Naloxegol, an opioid antagonist with reduced CNS penetration: Mode-of-action and human relevance for rat testicular tumours.

Naloxegol is an opioid antagonist which has been developed for the treatment of patients with opioid induced constipation. In the nonclinical safety program naloxegol was shown to have a very benign toxicity profile. In the rat, but not the mouse, 2-year carcinogenicity study a change in tumour pattern with an increase in testicular Leydig cell tumours (LCT) was observed after dosing at high (supra-pharmacological) concentrations.

Investigation into the effect of microsampling on mouse fetuses and pregnant mice in the embryofetal development study design.

The effects on fetal weights and maternal health of taking 32μL blood microsamples at the end of organogenesis in a mouse embryofetal development (EFD) study design was investigated with the aim of reducing satellite animal usage. The effects of warming, handling and sampling either 3 or 6 times on gestation day 16 was evaluated. Maternal body weight gain was transiently reduced when animals underwent warming and handling with or without microsampling.

Femoral Head Growth Plate Dysplasia and Fracture in Juvenile Rabbits Induced by Off-target Antiangiogenic Treatment.

Epiphyseal growth plate dysplasia (chondrodysplasia) might be considered as the pathognomonic feature of antiangiogenic treatment in preclinical species as it is reliably and dose-responsively induced in rodents and monkeys with vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor (FGF) receptor inhibitors, matrix metalloproteinase inhibitors, and vascular targeting agents. Here we report epiphyseal growth plate dysplasia in juvenile rabbits treated with an oral spleen tyrosine kinase inhibitor induced by off-target antiangiogenic inhibition of VEGF and FGF family kinase receptors. Epiphyseal growth plate dysplasia resulted in weakening and fracturing of the femoral head physis in 6 of 10 male and 1 of 10 female animals as well as microfracturing and dysplasia of the distal femoral articular cartilage in 1 male animal.

Reproductive senescence, fertility and reproductive tumour profile in ageing female Han Wistar rats.

A study using vehicle administration in 104 female rats investigated reproductive aging in Han Wistar rats as a useful tool to interprete carcinogenicity studies where hormonal patterns are perturbated. From 16 weeks of age oestrous cycles were monitored every 6 weeks to investigate reproductive ageing. A subset of 20 females was used to assess fertility at 21 months of age.

Time Course for Onset and Recovery from Effects of a Novel Male Reproductive Toxicant: Implications for Apical Preclinical Study Designs.

In the pharmaceutic ICH S5(R2) guidelines for reproductive toxicity testing, a premating dose duration of 14 days is considered sufficient for assessment of male fertility for compounds that are not testicular toxicants. A novel α7 subtype of nicotinic acetylcholine receptor (α7nAChR) agonist, originally intended for treatment of Alzheimer's disease, did not cause changes in sperm counts, motility, or testicular histopathology in rat toxicity studies of up to 6 months duration. However, profound decrements in male fertility (reduced pregnancy rates and litter sizes) occurred after 11 weeks of dosing in male rats.

The novel use of a heterozygous knockout mouse for embryofetal development assessment of a glucokinase activator.

Glucokinase activators (GKAs), such as AZD1656, are designed as antihyperglycemic agents for diabetics and can cause dose-limiting hypoglycemia in normal animals used in embryofetal development studies. Genetically modified heterozygous GK knockout (gkdel/wt) mice are less susceptible to severe GKA-induced hypoglycemia than wild-type mice due to their elevated baseline glucose levels. In this study, the gkdel/wt mouse was used as an alternative rodent strain for embryofetal development studies with AZD1656.

Reduced post-natal versus pre-natal incidence of bent long bones and scapulae in a preliminary investigation using the Han Wistar rat.

There is a "chondrodystrophy" syndrome in the Han Wistar rat fetus that manifests as characteristic skeletal abnormalities such as bent and/or short long bones, and is classified as permanent detrimental abnormalities (major malformations). This pilot study investigated whether these defects resolve after birth. Han Wistar rats were dosed during organogenesis either with vehicle or test article.

The inhibin B response in male rats treated with a GnRH agonist and an endothelin receptor antagonist.

Background: This study examined the correlation between Inhibin B and testicular pathology.

Methods: Male Han Wistar rats (approximately 10 weeks old) were administered either vehicle or an endothelin receptor antagonist (ET-An) orally for 28 days or a Gonadotropin Releasing Hormone (GnRH) agonist (GnRH-A) as a subcutaneous implant on day 1. Ten animals/group/time point were killed on days 4, 8, 15, and 29 (controls on days 15 and 29) for testes weights and histopathology.

Assessment of male rodent fertility in general toxicology 6-month studies.

An outcome and statistical review of male reproductive performance assessed by including a mating phase within 6-month general toxicity studies in the Han Wistar rat was undertaken. The basic study design was 16-20 animals per group dosed for approximately 9 weeks before pairing the male rats with undosed females. This design provides opportunity for remating and automatically includes general toxicity parameters.

Incidence and nature of testicular toxicity findings in pharmaceutical development.

Background: Testicular toxicity (TT) is a sporadic and challenging issue in pharmaceutical drug development. Efforts to develop TT screening assays or biomarkers have been overshadowed by consortium efforts to predict drug-induced toxicities such as hepatic injury, which are encountered more frequently.

Methods: To gauge the current state of the field and to prioritize future TT activities, the International Life Sciences Institute-Health and Environmental Sciences Institute Developmental and Reproductive Toxicology (DART) Technical Committee sponsored a survey to better understand the incidence and nature of TT findings encountered during drug development.

The cynomolgus monkey as a model for developmental toxicity studies: variability of pregnancy losses, statistical power estimates, and group size considerations.

Background: This work evaluates pregnancy and infant loss in 1,069 vehicle-treated cynomolgus monkeys from 78 embryo-fetal development (EFD) studies and 14 pre-postnatal development (PPND) studies accrued during 1981-2007.

Methods: Losses were analysed by survival function and hazard ratio using logistic regression for influence of year, study type (e.g.