this study was to identify hits with high binding affinity for the triterpene binding-allosteric sites of eNOS and CSE and to evaluate their vasodilator effect. Additionally, the mechanism of action of the most potent compound was explored. A high-throughput virtual screening (HTVS) of 107,373 compounds, obtained from four ZINC database libraries, was performed employing the crystallographic structures of eNOS and CSE. Among the nine top-scoring ligands, isoxsuprine showed the most potent vasodilator effect. Pharmacological evaluation, employing the rat aorta model, indicated that the vasodilation produced by this compound involved activation of the NO/cGMP and H2S/KATP signaling pathways and blockade of α1-adrenoceptors and L-type voltage-dependent Ca2+ channels. Incubation of aorta homogenates in the presence of isoxsuprine caused 2-fold greater levels of H2S, which supported our preliminary in silico data. This study provides evidence to propose that the vasodilator effect of isoxsuprine involves various mechanisms, which highlights its potential to treat a wide variety of cardiovascular diseases.

Binding interaction of isoxsuprine hydrochloride and levothyroxine to milk ß-lactoglobulin; from the perspective of comparison.

Isoxsuprine hydrochloride (ISO) and levothyroxine (LEV) are medicines which can be utilized alone or simultaneously by pregnant women. The purpose of this work is to investigate the separate and simultaneous interaction of ISO and LEV with ß-LG. The results showed that both drugs can bind to ß-LG; the static quenching was suggested for fluorescence quenching mechanism of ß-LG.The values of binding constants (Kß-LG-ISO = 2.69 × 104 M-1, Kß-LG-LEV = 0.54 × 103 M-1 and Kß-LG-ISO-LEV = 2.18 × 103 M-1 at 310 K) suggested that ISO has stronger binding affinity toward ß-LG than LEV and affinity of ß-LG to LEV is increased in the presence of ISO while the presence of LEV has no significant effect on the affinity of protein to ISO. Thermodynamic parameters showed that the binding of LEV to ß-LG are hydrogen bonding and Van der Waals forces but the formation of ß-LG-ISO is hydrophobic associations. The results of FT-IR and UV-visible measurements indicated that the binding of both drugs to ß-LG may induce conformational changes of protein. In silico molecular docking analyses confirmed that ISO and LEV binds to residues located at site I and site II of ß-LG, respectively.

Binding Studies of Isoxsuprine Hydrochloride to Calf Thymus DNA Using Multispectroscopic and Molecular Docking Techniques.

In the present work, the interaction of Isoxsuprine (ISX) with Calf thymus DNA (ct-DNA) under physiological conditions (Tris-HCl buffer of pH 7.4) was investigated by using electronic absorption, circular dichroism, viscosity, electrochemical studies, fluorescence techniques, salt effect studies and computational studies. Competitive fluorimetric studies with Hoechst 33258 have shown that ISX exhibit the ability to displace the DNA-bound Hoechst 33258, indicating that it binds to ct-DNA in strong competition with Hoechst 33258 for the minor groove binding. Furthermore, the resulting data showed that ISX cannot displace methylene blue or acridine orange, which are the common intercalator molecules. The viscosity of ct-DNA solution was almost unchanged on addition of ISX and circular dichroism (CD) spectra of ct-DNA showed small changes in the presence of ISX which is in agreement with groove binding mode of interaction. Thus all above studies showed that the ISX drug binds to ct-DNA in a groove binding mode.The salt-effect studies showed the non-electrostatic nature of binding of ISX to ct-DNA. Moreover, molecular docking results support the above experimental data and suggest that ISX prefers to bind on the minor groove of ct-DNA.

Comparative Study Between Zero-Order Spectra-Processing and Ratio Spectra-Manipulating Methods Applied for the Determination of Isoxsuprine Hydrochloride in the Presence of Its Oxidative Degradation Product.

Four accurate, precise, and validated stability-indicating spectrophotometric methods handling either zero-order spectra or ratio spectra have been developed and compared for the analysis of isoxsuprine hydrochloride (ISX) in the presence of its oxidative degradation product. The first two methods processed zero-order spectra, namely graphical absorbance ratio or Q-Analysis and area under the curve, whereas the third and fourth methods manipulated ratio spectra, namely the ratio difference spectrophotometric method and derivative ratio. The proposed methods showed good linearity in the range of 2-23 µg/mL. The methods were tested for specificity using laboratory-prepared mixtures containing the drug and its degradation product. The proposed methods were applied for the determination of ISX in Vascular tablets and the obtained results were acceptable, with small percentage RSD values. The validity of the proposed procedures was further assessed by applying the standard addition technique, which showed no interference from excipients. The obtained results were statistically compared with those obtained by the reported method, showing no significant differences when t- and F-tests were applied.

Exploring isoxsuprine hydrochloride binding with human serum albumin in the presence of folic acid and ascorbic acid using multispectroscopic and molecular modeling methods.

Isoxsuprine hydrochloride (vasodilator drug), folic acid and ascorbic acid are medicines which can be utilized alone or simultaneously by pregnant women. In the present work the competitive binding of isoxsuprine hydrochloride (ISO) with human serum albumin (HSA) in the absence and presence of folic acid (FOL) and ascorbic acid (AS) was investigated using different spectroscopic probes and molecular docking studies. The results of fluorescence suggested that isoxsuprine alone or in the presence of ascorbic acid can bind to HSA and quench the fluorescence of HSA with static mechanism but For HSA-folic acid-isoxsuprine system, dynamic type of quenching mechanisms is involved. The values of binding constants (KHSA-ISO~1.2×103M-1, KHSA-AS-ISO~2.1×103M-1and KHSA-FOL-ISO~0.7×103M-1) suggested that affinity of HSA to isoxsuprine increased in the presence of ascorbic acid while the presence of folic acid reduced the affinity of protein to isoxsuprine. The results of FT-IR and circular dichroism measurements indicated that the binding of isoxsuprine to HSA in the absence and the presence of folic acid and ascorbic acid may induce conformational and microenvironmental changes of protein. Not only do these types of spectroscopy techniques provide all the information about the systems, molecular docking, also emphasizes the results and is employed for the identification of the active site residues, bioactive conformer of Isoxsuprine and their critical interactions.

Spectrofluorimetric determination of certain adrenergic agonist drugs in their pure forms and pharmaceutical formulations: Content uniformity test application.

A new, simple, sensitive and rapid spectrofluorimetric method has been developed for determination of certain adrenergic agonists such as isoxsuprine hydrochloride, ritodrine hydrochloride and etilefrine hydrochloride in their pure forms and pharmaceutical dosage forms. The method depends on micellar enhancement of the native fluorescence of investigated drugs by using 2% w/v sodium dodecyl sulfate (SDS) as an anionic surfactant. The enhanced fluorescence intensity of investigated drugs was measured at 305 nm after excitation at 278 nm. The interaction of studied drugs with SDS was studied, and the enhanced fluorescence intensity was exploited to develop an assay method for the determination of investigated drugs. The relative fluorescence intensity-concentration plots were rectilinear over the range 0.15-3.00 µg ml-1 , with low quantification limits of 0.132, 0.123 and 0.118 µg mL-1 for isoxsuprine, ritodrine and etilefrine, respectively. The proposed method was successfully applied for determination of studied drugs in their pharmaceutical formulations. Moreover, the high sensitivity of the proposed method allows performing the content uniformity testing of the studied drugs in their tablets by using the official United States Pharmacopeia (USP) guidelines. Statistical comparisons of the results with those of the reported methods revealed excellent agreement and indicated no significant difference in accuracy and precision.

35Cl dynamic nuclear polarization solid-state NMR of active pharmaceutical ingredients.

In this work, we show how to obtain efficient dynamic nuclear polarization (DNP) enhanced 35Cl solid-state NMR (SSNMR) spectra at 9.4 T and demonstrate how they can be used to characterize the molecular-level structure of hydrochloride salts of active pharmaceutical ingredients (APIs) in both bulk and low wt% API dosage forms. 35Cl SSNMR central-transition powder patterns of chloride ions are typically tens to hundreds of kHz in breadth, and most cannot be excited uniformly with high-power rectangular pulses or acquired under conditions of magic-angle spinning (MAS). Herein, we demonstrate the combination of DNP and 1H-35Cl broadband adiabatic inversion cross polarization (BRAIN-CP) experiments for the acquisition of high quality wideline spectra of APIs under static sample conditions, and obtain signals up to 50 times greater than in spectra acquired without the use of DNP at 100 K. We report a new protocol, called spinning-on spinning-off (SOSO) acquisition, where MAS is applied during part of the polarization delay to increase the DNP enhancements and then the MAS rotation is stopped so that a wideline 35Cl NMR powder pattern free from the effects of spinning sidebands can be acquired under static conditions. This method provides an additional two-fold signal enhancement compared to DNP-enhanced SSNMR spectra acquired under purely static conditions. DNP-enhanced 35Cl experiments are used to characterize APIs in bulk and dosage forms with Cl contents as low as 0.45 wt%. These results are compared to DNP-enhanced 1H-13C CP/MAS spectra of APIs in dosage forms, which are often hindered by interfering signals arising from the binders, fillers and other excipient materials.

Effects of isoxsuprine hydrochloride on electrocardiographic and trace element status in sheeps.

OBJECTIVE: To study the effect of isoxsuprine hydrochloride on the ischaemic electrocardiographic change and trace element status in sheep. METHODS: This study was conducted from March 16 to 23, 2012, at Istanbul University, Turkey, and comprised sheep aged 6 months. The animals were divided into two equal groups. The control group was fed a standard diet and had free access to water. In the experimental group, isoxsuprine hydrochloride was injected at a dose of 0.6 mg/kg through the intramuscular route. Electrocardiographic changes, including creatine kinase and cardiac troponin-I, and serum levels of selenium, copper, calcium, magnesium, iron and zinc were investigated in healthy sheep. SPSS 15 was used for statistical analysis. RESULTS: The 14 sheep were divided into two groups of 7(50%) each. The overall mean weight of the study population was 35±10kg. Selenium, calcium, iron and zinc concentrations did not show any difference in serum samples (p>0.05). However, copper and magnesium concentrations decreased in serum after the administration of the drug (p<0.05). In the experimental group, ST segment depression and abnormal T-wave was found in 6(86%) animals within 60min. CONCLUSIONS: Isoxsuprine hydrochloride increased cardiotoxicity risk in sheep.

Doppler sonographic examination of uterine and placental perfusion in cows in the last month of gestation and effects of epidural anesthesia and isoxsuprine.

The massive increase in size of the fetus and uterus in the last trimester is accompanied by an increasing demand for nutrients and oxygen, and it is assumed that this demand is met by increasing uterine and fetal perfusion. The goals of this study were to measure the perfusion of the uterine arteries and the placentomes in the last month of gestation and to investigate the effect of epidural anesthesia and isoxsuprine on perfusion. During the last month of gestation, eight Braunvieh cows underwent nine color Doppler sonographic examinations of the uterine arteries to determine diameter (DM), pulse rate (PR), resistance index, time-averaged maximum blood flow velocity (TAMV), and blood flow volume (BFV), and power-mode Doppler sonography was used to determine perfusion of placentomes. The PR increased (P < 0.001), and the BFV and TAMV of the ipsilateral uterine artery decreased between 4.5 and 0.5 weeks prepartum (BFV, 236.8 ± 65.80 and 208 ± 41.52 cm(3)/s, P < 0.01; TAMV, 140.0 ± 26.53 cm/s and 125.2 ± 18.46 cm/s, P < 0.05). After sonographic examination, the cows received epidural administration of local anesthetic (100-mg lidocaine) in the sacrococcygeal space or isoxsuprine (200 mg/cow, iv), and the sonographic measurements were repeated 30 minutes later. After epidural anesthesia, the TAMV and BFV of the contralateral uterine artery increased by 5.4% (P < 0.05) and 7.9% (P < 0.01). In the placentomes of the gravid uterine horn, the relative placentome perfusion and the color pixel grading (Cp) increased by 10.1% (P < 0.05) and 11.5% (P < 0.01) after epidural anesthesia. After isoxsuprine, the DM, PR, and BFV increased by 4.7%, 49.3%, and 16.9% in the ipsilateral uterine artery and by 10.8%, 48.7%, and 22.8%, respectively in the contralateral uterine artery. The TAMV of the ipsilateral uterine artery increased by 7.1% (P < 0.01), and the resistance index decreased in both uterine arteries (ipsilateral 24.2%, contralateral 14.9%, both P < 0.00001). Isoxsuprine increased the relative placentome perfusion and the Cp of the placentomes by 18.1% and 18.3% in the gravid horn and by 10.2% and 24.2% in the nongravid horn. Blood flow variables changed little in the last month of gestation. However, epidural anesthesia and isoxsuprine caused changes in uterine and placentome perfusion that suggest improvement of placental nutrient and oxygen supply to the fetus.

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.

Prophylactic oral betamimetics for reducing preterm birth in women with a twin pregnancy.

BACKGROUND: Twin pregnancies are associated with a high risk of neonatal mortality and morbidity due to an increased rate of preterm birth. Betamimetics can decrease contraction frequency or delay preterm birth in singleton pregnancies by 24 to 48 hours. The efficacy of oral betamimetics in women with a twin pregnancy is unproven. OBJECTIVES: To assess the effectiveness of prophylactic oral betamimetics for the prevention of preterm labour and birth for women with twin pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 September 2015), MEDLINE (January 1966 to 31 July 2015), EMBASE (January 1985 to 31 July 2015) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials in twin pregnancies comparing oral betamimetics with placebo or any intervention with the specific aim of preventing preterm birth. Quasi-randomised controlled trials, cluster-randomised trials and cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two authors assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: Overall, the quality of evidence is low for the primary outcomes. All of the included trials had small numbers of participants and few events. Preterm birth, the most important primary outcome, had wide confidence intervals crossing the line of no effect.Six trials (374 twin pregnancies) were included, but only five trials (344 twin pregnancies) contributed data. All trials compared oral betamimetics with placebo.Betamimetics reduced the incidence of preterm labour (two trials, 194 twin pregnancies, risk ratio (RR) 0.37; 95% confidence interval (CI) 0.17 to 0.78; low quality evidence). However, betamimetics did not reduce prelabour rupture of membranes (one trial, 144 twin pregnancies, RR 1.42; 95% CI 0.42 to 4.82; low quality evidence), preterm birth less than 37 weeks' gestation (four trials, 276 twin pregnancies, RR 0.85; 95% CI 0.65 to 1.10; low quality evidence), or less than 34 weeks' gestation (one trial, 144 twin pregnancies, RR 0.47; 95% CI 0.15 to 1.50; low quality evidence). Mean neonatal birthweight in the betamimetic group was significantly higher than in the placebo group (three trials, 478 neonates, mean difference 111.22 g; 95% CI 22.21 to 200.24). Nevertheless, there was no evidence of an effect of betamimetics in reduction of low birthweight (two trials, 366 neonates, average RR 1.19; 95% CI 0.77 to 1.85, random-effects), or small-for-gestational age neonates (two trials, 178 neonates, average RR 0.90; 95% CI 0.41 to 1.99, random-effects). Two trials showed that betamimetics significantly reduced the incidence of respiratory distress syndrome (388 neonates, RR 0.30; 95% CI 0.12 to 0.77), but the difference was not significant when the analysis was adjusted to account for the non-independence of twins (194 twins, RR 0.35; 95% CI 0.11 to 1.16). Three trials showed no evidence of an effect of betamimetics in reducing neonatal mortality, either with the unadjusted analysis, assuming twins are completely independent of each other (452 neonates, average RR 0.90; 95% CI 0.15 to 5.37, random-effects), or in the adjusted analysis, assuming non-independence of twins (226 twins, average RR 0.74; 95% CI 0.23 to 2.38, random-effects). A maternal death was reported in one trial without a significant difference between the groups (144 women, RR 2.84; 95% CI 0.12 to 68.57). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of prophylactic oral betamimetics for preventing preterm birth in women with a twin pregnancy.

Analysis of effect isoxsuprine hydrochloride and nicotine in the Transverse Rectus Abdominis Myocutaneous flap (TRAM) in rats.

PURPOSE: To evaluate the effects of isoxsuprine and nicotine on TRAM. METHODS: Forty eight 48 Wistar rats distributed into four Groups (n=12). All rats received medication managed daily for 20 days: saline solution (SA), nicotine solution (NI), isoxsuprine solution (IS) and nicotine solution (NI) + isoxsuprine solution (IS). On day 21st the rats were submitted to the caudally based, right unipedicled TRAM flap and after 48 hours, made the macroscopic evaluation of the surface of the flap, photographic documentation and collection of material for histology. Data from macroscopic evaluation were analyzed by ANOVA and microscopic evaluation by Kruskal-Wallis test, with significance level of 5%. RESULTS: In the macroscopic evaluation of isoxsuprine Group retail presented absolute numbers: final area (p=0.001*) and viable area (p=0.006*) with the highest values; necrosis (p=0.001*) had the lowest value. Microscopic examination revealed no significant findings in the study of TRAM under the action of isoxsuprine and nicotine to the percentage of necrosis in the left and right cranial and caudal regions. CONCLUSIONS: There was significant improvement in viability of TRAM using the isoxsuprine solution alone. No influence using nicotine alone and in association with isoxsuprine.

Analysis of effect isoxsuprine hydrochloride and nicotine in the Transverse Rectus Abdominis Myocutaneous flap (TRAM) in rats

PURPOSE: To evaluate the effects of isoxsuprine and nicotine on TRAM. METHODS: Forty eight 48 Wistar rats distributed into four Groups (n=12). All rats received medication managed daily for 20 days: saline solution (SA), nicotine solution (NI), isoxsuprine solution (IS) and nicotine solution (NI) + isoxsuprine solution (IS). On day 21st the rats were submitted to the caudally based, right unipedicled TRAM flap and after 48 hours, made the macroscopic evaluation of the surface of the flap, photographic documentation and collection of material for histology. Data from macroscopic evaluation were analyzed by ANOVA and microscopic evaluation by Kruskal-Wallis test, with significance level of 5%. RESULTS: In the macroscopic evaluation of isoxsuprine Group retail presented absolute numbers: final area (p=0.001*) and viable area (p=0.006*) with the highest values; necrosis (p=0.001*) had the lowest value. Microscopic examination revealed no significant findings in the study of TRAM under the action of isoxsuprine and nicotine to the percentage of necrosis in the left and right cranial and caudal regions. CONCLUSIONS: There was significant improvement in viability of TRAM using the isoxsuprine solution alone. No influence using nicotine alone and in association with isoxsuprine. .

Rapid analysis of ractopamine in pig tissues by dummy-template imprinted solid-phase extraction coupling with surface-enhanced Raman spectroscopy.

Ritodrine has similar skeleton structure to ractopamine and it was selected as the dummy-template molecule to synthesize the molecular imprinted polymers (MIPs). The MIPs exhibited better selectivity to ractopamine than to the dummy-template molecule: the imprint factor for ractopamine was 8.9, while 7.6 for ritodrine. The MIPs were used as sorbents in solid-phase extraction for selective enrichment of ractopamine, and some key parameters were optimized. After that, a rapid surface-enhanced Raman spectroscopy method was developed for analysis of ractopamine and isoxuprine in pig tissue samples. Under the optimal conditions, good linearity was achieved in the range of 20.0-200.0 µg/L for ractopamine and isoxsuprine at 842 cm(-1) and 993 cm(-1), respectively. The limits of detection were 3.1-4.3 µg/L, which were lower than the maximum allowed by U. S. Food and Drug Administration. The recoveries of ractopamine and isoxsuprine were 72.4-79.7% and 71.0-78.2% for the spiked pork and pig liver, respectively, while the relative standard deviations ranging from 7.4% to 13.0%. The results suggest that the proposed method is sensitive and selective, and it has good potential on the quantitative analysis of trace amounts of ß-agonists in complex samples.

Resolution and isolation of enantiomers of (±)-isoxsuprine using thin silica gel layers impregnated with L-glutamic acid, comparison of separation of its diastereomers prepared with chiral derivatizing reagents having L-amino acids as chiral auxiliaries.

Thin silica gel layers impregnated with optically pure l-glutamic acid were used for direct resolution of enantiomers of (±)-isoxsuprine in their native form. Three chiral derivatizing reagents, based on DFDNB moiety, were synthesized having l-alanine, l-valine and S-benzyl-l-cysteine as chiral auxiliaries. These were used to prepare diastereomers under microwave irradiation and conventional heating. The diastereomers were separated by reversed-phase high-performance liquid chromatography on a C18 column with detection at 340 nm using gradient elution with mobile phase containing aqueous trifluoroacetic acid and acetonitrile in different compositions and by thin-layer chromatography (TLC) on reversed phase (RP) C18 plates. Diastereomers prepared with enantiomerically pure (+)-isoxsuprine were used as standards for the determination of the elution order of diastereomers of (±)-isoxsuprine. The elution order in the experimental study of RP-TLC and RP-HPLC supported the developed optimized structures of diastereomers based on density functional theory. The limit of detection was 0.1-0.09 µg/mL in TLC while it was in the range of 22-23 pg/mL in HPLC and 11-13 ng/mL in RP-TLC for each enantiomer. The conditions of derivatization and chromatographic separation were optimized. The method was validated for accuracy, precision, limit of detection and limit of quantification.