Effect of Gastric Fluid Volume on the in Vitro Dissolution and in Vivo Absorption of BCS Class II Drugs: A Case Study with Nifedipine

Nifedipine is a BCS Class II drug used for treatment of hypertension and preterm labor. Large inter-patient variability in nifedipine absorption results in variable exposure among different patients. We conducted in vitro dissolution studies to compare nifedipine dissolution from immediate release (IR) capsules with different volumes of dissolution media. Results from dissolution studies were used to design a crossover study in healthy volunteers to evaluate the effect of coadministered water volume with nifedipine 10 mg IR capsules on nifedipine pharmacokinetics, especially absorption (Cmax, tmax, and AUC0-6). Dissolution studies demonstrated that larger gastric fluid volumes result in enhanced nifedipine dissolution from 10 mg IR cosolvent capsules (73 vs. 17% in 200 and 100 mL simulated gastric fluid, respectively, at 30 min). The pharmacokinetic crossover study in healthy volunteers (N = 6) did not show a significant effect of the water volume administered with the capsule (50 vs. 250 mL) on Cmax, tmax, or AUC0-6 of orally administered nifedipine IR capsules (10 mg). However, administration of large water volumes resulted in lower variability in nifedipine Cmax (47 vs. 70% for 250 and 50 mL, respectively). Administration of large water volumes with nifedipine 10 mg IR cosolvent capsules may reduce inter-individual variability in plasma exposure. Evaluation of similar effects in other BCS Class II drugs is recommended

Osteopathology and insect traces in the Australopithecus africanus skeleton StW 431

We present the first application of high-resolution micro computed tomography in an analysis of both the internal and external morphology of the lumbar region of StW 431 – a hominin skeleton recovered from Member 4 infill of the Sterkfontein Caves (South Africa) in 1987. The lumbar vertebrae of the individual present a number of proliferative and erosive bony processes, which were investigated in this study. Investigations suggest a complex history of taphonomic alteration to pre-existing spinal degenerative joint disease (SDJD) as well as post-mortem modification by an unknown insect. This study is in agreement with previous pathological diagnoses of SDJD which affected StW 431 and is the first time insect traces on this hominin are described. The results of this analysis attest to the complex series of post-mortem processes affecting the Sterkfontein site and its fossil assemblages

Response to Thackeray (2016) – The possibility of lichen growth on bones of Homo naledi: Were they exposed to light?

Thackeray1 questions the hypothesis of deliberate body disposal in the Rising Star Cave by Homo naledi, as proposed by Dirks and colleagues2. Thackeray proposes that lichens produced mineral staining on the skeletal remains of H. naledi. As lichens require some exposure to light, in Thackeray’s opinion, the presence of mineral staining necessitates either a direct entrance deep into the Rising Star Cave that once admitted light into the Dinaledi Chamber, or relocation of mineral-stained bones from a location exposed to light. Here we consider multiple lines of evidence that reject Thackeray’s hypothesis that lichens deposited mineral staining upon the surface of these skeletal remains. We welcome the opportunity to address the inferences presented by Thackeray, and further hope that this response may dispel misinterpretations of our research2, and of other areas of the scientific literature that bear upon site formation processes at work within the Rising Star Cave system

Improving preclinical to clinical translation in Alzheimer\u27s disease research.

Introduction: Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer\u27s disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility during execution. In an effort to improve this translation, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium has established a rigorous screening strategy with go/no-go decision points that permits unbiased assessments of therapeutic agents. Methods: An initial screen evaluates drug stability, formulation, and pharmacokinetics (PK) to confirm appreciable brain exposure in the disease model at the pathologically relevant ages, followed by pharmacodynamics (PD) and predictive PK/PD modeling to inform the dose regimen for long-term studies. The secondary screen evaluates target engagement and disease modifying activity using non-invasive positron emission tomography/magnetic resonance imaging (PET/MRI). Provided the compound meets its go criteria for these endpoints, evaluation for efficacy on behavioral endpoints are conducted. Results: Validation of this pipeline using tool compounds revealed the importance of critical quality control (QC) steps that researchers need to be aware of when executing preclinical studies. These include confirmation of the active pharmaceutical ingredient and at the precise concentration expected; and an experimental design that is well powered and in line with the Animal Research Reporting of In vivo Experiments (ARRIVE) guidelines. Discussion: Taken together our experience executing a rigorous screening strategy with QC checkpoints provides insight to the challenges of conducting translational studies in animal models. The PTC pipeline is a National Institute on Aging (NIA)-supported resource accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), and these resources will ultimately enable better translational studies to be conducted

STOP-AD portal: Selecting the optimal pharmaceutical for preclinical drug testing in Alzheimer\u27s disease.

We propose an unbiased methodology to rank compounds for advancement into comprehensive preclinical testing for Alzheimer\u27s disease (AD). Translation of compounds to the clinic in AD has been hampered by poor predictive validity of models, compounds with limited pharmaceutical properties, and studies that lack rigor. To overcome this, MODEL-AD\u27s Preclinical Testing Core developed a standardized pipeline for assessing efficacy in AD mouse models. We hypothesize that rank-ordering compounds based upon pharmacokinetic, efficacy, and toxicity properties in preclinical models will enhance successful translation to the clinic. Previously compound selection was based solely on physiochemical properties, with arbitrary cutoff limits, making ranking challenging. Since no gold standard exists for systematic prioritization, validating a selection criteria has remained elusive. The STOP-AD framework evaluates the drug-like properties to rank compounds for in vivo studies, and uses an unbiased approach that overcomes the validation limitation by performing Monte-Carlo simulations. HIGHLIGHTS: Promising preclinical studies for AD drugs have not translated to clinical success. Systematic assessment of AD drug candidates may increase clinical translatability. We describe a well-defined framework for compound selection with clear selection metrics

Generation of renewable mouse intestinal epithelial cell monolayers and organoids for functional analyses

Abstract Background Conditional reprogramming has enabled the development of long-lived, normal epithelial cell lines from mice and humans by in vitro culture with ROCK inhibitor on a feeder layer. We applied this technology to mouse small intestine to create 2D mouse intestinal epithelial monolayers (IEC monolayers) from genetic mouse models for functional analysis. Results IEC monolayers form epithelial colonies that proliferate on a feeder cell layer and are able to maintain their genotype over long-term passage. IEC monolayers form 3D spheroids in matrigel culture and monolayers on transwell inserts making them useful for functional analyses. IEC monolayers derived from the Cystic Fibrosis (CF) mouse model CFTR ∆F508 fail to respond to CFTR activator forskolin in 3D matrigel culture as measured by spheroid swelling and transwell monolayer culture via Ussing chamber electrophysiology. Tumor IEC monolayers generated from the ApcMin/+ mouse intestinal cancer model grow more quickly than wild-type (WT) IEC monolayers both on feeders and as spheroids in matrigel culture. Conclusions These results indicate that generation of IEC monolayers is a useful model system for growing large numbers of genotype-specific mouse intestinal epithelial cells that may be used in functional studies to examine molecular mechanisms of disease and to identify and assess novel therapeutic compounds

Earliest hominin cancer: 1.7-million-year old osteosarcoma from Swartkrans Cave, South Africa

The reported incidence of neoplasia in the extinct human lineage is rare, with only a few confirmed cases of Middle or Later Pleistocene dates reported. It has generally been assumed that premodern incidence of neoplastic disease of any kind is rare and limited to benign conditions, but new fossil evidence suggests otherwise. We here present the earliest identifiable case of malignant neoplastic disease from an early human ancestor dated to 1.8–1.6 million years old. The diagnosis has been made possible only by advances in 3D imaging methods as diagnostic aids. We present a case report based on re-analysis of a hominin metatarsal specimen (SK 7923) from the cave site of Swartkrans in the Cradle of Humankind, South Africa. The expression of malignant osteosarcoma in the Swartkrans specimen indicates that whilst the upsurge in malignancy incidence is correlated with modern lifestyles, there is no reason to suspect that primary bone tumours would have been any less frequent in ancient specimens. Such tumours are not related to lifestyle and often occur in younger individuals. As such, malignancy has a considerable antiquity in the fossil record, as evidenced by this specimen