Large randomized trial comparing transabdominal ultrasound-guided embryo transfer with a technique based on uterine length measurement before embryo transfer.

OBJECTIVE: To compare in a randomized, non-inferiority trial the embryo transfer (ET) technique based on uterine length measurement before transfer (ULMbET) with transabdominal ultrasound-guided embryo transfer (TA-UGET) in a large population of patients undergoing in-vitro fertilization (IVF). METHODS: Patients undergoing IVF with ET with cleaving fresh embryos were randomized to receive ULMbET or TA-UGET. The transfer of one to three embryos on day 2-3 of culture was performed using a soft catheter either under transabdominal ultrasound guidance (TA-UGET group) or after measurement of the uterine cavity by transvaginal ultrasound and calculation of the discharge site (ULMbET group). The primary outcome measures were clinical pregnancy rate, ongoing pregnancy rate and implantation rate, and secondary outcomes included patient discomfort during ET. RESULTS: A total of 1648 patients undergoing IVF were randomized to receive ULMbET (n = 828) or TA-UGET (n = 820) and were included in the analysis. Comparable clinical pregnancy rate (38.2% vs 38.9%), implantation rate (24.8% vs 25.2%) and ongoing pregnancy rate (33.1% vs 34.8%) were observed in ULMbET and TA-UGET groups. The discomfort intensity score and the proportion of patients with moderate-to-severe discomfort during ET were significantly higher in the TA-UGET group (2.6 vs 1.5 visual analog scale points and 19.8% vs 1.2%; P = 0.045 and P = 0.003, respectively). CONCLUSION: The ULMbET technique leads to IVF results comparable to those obtained with UGET, but is better tolerated than is TA-UGET and is technically easier to perform for a single operator. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Fertility in patients with multiple sclerosis: current knowledge and future perspectives.

The issue of fertility in patients with multiple sclerosis (MS) has not been exhaustively studied. Epidemiological data have suggested that spontaneous fecundity might be reduced; several endocrine and sexual disturbances potentially interfering with reproduction have been evidenced in MS patients of both sexes. Moreover, some medical treatments used in MS (e. g., mitoxantrone, cyclophosphamide) may exert detrimental effects on spermatozoa as well as on oocytes, leading to early impairment of fertility. This review illustrates the factors potentially interfering with fertility in MS and discusses the therapeutic tools that may be used to promote fertility in these patients. The safety of hormonal therapies in MS is also examined. The current applications of assisted reproductive technology (ART) are discussed, including in vitro fertilisation (IVF) techniques. Currently available methods to preserve fertility in patients that undergo cytotoxic treatments by means of sperm/oocyte cryostorage or by ovarian fragment cryopreservation and autografting are considered.

Preserved insulin sensitivity and {beta}-cell activity, but decreased glucose effectiveness in normal-weight women with the polycystic ovary syndrome.

Insulin resistance and hyperinsulinemia are often considered intrinsic features of the polycystic ovary syndrome (PCOS). Nevertheless, conflicting results of insulin sensitivity and secretion have been obtained in the subgroup of normal-weight women with PCOS. Differences in body composition, ethnicity, and diet composition and a family history of metabolic diseases may act as confounding variables in women with PCOS. In the present study, insulin sensitivity and secretion were estimated by an iv glucose tolerance test (IVGTT), analyzed by minimal models, in 20 normal-weight healthy women with PCOS and no family history of type 2 diabetes mellitus and in 20 normally ovulating women, matched for age and body mass index. Insulin sensitivity [mean (95% confidence intervals); PCOS 4.0 (2.8-5.1) vs. controls 4.5 (3.5-5.4) 10(-4) min(-1)/microU.ml], and insulin secretion, expressed as the acute insulin response to glucose [PCOS 3.7 (3.3-4.2) vs. controls 3.7 (3.4-4.0) microU/ml] were similar in the two groups. The women with PCOS showed an increased proportion of total body fat (PCOS 29% vs. controls 27.2%; P < 0.01). They also showed decreased glucose effectiveness, i.e. the proportion of glucose uptake independent from insulin activity [PCOS 2.6 (2.1-3.0) vs. controls 3.8 (3.0-4.6) mg x 100 min(-1); P = 0.01]. The levels of insulin sensitivity and of glucose effectiveness did not correlate in either group. Whether the isolated finding of decreased glucose effectiveness could reflect an early stage in the development of the metabolic aberrations often associated with the syndrome remains to be clarified.

Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. I. Biochemical profile.

Befloxatone, a novel oxazolidinone derivative, inhibited selectively and competitively monoamine oxidase (MAO)-A in human and rat brain, heart, liver and duodenum homogenates with Ki values ranging from 1.9 to 3.6 nM for MAO-A and from 270 to 900 nM for MAO-B. In vitro, befloxatone was more potent at inhibiting MAO-A activity than reference compounds (befloxatone > harmaline > brofaromine > BW 137OU87 > RS 8359 > toloxatone > moclobemide). The inhibition of MAO-A by befloxatone was time-dependent and fully reversible after dilution. After p.o. administration, befloxatone induced a dose-dependent and selective inhibition of rat brain and duodenum MAO-A activities ex vivo with ED50 values of 0.06 and 0.025 mg/kg, respectively. Befloxatone (0.5 mg/kg p.o.) decreased MAO-B activity by only 20% in both tissues. In the brain, liver and duodenum, the inhibition of MAO-A activity by befloxatone was short lasting. Twenty-four hours after administration of befloxatone (0.75 mg/kg p.o.), a full recovery of MAO-A activity was observed in the brain, but the enzyme activity was still decreased by 38 and 56% in the duodenum and liver, respectively. In the rat brain, befloxatone (0.75 mg/kg p.o.) increased levels of norepinephrine, dopamine and 5-hydroxytryptamine and decreased levels of their respective deaminated metabolites. These variations were dose-dependent and reversed 24 hr after administration. In addition, befloxatone (0.75 mg/kg p.o.) decreased free 3,4-dihydroxyphenylethylene glycol levels in the brain and plasma. Befloxatone (10 microM) did not modify the activities of diamine or benzylamine oxidase and did not interact with monoamine uptake mechanisms or with a variety of neurotransmitter or drug receptor sites. In conclusion, the neurochemical profile of befloxatone demonstrates that this compound is a selective, competitive, potent and reversible MAO-A inhibitor.

Befloxatone, a new reversible and selective monoamine oxidase-A inhibitor. II. Pharmacological profile.

The pharmacological profile of befloxatone, a reversible, selective and competitive inhibitor of monoamine oxidase-A has been investigated in rodents. In mice, befloxatone was more active at potentiating generalized tremors induced by L-5-hydroxytryptophan (ED50, 0.21 mg/kg p.o.) than phenylethylamine-induced stereotypies (ED50, 58 mg/kg p.o.), indicating a very high in vivo selectivity for inhibition of the A form of monoamine oxidase. Befloxatone showed potent activity in behavioral models in rodents predictive of antidepressant activity (forced swimming test, learned helplessness and reserpine reversal) with minimal effective doses of 0.1 to 0.2 mg/kg p.o. In these tests, befloxatone was much more potent (10- to 500-fold) than reference antidepressant compounds (reversible and irreversible monoamine oxidase inhibitors and monoamine reuptake inhibitors). In rats, befloxatone increased rapid eye movement sleep latency and decreased rapid eye movement sleep duration, without rebound effects. Potential anxiolytic activity was observed in the elevated-plus maze test in rats (minimal effective dose, 1-2 mg/kg p.o.). Befloxatone had no effect on motor performance, did not induce sedative or stimulant activity up to doses of 200 mg/kg p.o. and was devoid of anticholinergic activity in mice. Interaction studies with p.o. dietary tyramine (12 mg/kg), carried out in freely moving rats, demonstrated that, in contrast to irreversible monoamine oxidase inhibitors, befloxatone did not potentiate the pressor effect of this amine in the range of doses which showed pharmacological activity in antidepressant behavioral models. Furthermore, of the compounds tested (moclobemide, brofaromine, nialamide and phenelzine), comparison of doses active in antidepressant models and doses potentiating the pressor effects of tyramine demonstrated that befloxatone had the best therapeutic index. The results suggest that befloxatone will show clinical antidepressant activity at low doses and will be devoid of the side effects associated with irreversible monoamine oxidase inhibitors.

Interaction of MAO inhibitors and dietary tyramine: a new experimental model in the conscious rat.

The aim of this study was to assess a new model for tyramine-induced pressor effects in the rat. The predictivity of the test is improved by simulating the real clinical situations where tyramine is ingested with food and beverages containing the amine. The pressor effect was investigated after oral administration of tyramine in a feed preparation or in a water solution by continuously recording blood pressure just above the aorta junction via a left-carotid catheter. The response was quantified by measurement of peak systolic blood pressure and as the percentage of tyramine-sensitive rats (TSR) in which the maximal pressor response to the amine was higher than 30 mm Hg (clinical risk threshold). Tyramine elicited, after oral administration (by gavage), a statistically significant dose-dependent increase in blood pressure from the dose of 10 mg/kg in solution (i.e. 23 +/- 3 mm Hg, N = 36) and 40 mg/kg in feed preparation (i.e., 20 +/- 2 mm Hg, N = 26). Almost all rats showed a systolic blood pressor increase higher than 30 mm Hg after oral administration of tyramine at a dose of 80 mg/kg p.o. in solution (TSR = 96%). Administration of tyramine in food (80 mg/kg) significantly delayed the time of the peak blood pressure (13 +/- 2 min instead of 7 +/- 0.5 min in solution, p < .001). Under these conditions, the tyramine threshold dose of TYR 30 (dose inducing an average response equivalent to the clinical risk threshold) was 14 mg/kg p.o. in solution and 67 mg/kg p.o. in feed preparation, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical pharmacology of befloxatone (MD370503), a new potent reversible MAO-A inhibitor.

In vitro and ex-vivo studies show that befloxatone, a new oxazolidinone derivative, is a potent, reversible, competitive and specific MAO-A inhibitor (KiA from 1.9 to 3.6 nM and KiB/KiA ratio between 100 and 400, in the Rat and in Man, depending on the tissue). Befloxatone possesses a marked activity in antidepressant-sensitive behavioral models in rats (from 0.03 to 0.15 mg/kg po) and mice (from 0.21 to 0.29 mg/kg po). At these doses, befloxatone does not induce a significant potentiation of oral tyramine. Befloxatone is devoid of sedative, anticholinergic and cardiovascular effects. Befloxatone is rapidly and extensively distributed in rat brain, the pharmacokinetics are linear in the rat and in man in a large range of doses. Befloxatone is well tolerated in healthy volunteers and is developed as an antidepressant.

Determination of antipyrine sulphoconjugates in isolated cultured rat hepatocytes.

1. An analytical method for the simultaneous determination of three major metabolites of antipyrine, namely, 3-hydroxymethylantipyrine (phase I), 4-hydroxyantipyrine sulphoconjugate (phase II) and norantipyrine sulphoconjugate (phase II) in cultured rat hepatocytes has been developed and applied to the study of induction or inhibition of these metabolic pathways following pretreatment of rats with several inducers or inhibitors. 2. Phenobarbital was the most effective inducer of the three pathways studied, particularly the formation of 4-hydroxyantipyrine sulphoconjugate; 3-methyl-cholanthrene (MC) increased the formation of the two sulphoconjugates, but decreased the formation of 3-hydroxymethylantipyrine. 3. Rifampicin inhibits antipyrine metabolism in rat. The three metabolic pathways studied were decreased by 30%. 4. SKF 525A markedly inhibited the three metabolic pathways; piperonyl butoxide and omeprazole decreased the three pathways but to a lesser extent. Cimetidine decreased the two sulphoconjugates pathways, but did not affect 3-hydroxymethylantipyrine formation.

Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects.

We examined the influence of toloxatone, a new reversible monoamine oxidase-A inhibitor used in the treatment of depression, on tyramine-induced pressor effect in healthy volunteers. The maximum increase in systolic blood pressure produced by four single oral doses of tyramine administered during a meal and ranging from 100 mg to 800 mg was compared during repeated (3 to 5 days) administration of placebo, 200 mg toloxatone three times a day and 400 mg toloxatone three times a day in a single-blind, three-period crossover study. Toloxatone by itself had no significant influence on blood pressure. During administration of toloxatone, no significant increase in tyramine-induced increase in systolic blood pressure was observed for tyramine doses of 200 mg or less that are consistently higher than those associated with normal food intake. However, toloxatone increased the tyramine-induced increase in blood pressure after 400 mg tyramine (400 mg toloxatone three times a day) and 800 mg tyramine (200 mg toloxatone three times a day and 400 mg toloxatone three times a day). This pharmacodynamic interaction could be explained by an increase in tyramine systemic bioavailability in the presence of toloxatone. It is concluded that interaction between tyramine in meals and toloxatone is unlikely to occur in patients after long-term administration of the drug at therapeutic dosages.

Pharmacokinetics of dextromoramide in surgical patients.

The pharmacokinetics of the narcotic analgesic dextromoramide was investigated by means of a specific GC-MS method in 9 patients who were given a single oral dose of the drug (7.5 mg) together with an anticholinergic before undergoing minor orthopedic surgery. Dextromoramide was rapidly absorbed from the gastrointestinal tract, with peak plasma levels between 68 and 177 micrograms/L usually achieved within 0.5-4.0 h after dosing. In 5 patients, the decline of plasma concentrations after the peak followed a biphasic pattern, with half-lives of 0.4-1.6 h for the first phase and 6.3-21.8 h for the terminal phase. In the remaining patients, no clear-cut biphasic pattern was seen and half-lives calculated over the period between 4 h and 10 h after administration ranged from 1.5 to 4.7 h. Apparent clearance and volume of distribution values ranged from 0.06 to 0.36 1.h-1.kg-1 and from 0.6 to 2.4 l.kg-1, respectively. Less than 0.06% of the dose was excreted unchanged in urine within 8 h of administration. The concentration of the drug in a CSF sample collected 1 h after dosing was below the limit of detection (2 micrograms/L) in all subjects.

The pharmacokinetics of bendazac-lysine and 5-hydroxybendazac, its main metabolite, in patients with hepatic cirrhosis.

We have studied the pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, in 11 patients with hepatic cirrhosis after the oral administration of a single 500 mg tablet of bendazac-lysine, and compared them with those obtained from 10 healthy adults. The rate of absorption of bendazac, as assessed by tmax and Cmax, is similar in patients and in healthy subjects. The drug is eliminated mostly by metabolism in healthy adults, more than 60% of the dose being excreted in the urine as 5-hydroxybendazac and its glucuronide. Hepatic insufficiency impairs this metabolism, a two-fold decrease in apparent plasma clearance (CL/f) being observed in the patients. Although the plasma unbound fraction of bendazac is increased in patients (the drug is highly bound to plasma albumin), the apparent volume of distribution (V/f) is unchanged. In consequence, the half-life of bendazac is increased two-fold in the patients. Impairment of metabolism decreases the formation of 5-hydroxybendazac, but metabolism remains the main route of its elimination. Renal excretion of bendazac accounts for about 10% of the dose in both patients with cirrhosis and healthy subjects. We conclude that in patients with severe hepatic insufficiency the daily dose of bendazac-lysine should be halved.

Pharmacokinetics of bendazac-lysine and 5-hydroxybendazac in patients with renal insufficiency.

The pharmacokinetics of bendazac and its major metabolite, 5-hydroxybendazac, have been investigated in 15 patients with moderate to severe renal insufficiency and renal failure following a single oral dose of 500 mg bendazac-lysine. The pharmacokinetic parameters were compared to those obtained in 10 healthy adult volunteers. The rate and the extent of absorption of bendazac was not modified in the patients with moderate and severe renal insufficiency, nor was there any change in plasma tmax, Cmax, apparent elimination t1/2 and AUC. There was a significant increase in the unbound fraction of bendazac in renal failure patients undergoing haemodialysis, with a consequent increase in the apparent volume of distribution (V/F) and apparent plasma clearance (CL/F), and a decrease in plasma Cmax and AUC. Simultaneous changes of V/F and CL/F lead to an unchanged plasma t1/2 in these patients. Renal clearance (CLR) was decreased, but CL/F was not affected, since renal excretion is a minor route of elimination of bendazac. Bendazac is mostly eliminated by metabolism to 5-hydroxybendazac, in healthy subjects greater than 60% of a dose being excreted in urine as 5-hydroxybendazac and its glucuronide. In patients with renal insufficiency urinary excretion of 5-hydroxybendazac was decreased and the systemic availability of the metabolite (AUC), was increased about three-fold, irrespective of the degree of renal failure. Plasma 5-hydroxybendazac glucuronide accumulated according to the degree of renal insufficiency. Overall it can be assumed that the pharmacological effect of the drug will not be enhanced in renal failure and that the dosage regimen of bendazac-lysine in such patients need not be modified.

Pharmacokinetics and metabolism of the anti-arrhythmic carocainide in man.

The pharmacokinetics and metabolism of the anti-arrhythmic drug carocainide have been investigated in six healthy adult volunteers following single 100 mg intravenous and oral doses. Carocainide was labelled with 14C in the benzofuran ring. After i.v. administration, plasma concentration/time decay of carocainide was triexponential. Mean plasma elimination half-life of the drug was 5.0 +/- 2.2 h (i.v.) and 5.4 +/- 1.1 h (p.o.). Carocainide was virtually completely absorbed after the oral dose. The drug was eliminated mostly as unchanged drug in urine by the two routes of administration. There was some evidence that carocainide underwent enterohepatic cycling. Binding of carocainide to plasma proteins was saturable although not in the concentration range found in vivo. The drug was bound almost entirely to the alpha 1-acid glycoprotein fraction, to one class of binding sites with a moderate affinity constant (5.5 X 10(-4) M-1). Metabolism of carocainide, a secondary elimination process, occurred by oxidative cleavage of the benzofuran ring and by N-oxidation of the pyrrolidine ring.

Can a 1,2-oxygen shift of a nicotinamide N-oxide derivative occur in vivo?

Using the N-oxide derivative of niaprazine, a nicotinamide-based drug, as substrate, the possibility of a 1,2-oxygen shift from N to adjacent C occurring in vivo has been investigated. By comparison of the percentage of the 6-pyridone derivative formed after administration of 14C-niaprazine to rats with that obtained after giving 14C-niaprazine N-oxide, it has been shown that a 1,2-oxygen shift might contribute to the formation of 6-pyridone derivatives as metabolites of nicotinamide-related drugs in vivo.

Determination of low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol using gas chromatography-negative-ion chemical ionization mass spectrometry.

Gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) allowed the detection of extremely low plasma concentrations of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG). Glucuronide and sulphate conjugates of MHPG were determined after enzymatic hydrolysis of plasma with beta-glucuronidase-arylsulphatase. A 1-ml plasma sample was extracted at the pH of the hydrolysis (pH 4.8) with ethyl acetate, and the dry extract was derivatized with pentafluoropropionic anhydride in ethyl acetate. After evaporation of the solvent, the residue was dissolved in benzene and an aliquot was analysed by GC-NICI-MS. A trideuterated analogue of MHPG was used as an internal standard. Negative-ion chemical ionization of the pentafluoropropionyl derivatives was carried out using ammonia. The ion-molecule adducts at m/e 766 and 785 (MHPG) and m/e 769 and 788 (internal standard) were formed from the pentafluoropropionyl derivatives with the ions of m/e 163 (CF3CF2COO-) and m/e 144 (loss of fluorine from m/e 163). The concentrations of the ions of m/e 163 and 144 play a major role in the sensitivity and precision of this technique, which allows the detection of free MHPG plasma concentrations as low as 100 pg/ml in routine analysis.

Reversed-phase high-performance liquid chromatographic separation of 14C-labelled toloxatone and its metabolites.

A method for the analytical and micropreparative separation of toloxatone and its urinary metabolites in man is described. Toloxatone was given as an aqueous solution and was labelled with 14C. Following solvent extraction of urine, before and after enzymatic hydrolysis, one-step thin-layer chromatography on silica gel in combination with reversed-phase high-performance liquid chromatography, gave a good micropreparative separation for mass spectrometric analysis. After lyophilization of the high-performance liquid chromatographic fractions, the purity of the metabolites was checked by thin-layer chromatography. Acetic acid was chosen to regulate the pH of the mobile phase (acetonitrile-water) because it can be easily removed by lyophilization when a preparative separation is desired. The retention times as a function of the pH have been evaluated. Formic acid is also proposed for the optimization of the high-performance liquid chromatographic analysis. The quantitative analysis of 14C-labelled toloxatone and its metabolites was carried out, after solvent extraction of 2 ml of urine, using the same high-performance liquid chromatographic method with off-line and flow-through radioactivity detection.

Pharmacokinetic and relative bioavailability studies of cimoxatone in humans.

The pharmacokinetics of the reversible MAO-A inhibitor, cimoxatone, and its O-demethyl metabolite MD 770222 were investigated in eight healthy adult volunteers following single doses of 20- and 40-mg tablets, and 40-mg aqueous suspension. Cimoxatone plasma conc./time curves were fitted using a one-compartment open model, with absorption and elimination half-lives of about 0.5 and 12.0 h, respectively. Visual fittings, parameter estimates, and statistical analysis (Akaike information criterion) showed that data were better fitted by first-order than by zero-order absorption rate. A lag time of 20-25 min was observed for both formulations. MD 770222, which is also a selective and reversible inhibitor of MAO A although less potent than cimoxatone, is the major plasma metabolite and its plasma elimination half-life is about three times longer than cimoxatone. Although cimoxatone solubility in water is only 5 ppm, the drug appears to be well absorbed as indicated by the tight conformity of the pharmacokinetic parameters. Cmax and AUC values doubled from the 20- to the 40-mg dose. A statistical analysis showed that the systemic availability of cimoxatone from the 40-mg tablet is higher than from the suspension (p less than 0.05), and this difference is even more pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone pronounced on analysis of the metabolite data (p less than 0.01). Particle size analysis of cimoxatone powder showed the formation of agglomerates for the suspension which, by reduction of surface area, could decrease the availability of the drug.

Effect of a reversible and selective MAO-A inhibitor (cimoxatone) on diurnal variation in plasma prolactin level in man.

Prolactin (PRL) secretion is stimulated by serotonin (5-HT) and inhibited by dopamine (DA). 5-HT is generally recognized as a substrate for type A monoamine oxidase (MAO), whereas DA is considered as a substrate for either A or B, or both forms of MAO, depending on the species and tissues used. The effect of cimoxatone, a reversible, selective MAO-A inhibitor, on diurnal variation in plasma PRL level was investigated in healthy adults after a single 40 mg oral dose, as an indirect approach to investigating whether DA is preferentially a substrate for Type A or B MAO in man. The circadian rhythm in PRL, stress conditions and diet were taken into account in the present study, which was placebo-controlled. There was a slight but significant reduction in circulating PRL in the six subjects, which persisted for at least 9 h after cimoxatone. However, the duration of the decrease in plasma PRL was shorter than the inhibition of MAO-A. The results are not inconsistent with the presence of both forms of MAO in the human hypothalamus and with DA as a substrate for both forms in this region, if it is assumed that the hypothalamic concentrations of the drug during the period 0-9 hours was sufficiently high to inhibit DA deamination by both forms of MAO.

Estimation of the elimination half-life of the monoamine oxidase inhibitor cimoxatone in rat brain on the basis of ex vivo inhibition data.

Cimoxatone is a reversible mixed-type selective inhibitor of monoamine oxidase-A. For a mixed-type inhibitor, it can be shown that (vo-vi)/Vi is proportional to the inhibitor concentration. This relationship has been used to estimate the t 1/2 of the elimination of cimoxatone in rat brain after a single dose of inhibitor. t 1/2 values, estimated with three monoamine oxidase substrates, were in the range 3.9-4.8 h, in reasonable agreement with t 1/2 values determined from the plasma and brain concentration/time curves of cimoxatone.