Effects of SA237, a humanized anti-interleukin-6 receptor monoclonal antibody, on pre- and postnatal development in cynomolgus monkey.

Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy.

Assessment of ixekizumab, an interleukin-17A monoclonal antibody, for potential effects on reproduction and development, including immune system function, in cynomolgus monkeys.

The study aimed to analyze the dynamics of the development of cortical and medullary cells of adrenal gland in the long-tailed macaque (Macaca fascicularis) during pre- and postnatal period. The samples of adrenal glands were taken from 5 fetuses aged 70, 85, 100, 120, and 150 days of gestation, a newborn aged 10, and an infant aged 105 days old. The samples of the adrenal glands were stained with hematoxylin-eosin and Masson trichrome (Goldner’s modification). The results showed that the fetal adrenal cortex consisted of a definitive and fetal zones, but in the late gestation (fetus aged 150 days of gestation), the transitional zone appeared between both zones. At the postnatal period, the definitive zone changed to glomerulosa zone, while the outer cells of the transitional zone changed to fasciculata zone which radially arranged. The results indicated that the fetal zone was present until birth and it will disappear gradually after birth. The medullary cells were found at the fetal stages as an irregular structure of small islands of chromaffin cells in the fetal zone. This structure migrated slowly to the center of the adrenal glands. The characteristics of mature chromaffin cells were found in the adrenal glands at postnatal period. In conclusion, the cortex adrenal of the newborn of long-tailed macaque consisted of zona glomerulosa, zona fasciculata, zona transitional, and the remaining fetal zone that has dissapeared gradually after birth.

The objective of this study is to observe the relationship of development of adrenocorticotropic hormone (ACTH) cells of adenohypophysis–adrenal cortex axis during pre and postnatal period of longtailed monkey (Macaca fascicularis). Five fetuses aged 70, 85, 100, 120, and 150 days of gestation and 2new born aged 10 and 105 days old were used as research materials. The sections of the pituitary gland stained immunohistochemically using human ACTH antiserum and the adrenal glands stained by Hematoxylin-Eosin procedures. At the fetus 120 days old, the ACTH cells and blood vessel of fetaladenohypophysis developed well and its similar that found in older age. This condition suggested distributing the ACTH to whole body optimally. At the same time, the adrenal cortex cells of fetus 120 days old were active in proliferation and differentiation processes to form transition zone that lies between definitive and fetal zones, and central vein also developed in adrenal gland. In fetus aged 150 days, the cortex adrenal structure was similar with found in older fetus. The adenohypophysis ACTH cells developed earlier than adrenal cortex and their secretion suggested influencing the development of adrenal cortex cells of long-tailed monkey.

Interleukin-6 (IL-6) overproduction has been involved in the pathogenesis of several chronic inflammatory diseases and the administration of an anti-IL-6 receptor monoclonal antibody has been proven clinically efficient to treat them. However, the drawbacks of monoclonal antibodies have led our group to develop an innovative anti-IL-6 strategy using a peptide-based active immunization. This approach has previously shown its efficacy in a mouse model of systemic sclerosis. Here the safety, immunogenicity, and efficacy of this strategy was assessed in non human primates. No unscheduled death and clinical signs of toxicity was observed during the study. Furthermore, the cynomolgus monkeys immunized against the IL-6 peptide produced high levels of anti-IL-6 antibodies as well as neutralizing antibodies compared to control groups. They also showed an important decrease of the cumulative inflammatory score following a delayed-type hypersensitivity reaction induced by the Tetanus vaccine compared to control groups (minus 57,9%, P = 0.014). These findings are highly significant because the immunizing IL-6 peptide used in this study is identical in humans and in monkeys and this novel anti-IL-6 strategy could thus represent a promising alternative to monoclonal antibodies.

ERK1, 2, and 5 expression and activation in dopaminergic brain regions during postnatal development

There are worldwide concerns regarding the potential adverse effect of melamine. This study investigated the potential effects of melamine on pregnant dams and embryo-fetal development in Sprague-Dawley rats following maternal exposure on gestational days (GD) 6-20. Melamine was administered to pregnant rats by gavage at doses of 0, 200, 400 and 800 mg kg⁻¹ per day (n = 8-10 for each group). All dams were subjected to a Caesarean section on GD 21 and their fetuses were examined for morphological abnormalities. With administration of melamine at 800 mg kg⁻¹ per day, maternal toxicity manifested as increased incidences of clinical signs and death, lower body weight gain and food intake, and increases in heart, adrenal gland and kidney weights. Histopathological examinations revealed an increase in incidences of congestion, tubular necrosis/degeneration, crystals, casts, inflammatory cells in tubules, tubular dilation and tubular hyaline droplets in the maternal kidneys, while fetal kidneys (one fetus/litter) did not show any histopathological changes. Developmental toxic effects included a decrease in fetal weight, an increase in the incidence of skeletal variations and a delay in fetal ossification. No treatment-related maternal or developmental effects were observed at doses ≤ 400 mg kg⁻¹ per day. These results show that 15-day repeated oral dosing of melamine is embryo-/fetotoxic at a maternotoxic dose, but not teratogenic in rats. The no-observed-adverse-effect level of melamine for pregnant dams and embryo-fetal development is considered to be 400 mg kg⁻¹ per day.

Despite the widespread use of diphenylhydantoin (DPH), there is a lack of reliable information on the teratogenic effects, correlation with maternal and developmental toxicity, and dose-response relationship of DPH. This study investigated the dose-response effects of DPH on pregnant dams and embryo-fetal development as well as the relationship between maternal and developmental toxicity. DPH was orally administered to pregnant rats from gestational days 6 through 15 at 0, 50, 150, and 300 mg/kg/day. At 300 mg/kg, maternal toxicity including increased clinical signs, suppressed body weight, decreased food intake, and increased weights of adrenal glands, liver, kidneys, and brain were observed in dams. Developmental toxicity, including a decrease in fetal and placental weights, increased incidence of morphological alterations, and a delay in fetal ossification delay also occurred. At 150 mg/kg, maternal toxicity manifested as an increased incidence of clinical signs, reduced body weight gain and food intake, and increased weights of adrenal glands and brain. Only minimal developmental toxicity, including decreased placental weight and an increased incidence of visceral and skeletal variations, was observed. No treatment-related maternal or developmental effects were observed at 50 mg/kg. These results show that DPH is minimally embryotoxic at a minimal maternotoxic dose (150 mg/kg/day) but is embryotoxic and teratogenic at an overt maternotoxic dose (300 mg/kg/day). Under these experimental conditions, the no-observed-adverse-effect level of DPH for pregnant dams and embryo-fetal development is considered to be 50 mg/kg/day. These data indicate that DPH is not a selective developmental toxicant in the rat.

Background: Slow-transit constipation (STC) lacks durable and safe prokinetics. Deglycosylated-azithromycin (Deg-AZM), a novel small-molecule transgelin agonist that restores colonic motility in STC, has been approved for clinical trials in 2024. Objectives: This study aimed to assess the genetic toxicity and embryo–fetal development (EFD) toxicity of Deg-AZM through a series of standardized non-clinical safety studies. Methods: We conducted Ames, in vivo micronucleus, and chromosomal aberration tests to evaluate genotoxicity. Acute and 28-day repeated-dose oral toxicity studies were performed in Sprague-Dawley rats. EFD toxicity was assessed in pregnant rats administered Deg-AZM from gestation day (GD) 6 to 15. Toxicokinetic analyses were integrated into repeated-dose and EFD studies. Results: Deg-AZM demonstrated no mutagenic potential in the bacterial reverse-mutation assay at concentrations up to 2500 µg/plate (with metabolic activation) or 150 µg/plate (without metabolic activation). No clastogenic effects were observed in micronucleus or chromosomal aberration assays. The median lethal dose (LD50) exceeded 1600 mg/kg in acute oral toxicity. In the 28-day study, no adverse effects were observed at doses up to 600 mg/kg, though mild hematological and hepatic changes were noted at high doses, all of which were reversible. In the EFD study, Deg-AZM did not induce maternal toxicity, teratogenicity, or adverse fetal outcomes at doses up to 600 mg/kg. Conclusions: Deg-AZM demonstrates a favorable safety profile with no evidence of genetic toxicity or developmental harm at pharmacologically relevant doses, supporting its further development as a therapeutic agent for STC.

Eating disorders (ED) are most prevalent in women of reproductive age. EDs affect fertility, maternal BMI, and obstetric outcomes. During the early postpartum period, women with an ED history are at high risk for relapse. However, research on the impact of ED on maternal and infant health and development during the first postpartum year is limited. This scoping review provides an overview of the current research on postpartum ED symptoms and their effects on mothers and their babies as well as limitations of current postpartum screening practices. This scoping review was conducted in accordance with JBI Scoping Review Methodology. It included all available English-language literature published between 2000 and January 2025 that was available on PubMed, SCOPUS, and APA PsycInfo electronic databases. We included peer-reviewed empirical manuscripts that measured maternal ED symptoms or diagnoses and that had outcomes on maternal mental health, infant development, or infant feeding interactions during the first year postpartum. Of 332 citations identified in the initial search, 43 articles were included in the review. The majority were conducted in North American and European countries. Several longitudinal studies found an increase in ED symptoms after childbirth, particularly among women with a lifetime history of EDs; compared to women with no history, women with a history of ED symptoms had elevated anxiety and depression during the postpartum period. Findings from studies assessing the relationship between ED history and breastfeeding outcomes were mixed, although infant feeding difficulties appear to be more common in women with a history of ED symptoms. This review provides novel insights into ED symptoms, effects, and care in the postpartum period. Women with ED symptoms are at higher risk for developing mental health conditions during postpartum and are more likely to experience a relapse. These symptoms likely affect the mother-infant feeding relationship. This review also highlighted the lack of research focused on tailored screening and treatment strategies for this population, indicating a need for further research on women with ED symptoms during a critical period.

Nyotran is a liposomally encapsulated i.v. formulation of the antifungal polyene nystatin. This drug was evaluated in a series of reproductive toxicity studies, according to the guidelines outlined by the International Conference on Harmonization (ICH). A fertility and early embryonic development study (SEG I) and a prenatal and postnatal development (SEG III) study were conducted in rats, and embryo-fetal development (SEG II) studies were conducted in rats and rabbits. Nyotran was administered iv in all studies. In SEG I and SEG III, rats were administered daily doses of 0.5, 1.5, or 3.0 mg/kg Nyotran. In both studies, parental mortality and toxicity in the 3.0 mg/kg dose group necessitated the lowering of the high dose to 2.0 mg/kg/day. Parental toxicity, in the form of decreased body weights, decreased food consumption, and piloerection were also observed at the 1.5 mg/kg/day dose level in the SEG I and SEG III studies. Despite the parentally toxic doses in the SEG I study, there was no effect of Nyotran on F0 male or female fertility or early embryonic development of F1 offspring. In the SEG III study, lactational body weights of the F1 generation were decreased at all Nyotran dose levels. There was no effect on pre-wean developmental landmarks, but post-wean development was affected by Nyotran administration at all dosage levels. Preputional separation was delayed in the 1.5 and 3.0/2.0 mg/kg/day F1 offspring, auditory startle function was decreased in F1 females at all dose levels, and motor activity was decreased in male F1 offspring at all dose levels. However, there were no treatment-related effects on the subsequent mating of the F1 generation and resulting F2 offspring. In SEG II studies, rats and rabbits were also administered 0.5, 1.5, or 3.0 mg/kg/day of Nyotran during gestation. The high dose in these SEG II studies was not lowered, as the maternal animals were able to tolerate the shorter duration of dosing. Maternal effects in rabbits were observed only in the high-dose group and were limited to decreased food consumption and decreased absolute and relative liver weight. Decreased food consumption in high-dose dams and clinical weight loss in some animals at the mid- and high-dose levels evidenced maternal toxicity in rats. Nyotran did not have any effect on Caesarian section parameters in either rats or rabbits and no effect on the incidence of fetal malformations in rabbits. A statistically significant increase in mild hydrocephaly, observed in 4 rat fetuses, was seen at the highest dose level of 3.0 mg/kg/day. The biological significance and relationship to Nyotran treatment of this finding is not clear. This finding may represent a change in the background incidence or a change in the pattern of responsiveness of this strain of rat fetus to the test chemical. Toxicokinetic data were also collected in the SEG II rabbit and rat studies for comparison to human exposures. In both species, systemic exposure to the nystatin at effective antifungal concentrations was demonstrated. The systemic exposures in rats and rabbits were, however, considerably less than have been reported in humans administered clinical doses of 2 or 4 mg/kg/day Nyotran. Thus, humans tolerate higher dosages and systemic exposures of Nyotran relative to rats and rabbits and there is no margin of safety in either dosage level or systemic exposure to drug. Given this lack of a margin of safety and the effects on postnatal development in F1 rats, caution should be exercised when using this drug in females of childbearing potential.

Key facts about the COVID-19 vaccination programme in the UK

Effects of prenatal irradiation with an accelerated heavy-ion beam on postnatal development in rats: II. Further study on neurophysiologic alterations

Maternal avoidance, anxiety cognitions and interactive behaviour predicts infant development at 12 months in the context of anxiety disorders in the postpartum period

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