Development and Validation of a Stability-Indicating UPLC Method for the Determination of Hexoprenaline in Injectable Dosage Form Using AQbD Principles.

A novel and efficient stability-indicating, reverse phase ultra-performance liquid chromatographic (UPLC®) analytical method was developed and validated for the determination of hexoprenaline in an injectable dosage form. The development of the method was performed using analytical quality by design (AQbD) principles, which are aligned with the future requirements from the regulatory agencies using AQbD principles. The method was developed by assessing the impact of ion pairing, the chromatographic column, pH and gradient elution. The development was achieved with a Waters Acquity HSS T3 (50 × 2.1 mm i.d., 1.8 µm) column at ambient temperature, using sodium dihydrogen phosphate 5 mM + octane-1-sulphonic acid sodium salt 10 mM buffer pH 3.0 (Solution A) and acetonitrile (Solution B) as mobile phases in gradient elution (t = 0 min, 5% B; t = 1 min, 5% B; t = 5 min, 50% B; t = 7 min, 5% B; t = 10 min, 5% B) at a flow rate of 0.5 mL/min and UV detection of 280 nm. The linearity was proven for hexoprenaline over a concentration range of 3.50-6.50 µg/mL (R2 = 0.9998). Forced degradation studies were performed by subjecting the samples to hydrolytic (acid and base), oxidative, and thermal stress conditions. Standard solution stability was also performed. The proposed validated method was successfully used for the quantitative analysis of bulk, stability and injectable dosage form samples of the desired drug product. Using the AQbD principles, it is possible to generate methodologies with enhanced knowledge, which can eventually lead to a reduced regulatory risk, high quality data and lower operational costs.

[Peculiarities of treatment of ulcerative gastrointestinal hemorrhage in pregnant women].

The occurrence rate of gastrointestinal hemorrhage (GIH) of nonvaricosal genesis in pregnant women was analyzed. The risk of complications occurrence in the pregnancy course while performing local endoscopic hemostasis and prophylaxis of the hemorrhage recurrence occurrence was established. Application of elaborated treatment method for GIH of nonvaricosic genesis in pregnant women have promoted reduction of the severe complications rate in the pregnancy course, applying elimination of the vasoconstrictor and uterotonic effects of adrenalin, reduction of esophagogastroduodenoscopy duration. While application of this procedure in pregnant women of a main group operative cessation of GIH was not applied. In a comparison group a hemostasis, using operative way, was done in 2 (13.3%) women patients with subsequent occurrence of preeclampsy, what resulted in antenathal fetal death.

Arg16 homozygosity of the beta2-adrenergic receptor improves the outcome after beta2-agonist tocolysis for preterm labor.

BACKGROUND: Beta(2)-adrenergic receptor (beta(2)AR) agonists are not consistently successful when administered as tocolytic therapy. The beta(2)AR displays genetic variability; an arginine-to-glycine substitution at codon 16 (Arg16Gly) has been shown to increase receptor desensitization in response to agonist exposure, whereas a substitution of glutamate for glutamine at codon 27 (Gln27Glu) decreases down-regulation. We have demonstrated that homozygosity for Arg16 protects against preterm delivery. Our goal was to determine whether beta(2)-agonists are more effective in women with the Arg16 genotype and preterm labor. METHODS: Sixty white women with preterm labor between 24 and 34 weeks' gestation were treated for 48 hours with intravenous hexoprenaline. The effect of tocolysis and outcome of pregnancy were recorded. The beta(2)AR genotypes at codons 16 and 27 of ADRB2 were determined. A control group of 116 women delivered at term was also genotyped. RESULTS: Preterm labor was not associated with beta(2)AR genotype at codon 16 (17% of patients with preterm labor were Arg16 homozygotes versus 19% of control subjects) or codon 27. Gestation was significantly prolonged in Arg16 homozygotes (median, 69 days; interquartile range, 63-79 days) compared with the other 2 genotypes (median, 58 days; interquartile range, 2-72 days) (P = .04). Tocolysis was 100% successful in delaying delivery for 48 hours in Arg16 homozygotes (n = 10), just failing to achieve statistical significance (P = .069). In contrast, only 37 of 50 women carrying 1 or 2 glycine alleles (74%) had delivery delayed by more than 48 hours with tocolysis. Neonatal outcomes were significantly better in babies born to mothers homozygous for arginine than in women with 1 or 2 Gly16 alleles. CONCLUSIONS: This is the first study examining the pharmacogenetics of beta(2)AR agonist therapy for preterm labor. It appears that Arg16 homozygosity improves pregnancy outcome after beta(2)-agonist tocolysis. The relatively low frequency of Arg16 homozygotes in our population limited the power of this investigation. Future assessments of tocolytic therapy may need to assess beta(2)AR genotype.

[The use of Gynipral (hexoprenaline) in suppression of uterus contractions]. / Zastosowanie gynipralu (hexoprenaliny) w hamowaniu czynnosci skurczowej macicy.

OBJECTIVE: The aim of of this study was to estimate the effectiveness and tolerance of Gynipral (hexoprenaline)-beta-2 sympathomimetic used as oral and intravenous tocolytic. MATERIAL AND METHODS: We analysed 110 pregnant women admitted to the hospital with premature uterus contractions between 17 and 37 week of pregnancy. Pregnant women were divided into two groups. Group I--86 patients with regular uterus contractions. In this group Gynipral was administered to suppress uterus contractions. Group two consisted of 24 patients without regular uterus contractions. In this group women were treated with Gynipral to keep pregnant uterus in maximum relaxation in such cases as IUGR, oligohydramnion, after Strassman procedure before pregnancy or cerclage procedure in current pregnancy. Group I was treated with intravenous Gynipral infusion and after suppression of uterus contractions the way of administration was changed into oral. Group II from the beginning was treated with oral tocolysis with Gynipral. Pregnant women were continually under CTG control and all ailments such as tachycardia, flapping tremor and anxiety were analysed and noted. RESULTS: Gynipral has effectively suppressed premature uterus contractions in 80 cases in group I (93%) and in 24 cases in group II (100%). In 106 cases (96%) patients have not presented any side effects. CONCLUSIONS: Gynipral is an effective tocolytic successfully used in premature labor treatment. Gynipral has a good tolerance administered both intravenously and orally as well and in most cases there was no need to add antiarrhythmic drugs to reduce side effects.

[beta 2-Adrenomimetics before and after extracorporeal lithotripsy]. / beta 2-Adrenomimetiki do i posle distantsionnoi litotripsii.

Successful disintegration of the calculus in nephrolithiasis patients is impossible without normalization of the upper urinary tracts urodynamics in dyskinesia. We employ combined treatment with high-selective beta-2-adrenomimetic hexoprenalin (hinipral) to improve migration of the concrement fragments and therefore to prevent ureteral occlusion, acute pyelonephritis and renal colic. Hexoprenalin (hinipral) is taken 6 tablets a day or intravenously in drops (5 ml per 100 ml of saline) 3-5 days before and for 10-12 days after extracorporeal shock-wave lithotripsy. Adjuvant use of hexoprenalin in combined treatment of nephrolithiasis complicated by ureteropelvic dysfunction allows effective conduction of lithotripsy.

Randomized, double blind, placebo controlled comparison of ritodrine and hexoprenaline for tocolysis prior to external cephalic version at term.

External cephalic versions in the study period were performed in a double blind design by 2 experienced practitioners. Sixty-three patients were allocated to treatment with either placebo, ritodrine or hexoprenaline. The main outcome measure studied was successful completion of external cephalic version. Hexoprenaline, but not ritodrine, was statistically more likely to be associated with successful version than placebo (p = 0.04 versus p = 0.22).

The extrapulmonary effects of inhaled hexoprenaline and salbutamol in healthy individuals.

We have investigated the cardiovascular and metabolic effects of multiple inhaled doses of salbutamol and hexoprenaline in 12 healthy volunteers. They inhaled 200 micrograms of salbutamol or hexoprenaline at 15 min intervals for 60 min from a metered dose inhaler (total dose 1000 micrograms). We measured heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval on the ECG, and plasma potassium at baseline, 10 min after each inhalation, and 30 and 60 min after the last inhalation. There was no difference in the effects of the two drugs on blood pressure, total electromechanical systole, or QTc interval. Salbutamol significantly increased heart rate compared with hexoprenaline. Hexoprenaline caused a significantly greater fall in plasma potassium compared with salbutamol.

[The significance of prostaglandin F2 alpha (PGFM)--and plasma oxytocin level in patients with premature labor]. / Zur Bedeutung von Prostaglandin F2 alpha (PGFM)--und Oxytocinplasmaspiegel bei Patientinnen mit vorzeitigen Wehen.

In the present study, plasma oxytocin and prostaglandin F2 alpha metabolite (PGFM) concentrations were measured in 46 patients admitted for preterm labour. Gestational age ranged from 20-34 weeks. Samples were collected 12 hours before and after initiation of tocolysis. Patients with a premature rupture of the membranes and/or intra-amniotic infection were excluded in this study. There was a significant difference in the oxytocin (p = 0.05) and PGFM levels (p = 0.007, after 12 hours: p = 0.004) between a control group without preterm labour and women with preterm labour. No differences were seen between the successfully treated (delivery more than 5 days after start of tocolysis) and the failure group. There was no significantly different increase or decrease in PGFM and Oxytocin plasma levels between treatment failures and successfully treated patients.

[Tocolysis in the first half of pregnancy]. / Tokolyse in der ersten Schwangerschaftshälfte.

This study includes a total of 60 gravidae with a pregnancy between 8 and 17 weeks of gestation and the signs of threatened abortion (contractions and bleeding). The sonographic examination had shown in 14 patients no gestational sac in the uterus; in 6 patients a deformed gestational sac; in 5 patients a fetus without signs of vitality. In all these patients curettage was performed. In 32 gravidae a therapy seems to be successful: in terms of bedrest and the administration of 0.33 mcg/min Hexoprenaline as a continuous infusion. In only 3 patients an abortion occurred before the end of the 20th week of gestation. In 29 gravidae pregnancy continued undisturbed.

[Hemodynamic changes during tocolysis with hexoprenaline and fenoterol]. / Hämodynamische Veränderungen bei der Wehenhemmung mit Hexoprenalin und Fenoterol.

The authors examined two groups of 50 patients each who had been given an average dose of 0.24 microgram/min Hexoprenaline or respectively 1.8 micrograms/min Fenoterol as beta-mimetics for premature labor. The patients who received Fenoterol were also given Verapamil as additional medication in a ratio of 1 : 40. In addition to blood pressure, heart rate, urine elimination and serum or urine osmolarity, the hemodynamic parameters stroke volume, cardiac output and total peripheral resistance were investigated. Stroke volume was measured by means of impedance cardiography. Giving equipotent doses, Hexoprenaline/Fenoterol dose ratio of 1 : 8, there was a slower and smaller increase in heart rate over 24 hours with Hexoprenaline, with identical suppression of uterine contractility (external tocography). This was also reflected in the cardiac output, while there were no differences in the stroke volumes. Inhibition of diuresis was lower with Hexoprenaline. This might be due to the fact that since there is no organ specificity for beta-1 or respectively beta-2 receptors and the patterns of distribution differ, Hexoprenaline has a somewhat less pronounced action on beta-1 receptors than Fenoterol, though the same beta-2 action.

Decrease of serum oestriol during intravenous hexoprenaline or salbutamol treatment.

Patients with premature labour were treated with intravenous hexoprenaline (18 patients) or salbutamol (10 patients) infusion between 26 and 36 weeks gestation. After at least 12 h infusion, oral therapy was started. Serum total oestriol was determined by radioimmunoassay every 6 h during intravenous beta-mimetic infusion (p less than 0.005). One day after stopping intravenous treatment, and then every day after stopping the infusion, for 4 days. The mean serum total oestriol concentration decreased significantly during the intravenous treatment, serum oestriol returned to pretreatment levels. The results show that fetal monitoring by maternal oestriol determinations is not reliable during intravenous beta-adrenoceptor agonist therapy.

[Bronchodilation in childhood asthma bronchiale (author's transl)]. / Broncholyse beim kindlichen Asthma.

The bronchodilation in childhood asthma bronchiale was studied by means of the suitable form of administration for that age, the paediatric syrup. We have chosen as active substance the hexoprenaline which has a long standing as a modern beta-2-selective bronchodilator. 2 different doses confirm a good effect and provide some margin, which is highly welcome, especially so in paediatry. The paper corroborates the importance of the measurement of the obstruction even in this age to confirm the diagnosis and the proposed therapy, we have used the optimal body plethysmography for that purpose. The plotting of the obstruction-pressure curve, which is a prerequisite for the calculation of the resistance, however, presents some methodical difficulties in infantile patients. The former statement of a possible sole information on the obstruction via the beta-flow curve was confirmed in a regression equation, it allows an about 80% significant determination of the resistance even without the alpha-curve.

Prevention of urological complications after radical operation of cervical carcinoma.

Cervical carcinomas of stage Ib and II have been treated for extended radical therapy by radioisotope radical surgery at the First Department of Obstetrics and Gynecology, University of Vienna, Austria. This extension of a more radical surgery requires to take measures in order to prevent urological and other postoperative complications. Chromocystoscopy, intravenous urography and functional scintigraphy of the kidney are carried out as routine preoperative investigations. Preservation of the adureter and an exact drainage of the field of operation are taken as intraoperative measures. Main emphasis of postoperative prophylaxis is the stimulation of ureter activity by distigminbromide and hexoprenaline. Distigminbromide stimulates the prevesical part of the ureter and increases the number of urinary excretions into the bladder. Hexoprenaline is a betamimetic substance which increases both local blood flow and number of ureter contractions. In addition, treatment by antibiotics, thrombosis prophylaxis with heparin and marcoumar and urine drainage by catheter are performed during surgery. The results of 187 radioisotope radical operations show that an uretero vaginal fistula was observed ruly in one patient (0.53%). Hydronephrosis was registered in 10 females (5.3%) and 42 subjects (22.5%) lack of bladder feeling was noted and incontinence was observed in 22 patients (11.8%) in the postoperative period.

Hexoprenaline pharmacokinetics in pregnant and nonpregnant sheep.

Hexoprenaline, a beta 2-sympathomimetic agent, is used to suppress uterine contractions in the treatment of premature labor. However, little is known regarding the potential of this drug to undergo placental transfer or whether the pregnant state alters any of the pharmacokinetic parameters. Using sheep as a model, intravenous doses of 14C-hexoprenaline were administered to pregnant and non-pregnant animals. Measurable levels of radioactivity did not appear in fetal blood samples. After intravenous bolus administration, blood concentrations in the ewe could be fitted by a triexponential curve characteristic of a three-compartment pharmacokinetic model. Following intravenous infusion, a biexponential curve described the decline in blood concentrations. Mean terminal half lives for total radioactivity ranged from 2.5 to 4.2 hours. The pregnant animals tended to exhibit smaller apparent volumes of distribution and lower values for total body clearance, normalized to body weight, compared to non-pregnant sheep.