Machine learning and drug discovery for neglected tropical diseases.

Neglected tropical diseases affect millions of individuals and cause loss of productivity worldwide. They are common in developing countries without the financial resources for research and drug development. With increased availability of data from high throughput screening, machine learning has been introduced into the drug discovery process.

PDGFRα monoclonal antibody: Assessment of embryo-fetal toxicity and time-dependent placental transfer of a murine surrogate antibody of olaratumab in mice.

Background: Olaratumab (Lartruvo™) is a recombinant human IgG monoclonal antibody that specifically binds PDGFRα. The maternal and in utero embryo-fetal toxicity and toxicokinetics of a human anti-mouse PDGFRα antibody (LSN3338786) were investigated in pregnant mice.

Methods: A pilot study was used to set doses for the definitive study.

Prenatal and Postnatal Assessment in Rabbits with Evacetrapib: A Cholesteryl Ester Transfer Protein Inhibitor.

Background: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was under development for the treatment of cardiovascular (CV) disease. The purpose of this pre-postnatal study in rabbits was to evaluate the effects of evacetrapib on pregnancy, parturition, and lactation of the maternal animals and on the growth, viability, development, and reproductive performance of the first filial (F1) offspring. The rabbit is considered a relevant species for toxicity testing with evacetrapib as it demonstrates significant CETP expression, whereas mice and rats do not express significant levels of CETP.

Fertility and Embryo-Fetal Development Assessment in Rats and Rabbits with Evacetrapib: A Cholesteryl Ester Transfer Protein Inhibitor.

Background: The purpose of these studies was to evaluate the effects of evacetrapib on male and female fertility and on embryo-fetal development (EFD).

Methods: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was administered daily by oral gavage starting 2 weeks (for female) or 4 weeks (for male) before mating, during cohabitation, and until necropsy in the male rat fertility study or through gestation day (GD) 17 in the female rat combined fertility/EFD study. For rabbit EFD studies, animals were dosed from GDs 7 to 19 or from 1 week before mating through GD 19.

Comparison of rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on the nature and severity of developmental effects.

Regulatory non-clinical safety testing of human pharmaceuticals typically requires embryo-fetal developmental toxicity (EFDT) testing in two species (one rodent and one non-rodent). The question has been raised whether under some conditions EFDT testing could be limited to one species, or whether the testing in a second species could be decided on a case-by-case basis. As part of a consortium initiative, we built and queried a database of 379 compounds with EFDT studies (in both rat and rabbit animal models) conducted for marketed and non-marketed pharmaceuticals for their potential for adverse developmental and maternal outcomes, including EFDT incidence and the nature and severity of adverse findings.

Comparing rat and rabbit embryo-fetal developmental toxicity data for 379 pharmaceuticals: on systemic dose and developmental effects.

A database of embryo-fetal developmental toxicity (EFDT) studies of 379 pharmaceutical compounds in rat and rabbit was analyzed for species differences based on toxicokinetic parameters of area under the curve (AUC) and maximum concentration (C) at the developmental lowest adverse effect level (dLOAEL). For the vast majority of cases (83% based on AUC of n = 283), dLOAELs in rats and rabbits were within the same order of magnitude (less than 10-fold different) when compared based on available data on AUC and C exposures. For 13.

TGF-β1 monoclonal antibody: Assessment of embryo-fetal toxicity in rats and rabbits.

A humanized monoclonal antibody targeting transforming growth factor β1 (TGF-β1 mab) has been used in development for the treatment of chronic kidney disease. Embryo-fetal development studies were conducted in rats and rabbits using 30 and 25 animals per group, respectively. The TGF-β1 mab was administered subcutaneously to rats at 0, 2, or 50 mg/kg/dose on gestation days (GDs) 6, 10, and 14 and intravenously to rabbits at 0 or 3 mg/kg/dose on GDs 7, 12 to 19, and at 30 mg/kg/dose on GDs 7, 12, 14, 16, and 18.

Birth Control in Clinical Trials: Industry Survey of Current Use Practices, Governance, and Monitoring.

The Health and Environmental Sciences Institute (HESI) Developmental and Reproductive Toxicology Technical Committee sponsored a pharmaceutical industry survey on current industry practices for contraception use during clinical trials. The objectives of the survey were to improve our understanding of the current industry practices for contraception requirements in clinical trials, the governance processes set up to promote consistency and/or compliance with contraception requirements, and the effectiveness of current contraception practices in preventing pregnancies during clinical trials. Opportunities for improvements in current practices were also considered.

Reprint of "Potential seminal transport of pharmaceuticals to the conceptus".

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins.

The use of periodization in exercise prescriptions for inactive adults: A systematic review.

Background: Periodization of exercise is a method typically used in sports training, but the impact of periodized exercise on health outcomes in untrained adults is unclear.

Purpose: This review aims to summarize existing research wherein aerobic or resistance exercise was prescribed to inactive adults using a recognized periodization method.

Methods: A search of relevant databases, conducted between January and February of 2014, yielded 21 studies published between 2000 and 2013 that assessed the impact of periodized exercise on health outcomes in untrained participants.

Potential seminal transport of pharmaceuticals to the conceptus.

Small molecule pharmaceutical products are assumed to reach concentrations in semen similar to those in blood plasma. Exposure modeling for these small-molecule products in humans assumes a daily dose of 5mL of semen and 100% absorption from the vagina with distribution to the conceptus through the maternal systemic circulation. Monoclonal antibody drugs are present in semen at concentrations about 2% or less of those in blood, and the modeling used for small molecules will over-estimate the possibility of conceptus exposure to immunoglobulins.

Developmental Toxicity and Fertility Assessment in Rabbits with Tabalumab: A Human IgG4 Monoclonal Antibody.

Tabalumab is a human immunoglobulin G subclass 4 monoclonal antibody that has been under development for autoimmune disorders. Tabalumab has full neutralizing activity against both soluble and membrane B-cell activating factor, a B-cell survival factor. The objectives of these studies were to assess the effects of tabalumab on embryo-fetal development and on male (M) and female (F) fertility in rabbits, a pharmacologically relevant species.

An Enhanced Pre- and Postnatal Development Study in Cynomolgus Monkeys with Tabalumab: A Human IgG4 Monoclonal Antibody.

Tabalumab, a human IgG4 monoclonal antibody (mAb) with neutralizing activity against both soluble and membrane B-cell activating factor (BAFF), has been under development for the treatment of autoimmune diseases. The purpose of this study was to determine the potential adverse effects of maternal tabalumab exposure on pregnancy, parturition, and lactation of the mothers and on the growth, viability, and development of the offspring through postnatal day (PND) 204. Tabalumab was administered by subcutaneous injection to presumed pregnant cynomolgus monkeys (16-19 per group) every 2 weeks from gestation day (GD) 20 to 22 until parturition at doses of 0, 0.

Assessment of fetal exposure risk following seminal excretion of a therapeutic IgG4 (T-IgG4) monoclonal antibody using a rabbit model.

Studies were conducted in New Zealand White rabbits to assess the seminal transfer, vaginal absorption, and placental transfer of a therapeutic monoclonal antibody (T-IgG4). T-IgG4 was administered by intravenous injection (IV) in males and by IV and intravaginal routes in females. Low levels of T-IgG4 were excreted into seminal plasma (100- to 370-fold lower than serum concentrations) and absorbed following vaginal dosing (three orders of magnitude lower than IV administration).

Placental transfer of Fc-containing biopharmaceuticals across species, an industry survey analysis.

Background: Understanding species differences in placental transfer of Fc-containing biopharmaceuticals (particularly monoclonal antibodies) will improve human risk extrapolation from nonclinical embryo-fetal development toxicity data.

Methods: Maternal and fetal concentration data from 10, 15, 8, and 34 Fc-containing biopharmaceuticals in the rabbit, rat, mouse, and cynomolgus monkey, respectively, from an industry survey were analyzed for trends in placental transfer.

Results And Conclusions: Embryonic (before the end of organogenesis) exposure was assessed in one molecule each in rabbit, rat, and mouse, but detectable levels were present only in rodents.

Fertility and developmental toxicity assessment in rats and rabbits with LY500307, a selective estrogen receptor beta (ERβ) agonist.

LY500307 is a selective estrogen receptor beta (ERβ) agonist that was developed for the treatment of benign prostatic hyperplasia. The in vitro functional selectivity of LY500307 for ERβ agonist activity is 32-fold above the activity at the alpha receptor (ERα). LY500307 was evaluated in a series of male (M) and female (F) rat fertility and rat and rabbit embryo-fetal development (EFD) studies, using 20 or 25 animals/group.

In vitro testicular toxicity models: opportunities for advancement via biomedical engineering techniques.

To address the pressing need for better in vitro testicular toxicity models, a workshop sponsored by the International Life Sciences Institute (ILSI), the Health and Environmental Science Institute (HESI), and the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), was held at the Mt. Washington Conference Center in Baltimore, MD, USA on October 26-27, 2011. At this workshop, experts in testis physiology, toxicology, and tissue engineering discussed approaches for creating improved in vitro environments that would be more conducive to maintaining spermatogenesis and steroidogenesis and could provide more predictive models for testicular toxicity testing.

Summary of the HESI consortium studies exploring circulating inhibin B as a potential biomarker of testis damage in the rat.

The Developmental and Reproductive Toxicity Technical Committee of the Health and Environmental Sciences Institute hosted a working consortium of companies to evaluate a new commercially available analytic assay for Inhibin B in rat serum or plasma. After demonstrating that the kit was stable and robust, the group performed a series of independent pathogenesis studies (23 different compound/investigator combinations) designed to examine the correlation between the appearance of lesions in the testis and changes in circulating levels of Inhibin B. These studies were reported individually in the previous articles in this series (this issue), and are discussed in this paper.

The inhibin B (InhB) response to the testicular toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ) following short-term repeat dosing in the male rat.

Objective: The objective of this study was to evaluate the utility of plasma Inhibin B (InhB) as a biomarker of testicular injury in adult rats following short-term exposure to the known Sertoli cell toxicants mono-2-ethylhexyl phthalate (MEHP), 1,3 dinitrobenzene (DNB), or carbendazim (CBZ).

Methods: Following oral gavage administration of the compounds for 2 or 7 days, the rats were evaluated for clinical signs, body weight, food consumption, organ weights, plasma hormone levels, and gross and microscopic pathology.

Results: MEHP, DNB, and CBZ produced a range of testicular toxicity characterized by minimal exfoliation of germ cells as demonstrated by increased cellular debris in the epididymis (MEHP) to more severe and dose/duration responsive Sertoli cell vacuolation, germ cell degeneration, and multinucleated giant cells of germ cell origin (DNB and CBZ).

Baker's yeast β-glucan supplementation increases monocytes and cytokines post-exercise: implications for infection risk?

Strenuous aerobic exercise is known to weaken the immune system, and while many nutritional supplements have been proposed to boost post-exercise immunity, few are known to be effective. The purpose of the present study was to evaluate whether 10 d of supplementation with a defined source of baker's yeast β-glucan (BG, Wellmune WGP®) could minimise post-exercise immunosuppression. Recreationally active men and women (n 60) completed two 10 d trial conditions using a cross-over design with a 7 d washout period: placebo (rice flour) and baker's yeast BG (250 mg/d of β-1,3/1,6-glucans derived from Saccharomyces cerevisiae) before a bout of cycling (49 ± 6 min) in a hot (38 ± 2°C), humid (45 ± 2 % relative humidity) environment.

Obese Mexican American children have elevated MCP-1, TNF-α, monocyte concentration, and dyslipidemia.

Background And Objective: Obesity is an independent risk factor for chronic disease. The prevalence of obesity is especially high among Mexican American children. Peripheral blood monocytes are altered with obesity contributing to elevated systemic inflammation and increased risk of chronic disease.

A one-year school-based diet/exercise intervention improves non-traditional disease biomarkers in Mexican-American children.

School-based interventions are an effective way to treat childhood obesity. The purpose of the present study was to biologically validate an established school-based intervention designed to reduce standardised body mass index (zBMI) over a period of 12 months. This intervention focused on a subset of Mexican-American children who were participating in a larger clinical weight loss study.

Aged mice have increased inflammatory monocyte concentration and altered expression of cell-surface functional receptors.

The expression of monocyte cell-surface receptors represents one index of immune dysfunction, which is common with aging. Although mouse models of aging are prevalent, monocyte subset assessment is rare. Our purpose was to compare cell receptor expression on classic (CD115+/Gr-1 high) and non-classic (CD115+/Gr-1 low) monocytes from 80- or 20-week-old CD-1 mice.