Highly sensitive and selective determination of methylergometrine maleate using carbon nanofibers/silver nanoparticles composite modified carbon paste electrode.

A highly sensitive and selective voltammetric method for determination of Methylergometrine maleate (MM) in pharmaceutical formulations, urine and blood serum samples has been developed based on enhanced electrochemical response of MM at carbon nanofibers and silver nanoparticles modified carbon paste electrode (CNF-AgNP-CPE). The electrode material was characterized by various techniques viz., X-ray diffraction, scanning electron microscopy and energy dispersive X-ray spectroscopy. The electrocatalytic response of MM at CNF-AgNP-CPE was studied by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). Under optimized conditions, the proposed sensor exhibits excellent electrochemical response towards MM. The DPV study shows greatly enhanced electrochemical signal for MM at CNF-AgNP-CPE lending high sensitivity to the proposed sensor for MM detection. The peak (Ip) current for MM is found to be rectilinear in the range 4.0×10(-8)-2.0×10(-5)M with a detection limit of 7.1×10(-9)M using DPV. The feasibility of the proposed sensor in analytical applications was investigated by conducting experiments on commercial pharmaceutical formulations, human urine and blood serum samples, which yielded satisfactory recoveries of MM. The proposed electrochemical sensor offers high sensitivity, selectivity, reproducibility and practical utility. We recommend it as an authentic and productive electrochemical sensor for successful determination of MM.

A sensitive LC-MS/MS method to quantify methylergonovine in human plasma and its application to a pharmacokinetic study.

Methylergonovine (ME) is a semisynthetic ergot alkaloid that is used for the treatment and prophylaxis of postpartum hemorrhage. In recent years, methylergonovine has been effective in the control of refractory headaches and is likely to be employed as chemosensitizers for cancer. However, this alkaloid sometimes causes elevated blood pressure. Therefore, a sensitive and accurate method for the quantification of this drug in biological matrices is necessary. In this study, ME was extracted from 500µL plasma samples by a liquid-liquid extraction under alkaline conditions and detected using positive multi-reaction-monitoring mode (+MRM) mass spectrometry. The method was validated according to US FDA guidelines and covered a working range from 0.025 to 10ng/mL with a lower limit of quantification (LLOQ) of 0.025ng/mL. In conclusion, a rapid, sensitive, selective and accurate quantification by an LC-MS/MS method was developed and successfully applied to a clinical pharmacokinetics study in female volunteers after a single intramuscular injection or oral administration of a 0.2mg dose of ME maleate. It is suitable for both preclinical and clinical studies on ME.

Comparison of the bioavailability and pharmacokinetics of oral methylergometrine in men and women.

OBJECTIVE: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women. DESIGN: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender). RESULTS: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%. CONCLUSION: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Pharmacokinetics of methysergide and its metabolite methylergometrine in the rat.

The pharmacokinetics of methysergide (MS) and its metabolite methylergometrine (MEM) was studied in male Sprague-Dawley rats. MS was administered iv in doses of 0.71 (0.25 mg/kg) or 2.8 mumol/kg (1.0 mg/kg). The metabolite MEM was administered as iv doses of 0.74 (0.25 mg/kg) or 2.9 mumol/kg (1.0 mg/kg). The steady state characteristics of these compounds were also studied after constant rate iv infusion of MS at two different rates, 0.70 and 14.0 nmol/min per kg. Plasma protein binding and blood/plasma partitioning for MS were determined over a range of concentrations. Plasma and blood concentrations of MS and MEM were measured by HPLC with fluorescence detection. The plasma clearance of MS was high and ranged from 74.2-102 ml/min per kg. The two iv doses of MS were not equivalent after dose correction; clearance, volume of distribution at steady-state and terminal half-life were significantly greater for the higher dose. Plasma clearance from the two iv infusions of MS were in accordance with that from the lower iv dose. Protein binding as well as the plasma/blood partitioning, of MS was constant over the range of concentrations observed in the disposition studies, averaging 84.2% and 1.67%, respectively. The metabolite MEM had a plasma clearance five to six times lower than that of the parent drug but a similar volume of distribution at steady state. The formation of MEM after MS administration was relatively low and appeared to be saturable since the formation clearance of MEM decreased significantly from 3.5 to 1.9 ml/min per kg for the low and the high rate of iv infusion of MS, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of ergot alkaloids in plasma by high-performance liquid chromatography and fluorescence detection.

Liquid chromatographic methods for the determination of ergotamine and methylergometrine in plasma have been developed. The samples are extracted with an organic solvent at pH 9.0 cleaned by extractions and finally injected on an ODS-Hypersil reversed-phase column with acetonitrile-ammonium carbonate buffer as the mobile phase. THe polarity of solvents used for extraction and the mobile phase are varied with the compounds of interest. Ergocristine is used as internal standard for ergotamine, and methysergide for the determination of methylergometrine. The stability of samples and standard solutions for calibration are discussed. Conditions for high selectivity and sensitivity of detection are given. Concentrations down to 100 pg/ml of plasma can be detected with a 3-ml sample.

Plasma and tissue concentrations of methylergometrine (methylergonovine) in the rabbit.

The concentrations of methylergometrine (M) (methylergonovine) in the plasma, uterus, liver, and kidneys of the rabbit were determined by a radioimmunoassay after a single 0.2 mg/kg intravenous injection and the drug response was studied in the uterus in situ. M disappeared quickly from the plasma with a mean distribution phase half-life of 0.91 min. According to the fast uterine tissue uptake of M the drug response in this effector organ began quickly. The stimulated concentrations in the peripheral compartment of the two-compartment open model can be useful in the understanding of the rapid drug effect, but they do not describe the real situation in any particular tissue.

Distribution of methylergometrine in the breast milk of dogs.

Distribution of methylergometrine maleate (MEM) was determined in plasma and milk of lactating beagle dogs after a single intravenous and oral dose and after prolonged administration. Plasma and milk levels were measured by a radioimmunoassay. MEM was found to be excreted into milk rapidly. The equilibrium between plasma and milk concentrations was reached at 30 min after intravenous and at 60 min after oral administration. The milk : plasma concentration ratio over post distribution period was one. The kinetics of MEM secretion process correspond to those which would be anticipated for a weak organic base transferred from plasma to milk by passive diffusion of the nonionized form.

Excretion of methylergometrine (methylergonovine) into the human breast milk.

Methylergometrine concentrations in the maternal plasma and breast milk were determined by a radioimmunoassay during continuous treatment with 0.125 mg of methylergometrine 3 times daily. On the fifth postpartum day at 8:00 a.m. the patients (n=8) took 2 tablets of Myomergin (0.250 mg of methylergometrine) orally, and the levels in the plasma and milk were determined at 1 and 8 hr after the drug administration. Measurable amounts of the drug were found only in 5 out of 16 milk samples. It was concluded that this oxytocic drug does not appear in the breast milk in quantities sufficient to affect the infant. No cumulation in the plasma or in the breast milk was found.

Quantitative determination of ergot alkaloids in biological fluids by radioimmunoassay.

1 Cross-reactivity of ergot alkaloids with an antiserum produced against lysergic acid conjugated with human serum, albumin was utilized to develop a radioimmunoassay for ergotamine, dihydroergotamine, dihydroergotoxine, ergometrine and methylergometrine in biological fluids. The antisera showed no cross-reactivity with simpler indole structures. 2 A procedure for extraction and concentration of alkaloids in biological fluids was developed. 3 The assay is sensitive for 1.8 ng/ml ergotamine, 1.5 ng/ml dihydroergotamine, 2.2 ng/ml dihydroergotoxine, 0.7 ng/ml ergotmetrine and 0.5 ng/ml methylergometrine. 4 The assay is sufficiently sensitive to permit the measurement of urine and plasma ergot alkaloid levels and it is suitable for determination in cases where a known ergot alkaloid is used.

Methylergometrine: comparison of plasma concentrations and clinical response of two brands.

There were no significant differences between the two brands of methylergometrine (methylergonovine), Methergin and Myomergin, in the radioimmunologically measured serum concentrations nor in the AUC after an oral 0.250 mg dose determined on the third or sixth postpartum day during a continuous treatment with methylergometrine 0.125 mg t.i.d., nor were there significant differences in the clinical response to this oxytocic drug. Peak serum concentrations were obtained at 3 hours (Methergin 6.3 nmol/1 and Myomergin 6.0 nmol/1), indicating a delayed gastrointestinal absorption in postpartum females in comparison with healthy male volunteers [6]. Spontaneous complaints of side-effects were rare and mild.

Methylergometrine (methylergonovine) concentrations in the human plasma and urine.

There were no significant differeneces in the radioimmunologically determined plasma concentrations of methylergometrine, nor in its 32-hour cumulative urinary excretion after a sinlge 0.250-mg p.o. dose of Methergin (Sandoz) or Myomergin (Leiras). Peak plasma concentrations were obtained as early as 0.5 hours after the drug administration. Approximately 3% of the 0.250-mg p.o. dose was excreted in the urine during a period of 32 hours. In two subjects, after a single 0.20-mg i.v. injection, the beta phase half-life in the plasma was 1.9 hours. From the ratio of the area under the plasma curve after p.o. and i.v. administration in these two subjects, it was estimated that 64% and 63% of the p.o. dose reached the systemic circulation. No cumulation in the plasma was observed after repeated p.o. doses of 0.125 mg of methylergometrine given thrice daily to the two subjects.

Plasma concentrations of methylergometrine after intravenous and intramuscular administration.

The concentrations of methylergometrine (M) in the plasma were determined by a new radioimmunoassay after a single intravenous and intramuscular administration of two brands. Methergin (Sandoz Pharmaceuticals, Inc, East Hanover, NJ, USA) and Myomergin (Leiras Pharmaceuticals, Turku, Finland). No significant differences between the two brands were found. After the intravenous injection, M distributed quickly from the plasma to the tissues, and according to the elimination phase half-life M has no cumulative properties. After the intramuscular injection, M was absorbed quickly with peak plasma concentrations at one-half hour.

Pharmacokinetics of methylergometrine (methylergonovine) in the rabbit and man.

Methylergometrine concentrations in human and rabbit plasma were determined by a new radioimmunoassay after a single intravenous injection (0.2 mg in man and 0.05, 0.1 and 0.2 mg/kg in rabbits). Both in man and in the rabbit methylergometrine disappeared quickly from the plasma with a mean T1/2alpha of 1.8 and 1.2-1.7 min. respectively. Similarly, the T1/2beta-values were 32.1 and 27.3-93.2 min. tthe mean maximal response in the rabbit uterus in situ after 0.05, 0.1 and 0.2 mg/kg intravenously dose was found at 40 sec., 26 sec., and 26 sec. after the drug administration, respectively, and the dose response curve was quite steep. A significant correlation was found between the dose and response.