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Celiac disease (CD) is one of the most common human intestinal malabsorption diseases. The only effective treatment for patients with CD is to follow a gluten-free (GF) diet strictly. Nowadays, the increasing incidence of CD promotes worldwide interests for various desirable GF products. However, baking without gluten, the key ingredient for bread structure and quality, is a big challenge for all bakers and cereal researchers. Several approaches have been applied to understand and improve gluten-free bread (GFB) elaboration and further studies are still required. The main focus of this review is to discuss the approaches for GFB improvements in recent 5 years, including the use of novel alternative flours, functional ingredients, processing aids, additives, innovative techniques, and their combinations.

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Two-pore PBPK models have been used for characterizing the PK of protein therapeutics since 1990s. However, widespread utilization of these models is hampered by the lack of a priori parameter values, which are typically estimated using the observed data. To overcome this hurdle, here we have presented the development of a two-pore PBPK model using de novo derived parameters. The PBPK model was validated using plasma PK data for different size proteins in mice. Using the "two pore theory" we were able to establish the relationship between protein size and key model parameters, such as: permeability-surface area product (PS), vascular reflection coefficient (σ), peclet number (Pe), and glomerular sieving coefficient (θ). The model accounted for size dependent changes in tissue extravasation and glomerular filtration. The model was able to a priori predict the PK of 8 different proteins: IgG (150 kDa), scFv-Fc (105 kDa), F(ab) 2 (100 kDa, minibody (80 kDa), scFv 2 (55 kDa), Fab (50 kDa), diabody (50 kDa), scFv (27 kDa), and nanobody (13 kDa). In addition, the model was able to provide unprecedented quantitative insight into the relative contribution of convective and diffusive pathway towards trans-capillary mass transportation of different size proteins. The two-pore PBPK model was also able to predict systemic clearance (CL) vs. Molecular Weight relationship for different size proteins reasonably well. As such, the PBPK model proposed here represents a bottom-up systems PK model for protein therapeutics, which can serve as a generalized platform for the development of truly translational PBPK model for protein therapeutics.

Protein and peptide conjugates have become an important component of therapeutic and diagnostic medicine. These conjugates are primarily designed to improve pharmacokinetics (PK) of those therapeutic or imaging agents, which do not possess optimal disposition characteristics. In this review we have summarized preclinical and clinical PK of diverse protein and peptide conjugates, and have showcased how different conjugation approaches are used to obtain the desired PK. We have classified the conjugates into peptide conjugates, non-targeted protein conjugates, and targeted protein conjugates, and have highlighted diagnostic and therapeutic applications of these conjugates. In general, peptide conjugates demonstrate very short half-life and rapid renal elimination, and they are mainly designed to achieve high contrast ratio for imaging agents or to deliver therapeutic agents at sites not reachable by bulky or non-targeted proteins. Conjugates made from non-targeted proteins like albumin are designed to increase the half-life of rapidly eliminating therapeutic or imaging agents, and improve their delivery to tissues like solid tumors and inflamed joints. Targeted protein conjugates are mainly developed from antibodies, antibody derivatives, or endogenous proteins, and they are designed to improve the contrast ratio of imaging agents or therapeutic index of therapeutic agents, by enhancing their delivery to the site-of-action.

In this study, a novel glycerosome carrier containing essential oils was prepared for topical administration of paeoniflorin (PF) to enhance its transdermal drug delivery and improve drug absorption in the synovium. The formulation of glycerosomes was optimized by a uniform design, and the final vehicle was composed of 5% (w/v) phospholipid, 0.6% (w/v) cholesterol, and 10% (v/v) glycerol, with 2% (v/v) Speranskia tuberculata essential oil (STO) as the transdermal enhancer. The in vitro transdermal flux of PF loaded in the STO-glycerosomes was 1.4-fold, 1.6-fold, and 1.7-fold higher than those of glycerosomes, liposomes, and tinctures, respectively. In vivo studies showed that the use of STO-glycerosomes was associated with a 3.1-fold greater accumulation of PF in the synovium than that of common glycerosomes. This finding was confirmed by in vivo imaging studies, which found that the fluorescence intensity of Cy5.5-loaded STO-glycerosomes in mice knee joints was 1.8-fold higher than that of the common glycerosomes 5 h after administration. The glycerosomes mediated by STO exhibited considerable skin permeability as well as improved drug absorption in the synovium, indicating that STO-glycerosomes may be a potential PF transdermal delivery vehicle for the treatment of rheumatoid arthritis caused by synovium lesions.

To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological functions of PDE9 inhibition.

Optimization efforts were devoted to discover novel PDE10A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension (PAH) starting from the previously synthesized inhibitor A . As a result, a potent and highly selective PDE10A inhibitor, 14· 3HCl (half maximal inhibitory concentration, IC 50 = 2.8 nmol/L and > 3500-fold selectivity) exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of 50% was identified with the aid of efficient methods of binding free energy predictions. Animal PAH studies showed that the improvement offered by 14· 3HCl [2.5 mg/kg, oral administration ( p.o .)] was comparable to tadalafil (5.0 mg/kg, p.o .), verifying the feasibility of PDE10A inhibitors for the anti-PAH treatment. The crystal structure of the PDE10A− 14 complex illustrates their binding pattern, which provided a guideline for rational design of highly selective PDE10A inhibitors.