The Calcivis story - enamel caries activity assessment from technology to practice.

The Calcivis story is one of innovation and collaboration to deliver new technology capable of helping dentists improve patient care through solving an unmet clinical need in assessing the activity of caries lesions in enamel. Presently, there is no system routinely used in dental practice that can, in a single visit, determine whether a non-cavitated caries lesion is active or not. Calcivis has evolved since 2005, when a potential link between basic science in luminescence and differentiating initial-stage caries lesions that are actively demineralising and likely to progress, from other lesions which are inactive and currently do not need interventive care, was recognised.

Exacerbation of Background Nuclear Cataracts in Sprague-Dawley Rats in Embryo-Fetal Development Studies With JNJ-42165279, a Fatty Acid Amide Hydrolase Inhibitor.

Fetal examinations in embryo-fetal developmental (EFD) studies are based on macroscopic and dissecting microscopic evaluations, and histopathology is rarely performed other than to confirm macroscopic findings. Fetal lens examination is therefore generally limited to the presence, size, shape, and color of any abnormality. In a Sprague-Dawley rat EFD study with the fatty acid amide hydrolase (FAAH) inhibitor JNJ-42165279, an unusually high incidence of macroscopic granular foci was noted within the lens of gestation day 21 fetuses across all groups including controls, with higher incidence in the high-dose group.

Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study.

Background: The 2013-16 Ebola virus disease epidemic in west Africa caused international alarm due to its rapid and extensive spread resulting in a significant death toll and social unrest within the affected region. The large number of cases provided an opportunity to study the long-term kinetics of Zaire ebolavirus-specific immune response of survivors in addition to known contacts of those infected with the virus.

Methods: In this observational cohort study, we worked with leaders of Ebola virus disease survivor associations in two regions of Guinea, Guéckédou and Coyah, to recruit survivors of Ebola virus disease, contacts from households of individuals known to have had Ebola virus disease, and individuals who were not knowingly associated with infected individuals or had not had Ebola virus disease symptoms to serve as negative controls.

Preclinical toxicity and pharmacokinetics of a new orally bioavailable flubendazole formulation and the impact for clinical trials and risk/benefit to patients.

Background: Flubendazole, originally developed to treat infections with intestinal nematodes, has been shown to be efficacious in animal models of filarial infections. For treatment of filarial nematodes, systemic exposure is needed. For this purpose, an orally bioavailable amorphous solid dispersion (ASD) formulation of flubendazole was developed.

Timing is everything for sperm assessment in fertility studies.

The fertility study design recommended in the ICH S5(R2) Harmonised Guideline for Detection of Toxicity to Reproduction for Medicinal Products emphasizes the importance of histopathological endpoints next to a pairing assessment in evaluating male fertility. However, in a male rat fertility study with JNJ-26489112, a CNS-active agent, while there were no effects on histological endpoints, mating performance or pregnancy outcomes, sperm assessment was included. The high dose males presented with reversible decreases in epididymal, but not testicular, sperm concentration and motility and an increase in abnormal sperm morphology.

"All pigs are equal" Does the background data from juvenile Göttingen minipigs support this?

For pediatric indications requiring juvenile toxicity testing, the rat is the preferred species. However, for some drugs it might not be an appropriate model or regulatory agencies may also request a non-rodent species. Due to the relatively recent use of Göttingen minipigs, little background data are available.

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.

Assessment of cervical passage of vital dyes in pregnant, nonpregnant, and mated rats and mice.

Risk assessment for indirect exposure to small molecule pharmaceuticals in semen to the conceptus has traditionally been handled by calculations based on assumptions that any embryo-fetal exposure would be secondary to maternal absorption and redistribution. This study was designed to assess the potential for transcervical passage of drugs from semen. Reproductive tracts of rodents were examined following vaginal dosing with vital dyes during the estrous cycle, mating, and pregnancy.

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.

Periradicular regenerative surgery in a maxillary central incisor: 7-year results including cone-beam computed tomography.

Introduction: A case of a symptomatic maxillary central incisor that underwent periradicular regenerative surgery with a successful long-term clinical and radiographic outcome is presented.

Methods: A 52-year old woman was referred to the Endodontology Clinic, UCL Eastman Dental Institute and Hospital, London, UK, in 2004 for swelling and discoloration of the maxillary right central incisor. There was a history of trauma 21 years previously.

Significance of Theileria orientalis types in individual affected beef herds in New South Wales based on clinical, smear and PCR findings.

Cattle within seven NSW herds with a history or risk of clinical Theileria orientalis disease associated with introductions of cattle were examined clinically and by haematological and PCR testing at sequential bleeds or at single sampling of different risk subgroups. The T. orientalis Ikeda type was detected in all herds and Chitose type was detected in six.

Theileria orientalis MPSP types in Australian cattle herds associated with outbreaks of clinical disease and their association with clinical pathology findings.

Between September 2010 and November 2011, 350 EDTA blood samples were received from 73 Australian cattle herds, as cases suspected to be infected with Theileria orientalis. Beef cattle were predominantly affected, with Angus and Angus-crossbred cattle representing 48% of smear positive samples examined. DNA extracts were tested in conventional polymerase chain reaction (PCR) assays for genes encoding the p32, Ikeda, Chitose and Buffeli major piroplasm surface proteins (MPSP).

Value of juvenile animal studies.

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development.

The value of juvenile animal studies "What have we learned from preclinical juvenile toxicity studies? II".

Recent changes in the regulations from the FDA and EMA have shifted the focus of juvenile toxicity studies more to the safe use of all pharmaceuticals and the absence of label or safety information for the pediatric population. Unlike other regulatory guidance, the need or design of these animal studies is not specified. Ideally these should be decided "case-by-case" based on the patient population, pharmacology, existing toxicological and clinical data, dosing regimen, and developing system impact.

Juvenile animal toxicity study designs to support pediatric drug development.

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance.

Pre- and postnatal developmental toxicity study design for pharmaceuticals.

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the ICH S5(R2) document. The studies that assess the hazard of both pre- and postnatal exposure are predominantly conducted in rodents (rat and mouse). Utilizing the collective experience of the authors, acceptable designs for both the range-finding and definitive studies are presented with detailed descriptions for the presentation of data.

Proton-linked dimerization of a retroviral capsid protein initiates capsid assembly.

In mature retroviral particles, the capsid protein (CA) forms a shell encasing the viral replication complex. Human immunodeficiency virus (HIV) CA dimerizes in solution, through its C-terminal domain (CTD), and this interaction is important for capsid assembly. In contrast, other retroviral capsid proteins, including that of Rous sarcoma virus (RSV), do not dimerize with measurable affinity.

What have we learned from pre-clinical juvenile toxicity studies?

Juvenile toxicity studies have assumed a higher priority within the pharmaceutical industry following recent changes in regulations. The requirement and designs of these studies should be on a 'case-by-case' basis. Discussions have suggested that recently the regulatory agencies have requested a more standard design incorporating multiple parameters, despite the disparity in the data available and the mode of action and indication of the respective drugs.

Structure-function analysis of RAMP1 by alanine mutagenesis.

Receptor activity modifying protein 1 (RAMP1) is an integral component of several receptors including the calcitonin gene-related peptide (CGRP) receptor. It forms a complex with the calcitonin receptor-like receptor (CLR) and is required for receptor trafficking and ligand binding. The N-terminus of RAMP1 comprises three helices.

The ontogeny of drug metabolizing enzymes and transporters in the rat.

Knowledge of the ontogeny of the various systems involved in distribution and elimination of drugs is important for adequate interpretation of the findings during safety studies in juvenile animals. The present study was designed to collect information on plasma concentrations of total protein and albumin, enzyme activity and mRNA expression of cytochrome P450 isoenzymes (CYP1A1/2, CYP2B1/2, CYP2E1, CYP3A1/2, and CYP4A1), carboxylesterase and thyroxin glucuronidation (T4-GT) activity in liver microsomes, and mRNA expression of transporters (Mdr1a/b, Mrp1-3 and 6, Bsep and Bcrp, Oct1-2, Oat1-3 and Oatp1a4) in liver, kidney and brain tissue during development in Sprague-Dawley rats. Enzyme activities were determined by measuring the metabolism of marker substrates; expression of mRNAs was assessed using RTq-PCR.