Multiple-dose Protocol Research Articles

Brazilian Clinical Strains of Actinobacillus pleuropneumoniae and Pasteurella multocida: Capsular Diversity, Antimicrobial Susceptibility (In Vitro) and Proof of Concept for Prevention of Natural Colonization by Multi-Doses Protocol of Tildipirosin.

One hundred Actinobacillus pleuropneumoniae (App) and sixty Pasteurella multocida subsp. multocida serogroup A (PmA) isolates were recovered from porcine pneumonic lungs collected from eight central or southern states of Brazil between 2014 and 2018 (App) or between 2017 and 2021 (PmA). A. pleuropneumoniae clinical isolates were typed by multiplex PCR and the most prevalent serovars were 8, 7 and 5 (43, 25% and 18%, respectively). In addition, three virulence genes were assessed in P. multocida isolates, all being positive to capA (PmA) and kmt1 genes, all negative to capD and toxA, and most of them (85%) negative to pfhA gene. The susceptibility of both pathogens to tildipirosin was investigated using a broth microdilution assay. The percentage of isolates susceptible to tildipirosin was 95% for App and 73.3% for PmA. The MIC50 values were 0.25 and 1 μg/mL and the MIC90 values were 4 and >64 μg/mL for App and PmA, respectively. Finally, a multiple-dose protocol of tildipirosin was tested in suckling piglets on a farm endemic for both pathogens. Tildipirosin was able to prevent the natural colonization of the tonsils by App and PmA and significantly (p < 0.0001) reduced the burden of Glaesserella parasuis in this tissue. In summary, our results demonstrate that: (i) tildipirosin can be included in the list of antibiotics to control outbreaks of lung disease caused by App regardless of the capsular type, and (ii) in the case of clinical strains of App and PmA that are sensitive to tildipirosin based on susceptibility testing, the use of this antibiotic in eradication programs for A. pleuropneumoniae and P. multocida can be strongly recommended.

Anti–Müllerian hormone and antral follicle count predict ovarian response in women less than 45 years following GnRH antagonist multiple–dose protocol

Objective: To speculate which of the following parameters: antral follicle count (AFC), anti-Müllerian hormone (AMH), follicle- stimulating hormone (FSH) and age can be used as a predictor of ovarian response to gonadotropin-releasing hormone (GnRH) antagonist stimulation multiple-dose protocol in women under 45 years, and to determine the cutoff value of these parameters and their correlations for predicting low and high ovarian response. Methods: This prospective study included 462 women with the mean age of (29.3±6.5) years. All women were subjected to the GnRH antagonist stimulation multiple-dose protocol. On the second day of the menstrual cycle, ultrasonography was conducted to determine AFC in both ovaries. Peripheral blood samples were collected to evaluate the level of estradiol, FSH, luteinizing hormone, prolactin, thyroid-stimulating hormone, and AMH. The women were divided into three groups: low response (AHH&lt;1 ng/mL, n=173), normal response (AMH=1.0-3.5 ng/mL, n=175), and high response (AMH &gt;3.5 ng/mL, n=114). Results: A significant decrease was found in the age and FSH level in the high response group compared to other groups (P&lt;0.001). Conversely, a significant increase was shown in AMH, estradiol on human chorionic gonadotropin (hCG) day, AFC, mature oocytes, fertilized oocytes, and embryos transferred in the high response group compared to the other two groups (P&lt;0.001). The receiver operating characteristic (ROC) curves demonstrated that AFC and AMH had the highest accuracy, followed by basal FSH level and age in the prediction of low ovarian reserves (P&lt;0.001) with cutoff values of ≤4.50 and ≤0.95 for AFC and AMH, respectively. Moreover, the ROC analysis showed that AFC had the highest accuracy, followed by AMH level and age in the prediction of high ovarian reserves with a cutoff value of ≥14.50, ≥3.63, and ≤27.50 years, respectively (P&lt;0.01). A significant decrease was observed in women's age, estradiol level, and oocyte fertilization rate in pregnant women compared to non-pregnant women (P&lt;0.001). Additionally, significant negative correlations were found between the AFC, the number of mature oocytes, fertilized oocytes, embryos transferred, and the age of pregnant women (P&lt;0.001). Conclusions: AFC and AMH predict low and high ovarian response to GnRH antagonist stimulation multiple-dose protocol in women under 45 years.

POS-138 COMPARATIVE STUDY BETWEEN SINGLE DOSE RITUXIMAB THERAPY VERSUS MULTIPLE DOSE REGIMEN IN IDIOPATHIC MEMBRANOUS NEPHROPATHY AND ITS CORRELATION WITH PERIPHERAL BLOOD CD19 COUNT

Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adult population and can lead to CKD if not treated properly. Conventional therapeutic options like Cyclophosphamide & CNI associated with significant toxicity & relapse rate. Though Rituximab is relatively safe multiple dose protocol leads to high cost burden. In this trial single dose Rituximab therapy has been compared with multiple dose regimen for this which will significantly cut down cost and drug related adverse effects.

Single-Dose Versus Multiple-Dose GnRH Agonist for Luteal-Phase Support in Women Undergoing IVF/ICSI Cycles: A Network Meta-Analysis of Randomized Controlled Trials.

BackgroundAlthough gonadotropin-releasing hormone (GnRH) agonist has been introduced as a beneficial luteal phase support (LPS), the optimal strategy of GnRH agonist remains unclear. This network meta-analysis was therefore performed to determine the comparative efficacy and safety of multiple-dose versus single-dose GnRH agonist protocol for LPS in patients undergoing IVF/ICSI cycles.MethodsWe searched relevant studies in PubMed, Embase and the Cochrane Registry of Controlled Trials (CENTRAL) from their inception util to September 2021. Live birth, clinical pregnancy rate, multiple pregnancy rate, and clinical abortion rate was evaluated. Pairwise and network meta-analysis were conducted using RevMan and ADDIS based on random-effects model, respectively. Moreover, the prioritization of protocols based on ranking probabilities for different outcomes were performed.ResultsSixteen RCTs met our eligibility criteria. Pairwise meta-analysis showed that multiple-dose protocol of GnRH agonist was effective for increasing live birth rate (OR 1.80, 95% CI 1.15 to 2.83, p=0.01) and clinical pregnancy rate (OR 1.89, 95% CI 1.01 to 3.56, p=0.05) as well as decreasing clinical abortion rate (OR 0.55, 95% CI 0.34 to 0.90, p=0.02). Meanwhile, single-dose protocol of GnRH agonist was effective for increasing clinical pregnancy rate (OR 1.45, 95% CI 1.11 to 1.89, p=0.007) and multiple pregnancy rate (OR 2.55, 95% CI 1.12 to 5.78, p=0.03). However, network meta-analysis only confirmed that multiple-dose protocol of GnRH agonist was the best efficacious strategy for live birth rate (OR 2.04, 95% CrI 1.19 to 3.93) and clinical pregnancy rate (OR 2.10, 95% CrI 1.26 to 3.54).ConclusionBased on the results of NMA, multiple-dose protocol may be the optimal strategy for patients undergoing IVF/ICSI cycles owing to its advantage in increasing live birth and clinical pregnancy rate. Moreover, single-dose protocol may be the optimal strategy for improving multiple pregnancy rate. However, with the limitations, more RCTs are required to confirm our findings.

Single-dose antibiotic prophylaxis compared with multiple-dose protocol in clean pediatric neurosurgical interventions: a nonrandomized, historically controlled equivalence trial.

Guidelines recommend antimicrobial prophylaxis (AMP) preoperatively for "clean" spinal and cranial surgeries, while dose and timing remain controversial. The use of multiple-dose AMP for such surgeries is under debate in the pediatric context. In this clinical study, the authors aimed to compare single-dose with multiple-dose prophylactic antibiotic usage in cranial and spinal neurosurgical interventions of pediatric patients. All neurosurgical patients aged 28 days to 18 years who underwent surgery at a single tertiary center were assessed. Three cohorts (noninstrumented clean spinal, noninstrumented cranial, and instrumented cranial interventions), each of which comprised two 50-patient arms (i.e., single-dose AMP and multiple-dose AMP), were included after propensity score-matched retrospective sampling and power analysis. Records were examined for surgical site infections. Using a previously published meta-analysis as the prior and 80% acceptance of equivalence (margin of OR 0.88-1.13), logistic regression was carried out for the total cohort and each subcohort and adjusted for etiology by consideration of multiple-dose AMP as reference. The overall sample included 300 age- and sex-matched patients who were evenly distributed in 3 bi-arm cohorts. There was no statistical intercohort difference based on etiology or type of operation (p < 0.05). Equivalence analysis revealed nondiscriminating results for the total cohort (adjusted OR 0.65, 95% CI 0.27-1.57) and each of the subcohorts (noninstrumented clean spinal, adjusted OR 0.65, 95% CI 0.12-3.44; noninstrumented cranial, adjusted OR 0.52, 95% CI 0.14-2.73; and instrumented cranial, adjusted OR 0.68, 95% CI 0.13-3.31). No significant benefit for multiple-dose compared with single-dose AMPs in any of the pediatric neurosurgery settings could be detected. Since unnecessary antibiotic use should be avoided as much as possible, it seems that usage of single-dose AMP is indicated.

Pharmacokinetic profile and effect on the faecal microbiome of a single dose of pradofloxacin oral suspension in the rabbit (Oryctolagus cuniculus).

Fluoroquinolones are often administered to pet rabbits given their perceived safety and limited effects on anaerobic gut microbiota. However, the pharmacokinetics and relative safety of pradofloxacin, a third-generation veterinary fluoroquinolone with a much broader spectrum of activity, have not been reported in this species. Here, we determined the pharmacokinetic profile of a single dose of oral pradofloxacin in rabbits and evaluated effects on the faecal microbiome. Four mature female rabbits were administered pradofloxacin (25mg/ml oral suspension), at a dose of 7.5mg/kg. The pradofloxacin median (range) Tmax was 4.50 (2.00-5.00) h, Cmax 600.66 (395.85-886.72) ng/ml and t½ was 1.27 (0.12-1.39) h. These results indicated that oral absorption of pradofloxacin was slower, and elimination faster compared with other fluoroquinolones in healthy rabbits, as well as relative to cats and dogs. Following treatment with pradofloxacin, faecal microbiota profiling showed some compositional differences between treated and control animals. This was the result of a significant decrease in the abundance of Proteobacteria, in particular bacteria belonging to the Pseudomonas, Atopostipes and Parabacteroides genera. The pharmacokinetic profile of pradofloxacin in rabbits should be further studied by increasing the sample size and using multiple-dose protocols (i.e. 7days) to confirm safety. Further information on the effects of protein binding, higher dosages and disease on pradofloxacin pharmacokinetics in rabbits are needed before an accurate dosing regimen can be recommended.

Single- versus multiple-dose methotrexate in cesarean scar pregnancies management: treatment and reproductive outcomes.

We aim to assess the outcome of the treatment of cesarean scar pregnancy (CSP) with single-dose methotrexate (MTX) versus multiple-dose MTX protocols. A retrospective cohort study including two tertiary medical centers was conducted. All women diagnosed with CSPs between the years 2011 and 2019 that were initially managed with systemic MTX were included. Single-dose MTX practiced in one medical center was compared to multiple-dose MTX, practiced in the other medical center. The study cohort included 31 women in the single dose and 32 women in the multiple-dose MTX groups. Baseline characteristics did not differ between groups. The primary outcome occurred in 12 (38.7%) of the cases in the single-dose group and in 6 (18.8%) in the multiple-dose group (p = 0.083). The rate of conversion to surgical treatment was similar in both groups (4 vs. 5 in the single vs. multiple-dose groups, respectively, p = 0.758). There was no significant difference between the single- and the multiple-dose groups in the administration of blood products (16.1% vs. 3.1%, respectively, p = 0.104), total days of admission (18 ± 9.3 vs. 17 ± 12.8days, respectively, p = 0.850), and readmission rate (32.3% vs. 21.9%, respectively, p = 0.353). Data regarding sequential pregnancies were available for 11 women in the single and 13 women in the multiple-dose MTX groups. There were no differences between the groups in rates of term deliveries, CSP recurrence, and abortions. Both single- and multiple-dose MTX treatment protocols offer high success rate with a relatively low complication rate in the treatment of CSP.

22 Strategies for oocyte collection procedures in free-roaming bison herds

The study was conducted to test the feasibility of protocols for field collection of cumulus–oocyte complexes (COC) for invitro embryo production (IVP) in wild bison. The study was done with captive wood bison during the late anovulatory season (July). In Experiment 1, bison were assigned randomly to 2 groups (n=8/group) in which transvaginal ultrasound-guided COC collection was done in a chute without sedation or in lateral recumbency after chemical immobilization using a dart gun to compare collection efficiencies. In Experiment 2, a 2×2 design was used to examine the effects of superstimulation treatments [single-dose equine chorionic gonadotrophin (eCG) vs. multiple-dose FSH] and methods of drug administration (manual injection vs. field darting) on COC collection and IVP. Initial COC collection was done to serve as a non-superstimulated random start and to synchronize follicular wave emergence on the following day (Day 0; n=16). Half of the bison were given a single dose of 5000IU of eCG intramuscularly (IM) on Day −1. The other half were given 200mg of FSH IM on Day 0 and Day 2, followed by 2000IU human chorionic gonadotrophin IM on Day 4. Superstimulatory treatments were given by manual injection (chute restrained) to half of the bison in each group and by field darting in the other half. The COC were collected on Day 4 in the eCG group and Day 5 in the FSH group. Recovered COC were matured invitro for 25 to 28h at 38.8°C, fertilized (2×106 sperm mL−1) and co-incubated at 38.8°C in 5% O2, 5% CO2, and 90% N2 for 18h. Presumptive zygotes were denuded and cultured at 38.8°C in 5% O2, 5% CO2, and 90% N2. A commercially available IVF media set was utilised (IVF Bioscience). Data were compared by ANOVA and GLIMMIX. In Experiment 1, no difference was detected between chute-restrained vs. chemically immobilized groups in the time required to complete COC collection (6.9±1.0 vs. 8.9±1.0 min; P=0.2), the number of follicles aspirated (11.5±1.9 vs. 9.3±1.8; P=0.4), or the COC recovery rate [COC recovered/follicle aspirated; 58/92 (63%) vs. 44/69 (64%); P=0.9]. In Experiment 2, no differences were detected between superstimulation treatments (eCG vs. FSH) or method of drug administration (manual injection vs. field darting) for any endpoint. The number of medium (4.5–7.5 mm; 9.5±1.0 vs. 2.5±0.6; P&amp;lt;0.0001) and large (&amp;gt;8 mm; 8.6±0.8 vs. 3.4±1.5; P=0.004) follicles available was greater after superstimulation (groups combined) than without superstimulation (random start). Although there was no difference in the number of recovered compact COC between the superstimulated and non-superstimulated bison (8.9±1.3 vs. 6.2±1.7; P=0.2), the embryo production rate (number of embryos produced/number of COC matured) was greater after superstimulation than without superstimulation [54/189 (39%) vs. 19/108 (18%); P&amp;lt;0.05]. We conclude that COC collection in a field setting is feasible and minimum-handling superstimulation with a single dose of eCG is as effective as a multiple-dose FSH protocol for the invitro production of embryos in bison. This research was supported by NSERC and Vetoquinol.

Does daily co administration of gonadotropins and letrozole during the ovarian stimulation improve IVF outcome for poor and sub optimal responders?

BackgroundCo-administration of letrozole during the first 5 days of ovarian stimulation was suggested to improve IVF outcomes in poor responders. We aimed to determine whether poor/sub-optimal responders might benefit from Letrozole co-treatment throughout the entire stimulation course.MethodsWe retrospectively reviewed the medical files of women who demonstrated poor (oocyte yield ≤3) and sub-optimal (4 ≤ oocyte yield ≤9) ovarian response during conventional multiple-dose antagonist stimulation protocols and were co-treated in a subsequent cycle with 5 mg Letrozole from the first day of stimulation until trigger day. A self-paired comparison between gonadotropins-only and gonadotropins-letrozole cycles was performed.ResultsTwenty-four patients were included. Mean patients’ age was 39.83 ± 4.60 and mean day-3-FSH was 12.77 ± 4.49 IU/m. Duration of stimulation and total gonadotropins dose were comparable between the two cycle groups. Peak estradiol levels were significantly lower in gonadotropins-letrozole cycles (2786.74 ± 2118.53 vs 1200.13 ± 535.98, p < 0.05). Number of retrieved oocytes (3.29 ± 2.15 vs 6.46 ± 3.20, p < 0.05), MII-oocytes (2.47 ± 1.65 vs 5.59 ± 3.20, p < 0.05), 2PN-embryos (1.78 ± 1.50, 4.04 ± 2.74, p < 0.05) and top-quality embryos (0.91 ± 0.97 vs. 2.35 ± 1.66, p < 0.05) were significantly higher in the gonadotropins-letrozole cycles. Clinical pregnancy rate in gonadotropins-letrozole cycles was 31.5%.ConclusionLetrozole co-treatment during the entire stimulation course improves ovarian response and IVF outcomes in poor/sub-optimal responders.

Assessing the Dating Potential of Violet Stimulated Luminescence Protocols

Violet stimulation is a new development in optical dating which has been suggested to extend the upper age limit of optically simulated luminescence (OSL) dating of quartz. Despite the reported advantage, few validation tests and applications have been published so far. The present study investigated the violet stimulated luminescence (VSL) using a single aliquot regenerative dose (SAR) protocol and a multiple aliquot additive dose (MAAD) protocol. Sedimentary quartz samples from four archaeological sites in Europe with independent age controls spanning 40–900 ka were used, including Grotte Mandrin (France), Brooksby Quarry (UK), Cueva Negra del Estrecho del Río Quípar (Spain) and Sima de las Palomas del Cabezo Gordo (Spain). The equivalent dose of a relatively young sample (∼40 ka) was successfully determined. However, significant underestimations were observed for older samples with higher doses. These findings indicate the need for further development of the measurement protocol to date high-dose natural samples.

Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol for patients with IVF failures due to poor embryo quality-A proof of concept

Stop GnRH-agonist combined with multiple-dose GnRH-antagonist protocol for patients with IVF failures due to poor embryo quality-A proof of concept

S128. Expectancy and Ketamine’s Rapid Antidepressant Effect: A Meta-Analysis

The role that expectancy plays in response in clinical trials involving ketamine has received little attention. We hypothesized that single dose intravenous ketamine protocols would be associated with increased immediate depressive symptom reduction relative to multiple dose protocols due to a trial design mediated expectation of rapid symptom change.

Performance of prognostic modelling of high and low ovarian response to ovarian stimulation for IVF.

What is the performance of previously established regression models in predicting low and high ovarian response to 150 μg corifollitropin alfa/GnRH-antagonist ovarian stimulation in an independent dataset? The outcome of ovarian stimulation with 150 μg corifollitropin alfa in a fixed, multiple dose GnRH-antagonist protocol can be validly predicted using logistic regression models with AMH being of paramount importance. Predictors of ovarian response have been identified in FSH/GnRH agonist protocols as well as ovarian stimulation with corifollitropin alfa/GnRH-antagonist. Multivariable response models have been established already, however, external validation of model performance has so far been lacking. Data from a prospective, multi-centre (n = 5), multi-national, investigator-initiated, observational cohort study were analysed. Infertile women (n = 211), body weight >60 kg, were undergoing ovarian stimulation with 150 μg corifollitropin alfa in a GnRH-antagonist multiple dose protocol for transvaginal oocyte retrieval for IVF. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle Day 2 or 3 of spontaneous menstruation before ovarian stimulation. Main outcomes were low (<6 oocytes) and high (>18 oocytes) ovarian response. Firstly, previously established prediction models for low ovarian response (LOR) and high ovarian response (HOR) were tested using the original parameters. Secondly, re-estimated parameters generated from the present data were tested on the established models. Thirdly, for the development of new predictive models of both LOR and HOR, several logistic regression models were estimated. Resulting prediction models were compared by means of the area under the receiver operating characteristic curve (AUC) and bias-corrected Akaike's Information Criterion (AICc) to identify the most reasonable model for each scenario. The previously established prediction models for low and high response performed remarkably well on this dataset (low response AUC 0.8879 (95% CI: 0.8185-0.9573) and high response AUC 0.8909 (95% CI: 0.8251-0.9568)). A newly developed simplified model for LOR with log-transformed AMH values and only age as another covariate showed an AUC of 0.8920 (95% CI: 0.8237-0.9603) with the lowest AICc of all models compared. For predicting HOR, we suggest a simplified model using AMH, FSH and AFC (AUC of 0.8976, 95% CI: 0.8206-0.9746). All analyses were done on data from women with a body weight >60 kg. The newly developed simplified models may suffer from overfitting and need to be tested in further independent data sets. Patient selection for ovarian stimulation with corifollitropin alfa should utilize established response prediction models. The clinical impact of this needs to be evaluated in future studies. The study was funded by university funds. M.O.S., T.L. and I.R.K. have nothing to declare. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Marckryl Pharma, VitroLife, NMC Healthcare, ReprodWissen, ZIVA and BioSilu. Not applicable.

Ovarian response to 150 µg corifollitropin alfa in a GnRH-antagonist multiple-dose protocol: a prospective cohort study

The incidence of low (<6 oocytes) and high (>18 oocytes) ovarian response to 150 µg corifollitropin alfa in relation to anti-Müllerian hormone (AMH) and other biomarkers was studied in a multi-centre (n = 5), multi-national, prospective, investigator-initiated, observational cohort study. Infertile women (n = 212), body weight >60 kg, underwent controlled ovarian stimulation in a gonadotrophin-releasing hormone-antagonist multiple-dose protocol. Demographic, sonographic and endocrine parameters were prospectively assessed on cycle day 2 or 3 of a spontaneous menstruation before the administration of 150 µg corifollitropin alfa. Serum AMH showed the best correlation with the number of oocytes obtained among all predictor variables. In receiver-operating characteristic analysis, AMH at a threshold of 0.91 ng/ml showed a sensitivity of 82.4%, specificity of 82.4%, positive predictive value 52.9%and negative predictive value 95.1% for predicting low response (area under the curve [AUC], 95% CI; P-value: 0.853, 0.769–0.936; <0.0001). For predicting high response, the optimal threshold for AMH was 2.58 ng/ml, relating to a sensitivity of 80.0%, specificity 82.1%, positive predictive value 42.5% and negative predictive value 96.1% (AUC, 95% CI; P-value: 0.871, 0.787–0.955; <0.0001). In conclusion, patients with serum AMH concentrations between approximately 0.9 and 2.6 ng/ml were unlikely to show extremes of response.

Clinical experience with an ovarian stimulation protocol for intrauterine insemination adopting a gonadotropin releasing hormone antagonist at low dose

Studies testing the effectiveness of GnRH antagonists in controlled ovarian stimulation (COS) for intrauterine insemination (IUI) have provided controversial results. The present study was undertaken to evaluate, whether the use of a half of the conventional dose of the GnRH antagonist cetrorelix can be effective in increasing the successful rate of IUI cycles. Patients started COS with human menopausal gonadotropin (hMG) on day three of the menstrual cycle. Cetrorelix was started when at least one follicle of ≥14 mm, was detected at the ultrasound scan, according to the flexible multiple daily dose protocol, and continued until the trigger day with recombinant hCG. Patients adopting GnRH antagonist at low dose had a pregnancy rate (21.7%) that was significantly higher (p < 0.05) in comparison to women receiving hMG only (8.7%). These results suggest that adding a reduced dose of GnRH antagonist to the COS for IUI cycles significantly improves the outcome of the procedure.

Review on Antagonists

ABSTRACTGonadotropin-releasing hormone (GnRH) antagonists have been a breakthrough in reproductive medicine. The third generation antagonists (cetrorelix and ganirelix) do not have histamine releasing capability in the used doses. The competitive blockade of GnRH receptors by GnRH antagonists leads to an immediate but reversible arrest of gonadotropin secretion. Antagonists can be used as single-dose or multiple dose protocol in a fixed or flexible approach during ovarian stimulation to prevent premature luteinizing hormone surge. The stimulation remains close to the normal cycle, and more convenient and friendly to the patient with lesser dose and duration of stimulation. Recent Cochrane analysis suggests that there is no significant difference in the live birth rate when antagonists are compared with agonists (OR 0.86) and there is a significant reduction in the incidence of ovarian hyperstimulation syndrome (OHSS) (OR 0.43) with the use of antagonists. Gonadotropin-releasing hormone antagonists are of special benefit for use in patients with polycystic ovaries where agonist trigger can be used and OHSS can be prevented completely. Gonadotropin-releasing hormone antagonists have particular advantage in poor responders with lesser pituitary suppression in the early part of cycle. Gonadotropinreleasing hormone antagonists can be used in modified natural cycle, intrauterine insemination cycles, and frozen embryo transfer cycles. Novel uses of antagonists include suppression of established OHSS, and in various gynecological conditions (endometriosis, fibroids, precocious puberty).How to cite this articleSardana D. Review on Antagonists. Int J Infertil Fetal Med 2015;6(1):1-10.

Pharmacokinetics of buprenorphine hydrochloride following intramuscular and intravenous administration to American kestrels (Falco sparverius).

To determine the pharmacokinetics of buprenorphine hydrochloride after IM and IV administration to American kestrels (Falco sparverius). 13 healthy 3-year-old captive-bred American kestrels. Buprenorphine hydrochloride (0.6 mg/kg) was administered IM to all birds. Blood samples were collected at 9 times, ranging from 5 minutes to 9 hours after drug administration. Plasma buprenorphine concentrations were measured by use of tandem liquid chromatography-mass spectrometry. Pharmacokinetic parameters were determined by use of least squares linear regression and noncompartmental analysis of naïve pooled data. After a washout period of 2 weeks, the same dose of buprenorphine was administered IV to all birds and blood samples were collected at the same times after drug administration. Maximum plasma buprenorphine concentration was achieved within 5 minutes after IM administration. For IM administration, bioavailability was 94.8% and elimination half-life was 92.1 minutes. For IV administration, steady-state volume of distribution was 4,023.8 mL/kg, plasma clearance was 49.2 mL/min/kg, and elimination half-life was 105.5 minutes. Buprenorphine was rapidly absorbed, and bioavailability was good after IM administration to American kestrels. Plasma buprenorphine concentrations were > 1 ng/mL for 9 hours after both IM and IV administration. These results, in combination with those of a pharmacodynamic study, suggested that the analgesic effects of buprenorphine could last at least 6 to 9 hours in this species. Further investigations of the duration of analgesic effects, multiple-dose protocols, and potential adverse effects of buprenorphine are warranted in American kestrels and other raptors.

Pharmacokinetics and bone resorption evaluation of a novel Cathepsin K inhibitor (VEL-0230) in healthy adult horses.

Plasma pharmacokinetic (PK) and bone resorption biomarker [carboxy-terminal cross-linking telopeptide of type I collagen (CTX-1)] analyses were performed following single and multiple oral dose protocols of a Cathepsin K inhibitor (VEL-0230) in horses. Outcomes included plasma and urine drug and CTX-1 concentrations. In the dose range study, 2, 4, and 8 mg/kg body weight (b.w.) doses were administered in a Latin square design to three mares and evaluated for 1 week. Based on the PK characteristics of VEL-0230, 4 mg/kg b.w. was selected for the dose interval study in which 3.25 days (d) and 7 days dose intervals were evaluated over three administrations using four exercising horses in a Latin square design. The 3.25 days and 7 days dose intervals provided a rapid inhibition of bone resorption based on plasma CTX-1. CTX-1 inhibition prior to next dose administration was not different from baseline in the 3.25 days and 7 days protocols, and for the first 3 days but the sustained CTX-1 inhibition in the 7 days protocol along with the cost and logistic benefits for weekly administration made the 7 days protocol preferable. Weekly administration of VEL-0230 may provide effective inhibition of bone resorption in young exercising horses that returns to baseline within 7 days after drug withdrawal even after multiple doses.

The effect of aromatase inhibitor letrozole incorporated in gonadotrophin-releasing hormone antagonist multiple dose protocol in poor responders undergoing in vitro fertilization.

ObjectiveTo evaluate whether letrozole incorporated in a gonadotrophin-releasing hormone (GnRH) antagonist multiple dose protocol (MDP) improved controlled ovarian stimulation (COS) and in vitro fertilization (IVF) results in poor responders who underwent IVF treatment.MethodsIn this retrospective cohort study, a total of 103 consecutive IVF cycles that were performed during either the letrozole/GnRH antagonist MDP cycles (letrozole group, n=46) or the standard GnRH antagonist MDP cycles (control group, n=57) were included in 103 poor responders. COS results and IVF outcomes were compared between the two groups.ResultsTotal dose and days of recombinant human follicle stimulating hormone (rhFSH) administered were significantly fewer in the letrozole group than in the control group. Duration of GnRH antagonist administered was also shorter in the letrozole group. The number of oocytes retrieved was significantly higher in the letrozole group. However, clinical pregnancy rate per cycle initiated, clinical pregnancy rate per embryo transfer, embryo implantation rate and miscarriage rate were similar in the two groups.ConclusionThe letrozole incorporated in GnRH antagonist MDP may be more effective because it results comparable pregnancy outcomes with shorter duration and smaller dose of rhFSH, when compared with the standard GnRH antagonist MDP.

The comparison of the effect on IVF results of metformin and insulin used during IVF cycles of infertile women with overt diabetes

To compare the effect of metformin and insulin on controlled ovarian stimulation (COS) and IVF results in infertile women with type 2 diabetes undergoing IVF/intracytoplasmic sperm injection (ICSI). Retrospective cohort study. A total of 52 consecutive IVF/ICSI cycles were included in 35 women with preexisting type 2 diabetes who were treated with either the metformin (metformin group, 29 cycles) or the insulin (insulin group, 23 cycles) for glycemic control. IVF/ICSI cycles in which a GnRH antagonist multiple dose protocol (MDP) is used for COS was included in this study. There were no significant differences in patient's characteristics between metformin and insulin groups. There were also no differences in total dose and days of recombinant human FSH (rhFSH) administered, and numbers of retrieved oocytes, mature oocytes, fertilized oocytes, and embryos transferred between the two groups. However, the number of grade 1 or 2 embryos was significantly higher in metformin group of 3.9 ± 2.9 compared with 2.2 ± 2.3 in insulin group (P = .025). Follicular fluid (FF) TNF-a and IL-6 concentrations at oocyte retrieval were significantly lower in metformin group than in insulin group (P = .030, P = .009). There were no differences in the clinical pregnancy rate, embryo implantation rate, miscarriage rate and multiple pregnancy rate between the two groups. The use of metformin for glycemic control is more effective in reducing FF TNF-a and IL-6 levels in COS cycles and improving embryo quality compared with insulin treatment in infertile women with type 2 diabetes undergoing IVF/ICSI.