Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products.

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1M HCl for 2h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer

Wireless pH-motility capsule for colonic transit: prospective comparison with radiopaque markers in chronic constipation

Colon transit (CT) measurements are used in the management of significant constipation. The radiopaque marker (ROM) method provides limited information.We proposed to validate wireless motility capsule (WMC), that measures pH, pressure and temperature, to ROM measurement of CT in patients with symptomatic constipation evaluated at multiple centers. Of 208 patients recruited, 158 eligible patients underwent simultaneous measurement of colonic transit time (CTT) using ROM (Metcalf method, cut off for delay >67 h), and WMC (cutoff for delay >59 h). The study was designed to demonstrate substantial equivalence, defined as diagnostic agreement >65% for patients who had normal or delayed ROM transit.Fifty-nine of 157 patients had delayed ROM CT. Transit results by the two methods differed: ROM median 55.0 h [IQR 31.0–85.0] and WMC (43.5 h [21.7–70.3], P  < 0.001. The positive percent agreement between WMC and ROM for delayed transit was ∼80%; positive agreement in 47 by WMC/59 by ROM or 0.796 (95% CI = 0.67–0.98); agreement vs null hypothesis (65%) P  = 0.01. The negative percent agreement (normal transit) was ∼91%: 89 by WMC/98 by ROM or 0.908 (95% CI = 0.83–0.96); agreement vs null hypothesis (65%), P  = 0.00001. Overall device agreement was 87%. There were significant correlations ( P  < 0.001) between ROM and WMC transit (CTT [ r  = 0.707] and between ROM and combined small and large bowel transit [ r  = 0.704]). There were no significant adverse events.The 87% overall agreement (positive and negative) validates WMC relative to ROM in differentiating slow vs normal CT in a multicenter clinical study of constipation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79053/1/j.1365-2982.2010.01517.x.pd

Phage therapy efficacy: a review of the last 10 years of preclinical studies

Due to the rise of multidrug-resistant infections in humans, phage therapy is gaining renewed attention in Western medicine. Despite the increasing number of publications focussed on the isolation, characterization and in vitro performance of different phages, there is still a lack of concise pre-clinical information to guide the application of phage therapy in clinical practice. Nevertheless, over the last decade, efforts have been made to conduct more detailed studies of the in vivo efficacy of phages. Here, we review the most relevant in vivo studies performed in the last decade covering phage efficacy in both preclinical and clinical trials. We compare different routes of administration, dosage effect and different animal models of distinct types of infections. Moreover, insights into case studies and results from clinical trials are presented. Challenges and limitations of phage use as evidenced by the current state of research are also discussed in order to improve both the trustworthiness and success of the implementation of phage therapy.This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit, COMPETE 2020 [POCI-01-0145-FEDER-006684] and Projects PTDC/SAU-PUB/29182/2017 [POCI-01-0145-FEDER-029182] and PTDC/CVTCVT/29628/2017 [POCI-01-0145-FEDER-029628]. This work was also supported by BioTecNorte operation [NORTE-01- 0145-FEDER-000004] funded by the European Regional Development Fund under the scope of Norte2020 - Programa Operacional Regional do Norte. DPP was supported by a FCT grant [SFRH/BPD/116187/2016]. KD is the recipient of the National Science Centre in Poland grant [UMO-2018/29/B/NZ6/01659]. The funding bodies had no role in study design, data collection and analysis, preparation of the manuscript, or the decision to publish.info:eu-repo/semantics/publishedVersio

Quantum mechanical polar surface area

A correlation has been established between the absorbed fraction of training-set molecules after oral administration in humans and the Quantum Mechanical Polar Surface Area (QMPSA). This correlation holds for the QMPSA calculated with structures where carboxyl groups are deprotonated. The correlation of the absorbed fraction and the QMPSA calculated on the neutral gas phase optimized structures is much less pronounced. This suggests that the absorption process is mainly determined by polar interactions of the drug molecules in water solution. Rules are given to derive the optimal polar/apolar ranges of the electrostatic potential

Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo- controlled trial

ABSTRACT Objective: To evaluate the efficacy and safety of longterm budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis

A proposal for a study on treatment selection and lifestyle recommendations in chronic inflammatory diseases:A danish multidisciplinary collaboration on prognostic factors and personalised medicine

Chronic inflammatory diseases (CIDs), including Crohn’s disease and ulcerative colitis (inflammatory bowel diseases, IBD), rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritides, hidradenitis suppurativa, and immune-mediated uveitis, are treated with biologics targeting the pro-inflammatory molecule tumour necrosis factor-α (TNF) (i.e., TNF inhibitors). Approximately one-third of the patients do not respond to the treatment. Genetics and lifestyle may affect the treatment results. The aims of this multidisciplinary collaboration are to identify (1) molecular signatures of prognostic value to help tailor treatment decisions to an individual likely to initiate TNF inhibitor therapy, followed by (2) lifestyle factors that support achievement of optimised treatment outcome. This report describes the establishment of a cohort that aims to obtain this information. Clinical data including lifestyle and treatment response and biological specimens (blood, faeces, urine, and, in IBD patients, intestinal biopsies) are sampled prior to and while on TNF inhibitor therapy. Both hypothesis-driven and data-driven analyses will be performed according to pre-specified protocols including pathway analyses resulting from candidate gene expression analyses and global approaches (e.g., metabolomics, metagenomics, proteomics). The final purpose is to improve the lives of patients suffering from CIDs, by providing tools facilitating treatment selection and dietary recommendations likely to improve the clinical outcome