Absorption via the intestinal lymphatic system is known to be important for some highly lipophilic compounds, and can be associated with unique pharmacokinetic properties due to evasion of hepatic first-pass metabolism. This work aimed to develop a physiologically-based pharmacokinetic model incorporating the role of lymphatic transport in a physiologically-based, mechanistic oral absorption model, using halofantrine as a model compound. Simcyp V19 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model, and the model was constructed and verified using parameters derived from in vitro experiments and clinical PK data. The final model appeared to adequately capture halofantrine pharmacokinetics in the fasted state and the magnitude of the effect of food on halofantrine total exposure; the effect of food on peak exposure was slightly underpredicted, which may be due to transient post-prandial changes in protein binding. The model simulated halofantrine fraction absorbed (fa) via the lymph in the fed state was 0.26, representing 62% of the increase in fa in the fed state over fasting. This work demonstrates that a PBPK modeling approach can be used to mechanistically describe oral absorption incorporating intestinal lymphatic transport.Membrane permeation enhancers have received significant attention in recent years for enabling the oral absorption of poorly permeable drug molecules. In this study, we investigated the ability of His-Ala-Val (HAV) and Ala-Asp-Thr (ADT) peptides derived from the extracellular-1 (EC1) domain of E-cadherin proteins to increase the paracellular permeation and intestinal bioavailability of the poorly permeable model macromolecule, fluorescein-isothiocyanate dextran with average molecular weight 4000 (FD4). The in vitro enzymatic stability of linear and cyclic E-cadherin peptides was characterized under simulated gastric and intestinal conditions, and the cyclic E-cadherin peptides, HAVN1 and ADTC5, which demonstrated excellent stability in vitro, were advanced to in vivo intestinal instillation studies and compared against the established surfactant membrane permeation enhancer, sodium caprate (C10). Cyclic HAVN1 and ADTC5 peptides increased FD4 bioavailability by 7.2- and 4.4-fold compared to control, respectively (not statistically significant). In contrast, C10 provided a statistically significant 10.7-fold relative bioavailability enhancement for FD4. Importantly, this study represents the first report of cyclic E-cadherin peptides as intestinal membrane permeation enhancers. The findings described herein demonstrate the potential of enzymatically stabilized cyclic E-cadherin peptides for increasing poorly permeable drug absorption via the oral route.A recently published mechanistic skin permeability model (Kasting et al., 2019. J Pharm Sci 108337-349) that included a follicular diffusion pathway has been extended to describe transient diffusion and finite dose applications. The model follows the disposition of two components, solute and solvent, so that solvent deposition processes can be explicitly represented. Experimentally-calibrated permeability characteristics of the follicular pathway leading to the permeation of highly hydrophilic permeants are further refined.  https://www.selleckchem.com/products/Puromycin-2HCl.html  Details of the refinements and a comparison with the earlier model using two large experimental datasets are presented. An example calculation shows the marked difference between the time scales for achievement of near steady-state diffusion for large hydrophilic and lipophilic compounds, with the former being more than 100-fold faster than the latter. However, the true steady state for the hydrophilic compound is not reached until much later due to the very slow filling of the corneocyte phase.Nitrate reductase (NR) from the fungus Neurospora crassa is a complex homodimeric metallo-flavoenzyme, where each protomer contains three distinct domains; the catalytically active terminal molybdopterin cofactor, a central heme-containing domain, and an FAD domain which binds with the natural electron donor NADPH. Here, we demonstrate the catalytic voltammetry of variants of N. crassa NRs on a modified Au electrode with the electrochemically reduced forms of benzyl viologen (BV2+) and anthraquinone sulfonate (AQS-) acting as artificial electron donors. The biopolymer chitosan used to entrap NR on the electrode non-covalently and the enzyme film was both stable and highly active. Electrochemistry was conducted on two distinct forms; one lacking the FAD cofactor and the other lacking both the FAD and heme cofactors. While both enzymes showed catalytic nitrate reductase activity, removal of the heme cofactor resulted in a more significant effect on the rate of nitrate reduction. Electrochemical simulation was carried out to enable kinetic characterisation of both the NRnitrate and NRmediator reactions.The mitochondrial permeability transition pore (mPTP) is a channel that, when open, is responsible for a dramatic increase in the permeability of the mitochondrial inner membrane, a process known as the mitochondrial permeability transition (mPT). mPTP activation during Ca2+ dyshomeostasis and oxidative stress disrupts normal mitochondrial function and induces cell death. mPTP opening has been implicated as a critical event in many diseases, including hypoxic injuries, neurodegeneration, and diabetes. Discoveries of recent years indicate that mPTP demonstrates very complicated behavior and regulation, and depending on specific induction or stress conditions, it can function as a high-conductance pore, a small channel, or a non-specific membrane leak. The focus of this review is to summarize the literature on the electrophysiological properties of the mPTP and to evaluate the evidence that it has multiple molecular identities. This review also provides perspective on how an electrophysiological approach can be used to quantitatively investigate the biophysical properties of the mPTP under physiological, pharmacological, pathophysiological, and disease conditions.
  Early brain injury (EBI) and delayed cerebral ischemia (DCI) after subarachnoid haemorrhage (SAH) has devastating consequences but therapeutic options and the underlying pathogenesis remain poorly understood despite extensive preclinical and clinical research. One of the drawbacks of most preclinical studies to date is that the mechanisms behind DCI after SAH are studied only in male animals. In this study we therefore established a female rat model of SAH in order to determine subacute pathophysiological changes that may contribute to DCI in females.
 
  Experimental SAH was induced in female rats by intracisternal injection of 300μL of autologous blood. Sham operation served as a control. Neurological deficits and intracranial pressure measurements were evaluated at both 1 and 2days after surgery. Additionally, changes in cerebral vascular contractility were evaluated 2days after surgery using wire myography.
 
  SAH in female rats resulted in sensorimotor deficits and decreased general wellbeing on both day 1 and day 2 after SAH.