Linking the concentrations of itraconazole and 2-hydroxypropyl-β-cyclodextrin in human intestinal fluids after oral intake of Sporanox^®

In a previously performed small-scale clinical study, healthy volunteers were asked to ingest an oral solution of itraconazole (Sporanox®) containing 40% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) (i) with or (ii) without a standardized volume of water (240 mL) after which gastrointestinal and blood samples were collected. Although omitting water during the administration of Sporanox® resulted in noticeably higher duodenal concentrations of itraconazole, systemic exposure was almost unaffected. It is assumed that this discrepancy can be explained by differences in the extent of entrapment of itraconazole in the duodenum caused by differential complexation depending on the concentration of cyclodextrins. To further substantiate this hypothesis, the quantification of HP-β-CD concentrations in the aspirated intestinal fluids was performed by LC-MS/MS. When comparing the intestinal concentrations of itraconazole and HP-β-CD for one single healthy volunteer (HV02) in both test conditions, an excellent correlation was observed (Spearman's rank coefficient of 0.96). Moreover, the data suggest that, similar to aqueous buffer media, also in human intestinal fluids a non-linear relationship exists between itraconazole solubility and HP-β-CD concentration (Ap-type profile; Spearman's rank coefficient of 0.78), indicating that higher order complexes are formed at higher concentrations of HP-β-CD. This difference in extent of entrapment in the inclusion complexes helps to understand the observed impact of water intake on precipitation and permeation behavior of itraconazole in man. Without water intake, higher HP-β-CD concentrations resulted in less precipitation and increased duodenal concentrations of itraconazole. On the other hand, the stronger interaction at higher HP-β-CD concentrations reduced the free fraction of the drug explaining that increased intraluminal concentrations of itraconazole were not translated into an enhanced uptake. In conclusion, quantifying the concentrations of the solubilizing agent HP-β-CD in human intestinal fluids appeared to be of crucial importance to interpret the intraluminal behavior of an orally administered cyclodextrin-based solution

An adolescent with both Wegener's Granulomatosis and chronic blastomycosis

We report a case of Wegener's Granulomatosis (WG) associated with blastomycosis. This appears to be the first case report of WG co-existing with a tissue proven blastomycosis infection. The temporal correlation of the two conditions suggests that blastomycosis infection (and therefore possibly other fungal infections), may trigger the systemic granulomatous vasculitis in a predisposed individual; a provocative supposition warranting further study

Methodological quality of a systematic review on physical therapy for temporomandibular disorders: influence of hand search and quality scales

The validity of a systematic review depends on completeness of identifying randomised clinical trials (RCTs) and the quality of the included RCTs. The aim of this study was to analyse the effects of hand search on the number of identified RCTs and of four quality lists on the outcome of quality assessment of RCTs evaluating the effect of physical therapy on temporomandibular disorders. In addition, we investigated the association between publication year and the methodological quality of these RCTs. Cochrane, Medline and Embase databases were searched electronically. The references of the included studies were checked for additional trials. Studies not electronically identified were labelled as “obtained by means of hand search”. The included RCTs (69) concerning physical therapy for temporomandibular disorders were assessed using four different quality lists: the Delphi list, the Jadad list, the Megens & Harris list and the Risk of Bias list. The association between the quality scores and the year of publication were calculated. After electronic database search, hand search resulted in an additional 17 RCTs (25%). The mean quality score of the RCTs, expressed as a percentage of the maximum score, was low to moderate and varied from 35.1% for the Delphi list to 54.3% for the Risk of Bias list. The agreement among the four quality assessment lists, calculated by the Interclass Correlation Coefficient, was 0.603 (95% CI, 0.389; 0.749). The Delphi list scored significantly lower than the other lists. The Risk of Bias list scored significantly higher than the Jadad list. A moderate association was found between year of publication and scores on the Delphi list (r = 0.50), the Jadad list (r = 0.33) and the Megens & Harris list (r = 0.43)

Comparison between Bipolar Hemiarthroplasty and Total Hip Arthroplasty for Unstable Intertrochanteric Fractures in Elderly Osteoporotic Patients

The present study was conducted to compare bipolar hemiarthroplasty (BA) with total hip arthroplasty (THA) in treatment of unstable intertrochanteric fractures in elderly osteoporotic patients. The THA group included 14 males and 26 females with a mean age of 73.4 years, and the BA group included 27 males and 45 females with a mean age of 76.5 years. Significant difference existed between the two groups in operation time, blood loss, transfusion volume and cost of hospitalization, while no remarkable difference was identified in hospitalization period, general complications, joint function, pain, rate of revision and mortality. No dislocation was observed in BA group while 3 occurred in THA group. The results indicated that for unstable intertrochanteric fractures in elderly osteoporotic patients, BA seems to be a better or more reasonable choice compared with THA for the reason of less blood loss, shorter operation time, lower cost and no dislocation

Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities

Various gastrointestinal (GI) factors affect drug and formulation behavior after oral administration, including GI transfer, motility, pH and GI fluid volume and composition. An in-depth understanding of these physiological and anatomical variables is critical for a continued progress in oral drug development. In this review, different methodologies (invasive versus non-invasive) to explore the impact of physiological variables on formulation behavior in the human GI tract are presented, revealing their strengths and limitations. The techniques mentioned allow for an improved understanding of the role of following GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and intraluminal pH (intraluminal sampling and telemetry)

ND:GLASS LASER DESIGN FOR LASER ICF FISSION ENERGY (LIFE)

ABSTRAC

Pre-formulation and delivery strategies for the development of bacteriocins as next generation antibiotics

peer-reviewedBacteriocins, a class of antimicrobial peptide produced by bacteria, may offer a potential alternative to traditional antibiotics, an important step towards mitigating the ever increasing antimicrobial resistance crisis. They are active against a range of clinically relevant Gram-positive and Gram-negative bacteria. Bacteriocins have been discussed in the literature for over a century. Although they are used as preservatives in food, no medicine based on their antimicrobial activity exists on the market today. In order to formulate them into clinical antibiotics, pre-formulation studies on their biophysical and physicochemical properties that will influence their activity in vivo and their stability during manufacture must be elucidated. Thermal, pH and enzymatic stability of bacteriocins are commonly studied and regularly reported in the literature. Solubility, permeability and aggregation properties on the other hand are less frequently reported for many bacteriocins, which may contribute to their poor clinical progression. Promising cytotoxicity studies report that bacteriocins exhibit few cytotoxic effects on a variety of mammalian cell lines, at active concentrations. This review highlights the lack of quantitative data and in many cases even qualitative data, on bacteriocins’ solubility, stability, aggregation, permeability and cytotoxicity. The formulation strategies that have been explored to date, proposed routes of administration, trends in in vitro/in vivo behaviour and efforts in clinical development are discussed. The future promise of bacteriocins as a new generation of antibiotics may require tailored local delivery strategies to fulfil their potential as a force to combat antimicrobial-resistant bacterial infections

Adiabatic following model for two-photon transitions: Nonlinear mixing and pulse propagation

Two-photon resonantly enhanced parametric generation processes have generally been described using time-dependent perturbation theory. In this paper we show that a theory of two-photon coherent effects can be used to derive and explain these nonlinear mixing processes. Our technique makes use of the adiabatic following (AF) approximation to obtain solutions to a vector model describing the two-photon resonance. We show that the usual results for the nonlinear susceptibilities correspond to the r vector of Feynman, Vernon, and Hellwarth adiabatically following the gamma vector in the small-angle limit. Consequently, the theory allows a natural extension to large angles, and power-dependent nonlinear susceptibilities are obtained. We then use these AF results for the polarization to study the propagation of pulses nearly resonant with a two-photon transition, and we demonstrate that the pulse reshaping is due to the two related effects of a nonlinear pulse velocity and self-phase modulation.Peer reviewedElectrical and Computer Engineerin