scholarly journals Group size experiences with enhanced pre- and postnatal development studies in the long-tailed macaque (<i>Macaca fascicularis</i>)

2020 ◽  
Vol 7 (1) ◽  
pp. 1-4 ◽  
Author(s):  
C. Marc Luetjens ◽  
Antje Fuchs ◽  
Ann Baker ◽  
Gerhard F. Weinbauer

Abstract. Enhanced pre- and postnatal development (ePPND) studies have become the default developmental toxicity test for biopharmaceuticals if nonhuman primates represent the relevant species. Spontaneous pregnancy losses and infant deaths can be significant in macaques such as long-tailed macaques. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline S6(R1) states that pregnancy outcome can be judged also by the normogram-based variability of reference data according to a publication by Jarvis et al. (2010) defining a study as valid with six to eight live infants in the control group on postnatal day 7 (PND7). Since the release of ICH S6(R1) (2011), ePPND studies for biologics have replaced the former separate embryo-fetal and PPND study types. This work provides a retrospective analysis of pregnancy outcomes from 21 ePPND studies and group sizes of 14–24 animals per group. All studies reached the goal of at least six to eight infants on PND7, with overall losses ranging between 5 % and 45 %. Consistently, a group size of 14–24 maternal animals yielded more than six to eight infants on PND7. Therefore, it is suggested to reduce ePPND study group sizes from 20 to 14, yielding an animal number reduction of approx. 30 %.

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
S Gordts

Abstract text Endoscopic management of the unexplained infertility, what does it add? Stephan Gordts [email protected] Unexplained infertility “strictu sensu” is not a diagnosis, but a description of a status where no causal factor is identified in a couple trying to conceive for at least one year. The more parameters are assessed, the more likely to identify an etiology, the less likely becomes “unexplained” infertility. Limiting the fertility exploration to indirect visualization techniques like ultrasound, HSG or HycoSy involves the risk of missing existing pathologies. Uterus Uterine volumetric abnormalities can be detected by indirect techniques, but information is lacking on the visualization of the endometrium in case of chronic endometritis and the presence of endometrial defects and hypervascularization areas as seen in patients with adenomyosis. Tubo-ovarian Even with the increased accuracy of indirect visualization techniques, lesions of minimal endometriosis and tubo-ovarian adhesions are not detected (Table). Tubal normality constitutes not only normal tubal patency but also normal tubal function. The importance of subtle tubal lesions is underestimated. Hydatid of Morgagni are detected in 38.1% in patients with infertility versus only in 16,7% in fertile women (Gupta et al. JMIG 2017).Removal of these lesions resulted in a spontaneous pregnancy rate of 58.7% versus 20.6 in the non-treated group (Rasheed et al. EJOG Repr. 2011). Endometriosis In a series of 107 patients with unexplained infertility and 3 failed IVF cycles (Agni Pantou et al. J. Clin. Med. 2019)laparoscopy revealed the presence of endometriosis in 57.97%, peri-adnexal adhesions in 23.3% and was normal in 18.69%. Also, in a group of patients with 3 failed IVF cycles and unexplained infertility (Xiaoming Yu et al.Medicine 2019) laparoscopy showed endometriosis in 57.7%, tubal abnormalities in 31.1% and adhesions in 33.3%. Laparoscopic correction of these pathologies did not only result in a spontaneous pregnancy rate of 35% but resulted also in a higher pregnancy rate after IVF compared to the non-treated control group. Unexplained infertility hides frequently undiagnosed endometriosis. Endometrial BCL6 levels, a proto-oncogene where overexpression is associated with increased cellular proliferation and progesterone resistance, are increased in patients with endometriosis. In case of elevated BCL6 in patients with unexplained infertility, laparoscopy confirmed the presence of endometriosis in 93.8% (Evans-Hoeker et al. 2016). Abnormal BCL6 expression in a population with unexplained infertility reduced the chance of having a successful IVF treatment in 74% of the population (Almquist et al. Fertil Steril 2017). Transvaginal Hydro Laparoscopy Direct endoscopic visualization remains important but due to the invasiveness, diagnostic standard laparoscopy is frequently postponed or omitted in the exploration of the infertile patient. The technique of transvaginal hydro-laparoscopy allows in a minimal invasive way the inspection of the pelvis. In a consecutive series of 2288 patients without obvious pelvic pathology, findings were normal in 49.3%, endometriosis was diagnosed in 15.9% and tubal pathology in 14.5% of the patients (Gordts et al. FVV 2021). The rate of failed access was 1% and the complication rate 0.74%. Causing a minimal ovarian trauma, treatment of these early endometriotic lesions resulted in a spontaneous pregnancy rate of 73.2%. Conclusion The inappropriate use of “unexplained infertility” by omitting the diagnostic endoscopy in the exploration of the infertile patient, can hide undiagnosed and treatable pathology, jeopardizing possibilities for patients for a spontaneous conception and can be responsible for reduced pregnancy rates after IVF.


1995 ◽  
Vol 14 (4) ◽  
pp. 293-327 ◽  
Author(s):  
Beate Ulbrich ◽  
Anthony K. Palmer

The 1CH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) Guideline for Detection of Toxicity to Reproduction for Medicinal Products, adopted at the Second ICH Conference in Orlando, FL, U.S.A., emphasized the need for research into the suitability of various methods for the detection of effects on fertility in males. The current project was undertaken to compare the efficiency of methods by evaluating reports in the open literature. The results of the examination of 117 substances or substance classes support the view that histopathology and organ weight analysis provide the best general-purpose means of detecting substances with the potential to affect male fertility. Examinations at up to 4 weeks of treatment appear to be as effective as examinations conducted at later times. Mating with females for detection of effects unrelated to interference with sperm production appears to provide an optimal combination because adding other methodologies does not materially improve the detection rate. As to the timing of the mating trial, a 2-week premating period is as efficient as mating at 4 weeks and apparently more efficient than mating after prolonged premating treatment.


2020 ◽  
Vol 42 (1) ◽  
Author(s):  
Robert S. Foster ◽  
Adrian Fowkes ◽  
Alex Cayley ◽  
Andrew Thresher ◽  
Anne-Laure D. Werner ◽  
...  

Abstract The use of in silico predictions for the assessment of bacterial mutagenicity under the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M7 guideline is recommended when two complementary (quantitative) structure-activity relationship (Q)SAR models are used. Using two systems may increase the sensitivity and accuracy of predictions but also increases the need to review predictions, particularly in situations where results disagree. During the 4th ICH M7/QSAR Workshop held during the Joint Meeting of the 6th Asian Congress on Environmental Mutagens (ACEM) and the 48th Annual Meeting of the Japanese Environmental Mutagen Society (JEMS) 2019, speakers demonstrated their approaches to expert review using 20 compounds provided ahead of the workshop that were expected to yield ambiguous (Q)SAR results. Dr. Chris Barber presented a selection of the reviews carried out using Derek Nexus and Sarah Nexus provided by Lhasa Limited. On review of these compounds, common situations were recognised and are discussed in this paper along with standardised arguments that may be used for such scenarios in future.


2002 ◽  
Vol 21 (9-10) ◽  
pp. 507-512 ◽  
Author(s):  
D J Herzyk ◽  
P J Bugelski ◽  
T K Hart ◽  
P J Wier

Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a preand postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (F0) with keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of preand postnatal development designed in accordance with ICH Guidelines.


2000 ◽  
Vol 19 (4) ◽  
pp. 257-264 ◽  
Author(s):  
B. M. Ryan ◽  
R. Henrich ◽  
R. I. Freudenthal

Fyrolflex resorcinolbis-diphenylphosphate (RDP) is a nonhalogenphosphate ester product that is widely used as a flame retardant for petrochemicalplastics and high-temperature lubricant additive applications. The potential developmental toxicity of RDP was evaluated in rabbits. Groups of 27 sperm-positive New Zealand white rabbits (Hazelton Research Products Inc., Denver, PA) were administered graded concentrations of 50, 200, or 1000 mg/kg/day of RDP in corn oil. A vehicle control group of equal size was administered corn oil alone. Rabbits were dosed daily (1.5 ml/kg) on gestationdays 6 to 28 and sacrificed on gestationday 29. The fetuses were removed by cesarean section and examined for gross external, visceral, cephalic, and skeletal anomalies. No treatment-related clinical signs of toxicity were observed. No treatment-related effects in maternal food consumption, body weight, body weight gain, or on uterus, liver, kidney, and spleen weights were detected. Fetal viability and body weight, as well as developmental end points were also unaffected by treatment. Accordingly, exposure of pregnant rabbits to doses ranging from 50 to 1000 mg/kg/day of RDP during the periods of major organogenesis and histogenesis did not result in any biologically significant toxic or teratogenic/developmental effect in the dams or fetuses.


2020 ◽  
Vol 7 ◽  
Author(s):  
Xingyao Pei ◽  
Xilong Xiao ◽  
Jianling Liao ◽  
Linfu Ke ◽  
Daowen Li ◽  
...  

Plant soot, as a novel feed additive, could not only improve digestive function but also adsorb mycotoxins and inhibit bacterial infections. The subchronic toxicity and prenatal developmental effects of plant soot were studied for the first time. Our results indicated that there was no subchronic toxicity in the range of 2,000–50,000 mg/kg plant soot added in the feed, and there was no significant difference in reproductive function, embryo development, and teratogenicity between the pregnant rats exposed to 312.5, 1,250, and 5,000 mg/kg plant soot and the control group. The maximum no-observed effect level (NOEL) of supplemental dosage in feed could be set to 50,000 mg/kg, and the maximum intragastric NOEL could be set to 5,000 mg/kg, which preliminarily provided guidance on daily additive amount or clinical protocols for plant soot, as well as promoting the development and application of this harmless antibiotic substitutes.


Author(s):  
Suzan Samir Elsharkawy

Background: Failure to achieve conception after 12 months of regular unprotected intercourse is defined as infertility. The aim of this study was evaluating SIS done under high pressure (SIStreat) as a treatment procedure, for relieving simple tubal obstruction and on cumulative pregnancy rate in infertile women.Methods: A prospective, interventional trial was done (October 2017 - November 2018) on 106 eligible women. All patients performed SIS. Patient with tubes patent under low pressure were assigned as control group, the rest of them were subjected to SIStreat, this group was farther divided into Group 2-a (patent under high pressure) and Group 2-b (occluded under high pressure). All patients had regular intercourse for 6 months. Pregnancy was confirmed by serum B-HCG.Results: we compared patients who performed conventional SIS (n = 100 cases) to patients who performed SIStreat afterwards (n = 84) according to the number of patent tubes. There was a high statistically significant difference in favor of SIStreat group (p < 0.001). Also, there was no significant difference in pregnancy rate between control group 62.5% and Group 2-a 45.7% (p = 0.226).Conclusions: SIStreat is a whole new procedure for opening fallopian tubes (diagnosed occluded by SIS). Patients who were successfully treated by SIStreat had cumulative pregnancy rate comparable to patients who were diagnosed to have patent tubes using conventional SIS.


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