Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropyl methyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media

Impact of Bile Salts on Solution Crystal Growth Rate and Residual Supersaturation of an Active Pharmaceutical Ingredient

Supersaturating formulations have become a popular approach to address the issue of inadequate aqueous solubility for small molecules. Given that prevention of nucleation may not be always possible, it is of particular interest to control crystal growth from supersaturated solutions in order to maximize the extent of oral absorption of therapeutic agents. Bile salts are endogenous surfactants that are present in biorelevant dissolution media and can have direct impact on the in vivo performance of therapeutic agents due to their presence in the gastrointestinal tract. In this study, an in situ common history seeding method was implemented to provide seeds that better mimic crystals formed from aqueous supersaturated solutions. By forming seeds in situ and then regenerating supersaturation, we were able to probe the influence of biorelevant bile salts on telaprevir crystal growth rates and secondary nucleation. The extent of growth inhibition was found to vary with bile salt chemistry and aggregation level. It was also noted that sodium taurocholate and sodium taurochenodeoxycholate inhibited secondary nucleation of telaprevir from highly supersaturated solutions. The impact of bile salts on crystal growth and secondary nucleation is of relevance for improved understanding of precipitation kinetics of supersaturating dosage forms

A 14-year experience with kidney transplantation.

Between November, 1962 and August, 1975, 668 kidney transplants were done in 556 consecutive patients at Denver, Colorado. The Denver experience has been divided into 7 periods of time, according to the conditions of care during each period. The results in related transplantation have changed little during the decade beginning in 1966. The results in unrelated transplantation have not materially changed since 1968. The long-term patient survival after related transplantation has been better than after cadaver transplantation. The results of transplantation in 57 children ages 3 to 18 years have been slightly better than the results of adult transplantation. The outcome of kidney transplantation and the feasibility of improving this therapy with present techniques are limited by our inability to accurately match each patient with the immunologically best donor and by our inability to precisely control the immune system of the recipient. Rejection is still the main reason for graft loss, and sepsis remains the main cause of patient mortality. More specific and less toxic means of achieving graft acceptance are needed before a higher level of patient service can be realized. However, even with the tools now available, thousands of recipients throughout the world have been returned to useful lives

The Atmospheric Chemistry Suite (ACS) of Three Spectrometers for the ExoMars 2016 Trace Gas Orbiter

The Atmospheric Chemistry Suite (ACS) package is an element of the Russian contribution to the ESA-Roscosmos ExoMars 2016 Trace Gas Orbiter (TGO) mission. ACS consists of three separate infrared spectrometers, sharing common mechanical, electrical, and thermal interfaces. This ensemble of spectrometers has been designed and developed in response to the Trace Gas Orbiter mission objectives that specifically address the requirement of high sensitivity instruments to enable the unambiguous detection of trace gases of potential geophysical or biological interest. For this reason, ACS embarks a set of instruments achieving simultaneously very high accuracy (ppt level), very high resolving power (>10,000) and large spectral coverage (0.7 to 17 μm—the visible to thermal infrared range). The near-infrared (NIR) channel is a versatile spectrometer covering the 0.7–1.6 μm spectral range with a resolving power of ∼20,000. NIR employs the combination of an echelle grating with an AOTF (Acousto-Optical Tunable Filter) as diffraction order selector. This channel will be mainly operated in solar occultation and nadir, and can also perform limb observations. The scientific goals of NIR are the measurements of water vapor, aerosols, and dayside or night side airglows. The mid-infrared (MIR) channel is a cross-dispersion echelle instrument dedicated to solar occultation measurements in the 2.2–4.4 μm range. MIR achieves a resolving power of >50,000. It has been designed to accomplish the most sensitive measurements ever of the trace gases present in the Martian atmosphere. The thermal-infrared channel (TIRVIM) is a 2-inch double pendulum Fourier-transform spectrometer encompassing the spectral range of 1.7–17 μm with apodized resolution varying from 0.2 to 1.3 cm−1. TIRVIM is primarily dedicated to profiling temperature from the surface up to ∼60 km and to monitor aerosol abundance in nadir. TIRVIM also has a limb and solar occultation capability. The technical concept of the instrument, its accommodation on the spacecraft, the optical designs as well as some of the calibrations, and the expected performances for its three channels are described

An overview of anti-diabetic plants used in Gabon: Pharmacology and Toxicology

© 2017 Elsevier B.V. All rights reserved.Ethnopharmacological relevance: The management of diabetes mellitus management in African communities, especially in Gabon, is not well established as more than 60% of population rely on traditional treatments as primary healthcare. The aim of this review was to collect and present the scientific evidence for the use of medicinal plants that are in currect by Gabonese traditional healers to manage diabetes or hyperglycaemia based here on the pharmacological and toxicological profiles of plants with anti-diabetic activity. There are presented in order to promote their therapeutic value, ensure a safer use by population and provide some bases for further study on high potential plants reviewed. Materials and methods: Ethnobotanical studies were sourced using databases such as Online Wiley library, Pubmed, Google Scholar, PROTA, books and unpublished data including Ph.D. and Master thesis, African and Asian journals. Keywords including ‘Diabetes’ ‘Gabon’ ‘Toxicity’ ‘Constituents’ ‘hyperglycaemia’ were used. Results: A total of 69 plants currently used in Gabon with potential anti-diabetic activity have been identified in the literature, all of which have been used in in vivo or in vitro studies. Most of the plants have been studied in human or animal models for their ability to reduce blood glucose, stimulate insulin secretion or inhibit carbohydrates enzymes. Active substances have been identified in 12 out of 69 plants outlined in this review, these include Allium cepa and Tabernanthe iboga. Only eight plants have their active substances tested for anti-diabetic activity and are suitables for further investigation. Toxicological data is scarce and is dose-related to the functional parameters of major organs such as kidney and liver. Conclusion: An in-depth understanding on the pharmacology and toxicology of Gabonese anti-diabetic plants is lacking yet there is a great scope for new treatments. With further research, the use of Gabonese anti-diabetic plants is important to ensure the safety of the diabetic patients in Gabon.Peer reviewedFinal Accepted Versio

Search for lepton-flavor violation at HERA

A search for lepton-flavor-violating interactions $e p \to \mu X$ and $e p\to \tau X$ has been performed with the ZEUS detector using the entire HERA I data sample, corresponding to an integrated luminosity of 130 pb^{-1}. The data were taken at center-of-mass energies, $\sqrt{s}$, of 300 and 318 GeV. No evidence of lepton-flavor violation was found, and constraints were derived on leptoquarks (LQs) that could mediate such interactions. For LQ masses below $\sqrt{s}$, limits were set on $\lambda_{eq_1} \sqrt{\beta_{\ell q}}$, where $\lambda_{eq_1}$ is the coupling of the LQ to an electron and a first-generation quark $q_1$, and $\beta_{\ell q}$ is the branching ratio of the LQ to the final-state lepton $\ell$ ($\mu$ or $\tau$) and a quark $q$. For LQ masses much larger than $\sqrt{s}$, limits were set on the four-fermion interaction term $\lambda_{e q_\alpha} \lambda_{\ell q_\beta} / M_{\mathrm{LQ}}^2$ for LQs that couple to an electron and a quark $q_\alpha$ and to a lepton $\ell$ and a quark $q_\beta$, where $\alpha$ and $\beta$ are quark generation indices. Some of the limits are also applicable to lepton-flavor-violating processes mediated by squarks in $R$-Parity-violating supersymmetric models. In some cases, especially when a higher-generation quark is involved and for the process $e p\to \tau X$, the ZEUS limits are the most stringent to date.Comment: 37 pages, 10 figures, Accepted by EPJC. References and 1 figure (Fig. 6) adde

Multijet production in neutral current deep inelastic scattering at HERA and determination of alpha_s

Multijet production rates in neutral current deep inelastic scattering have been measured in the range of exchanged boson virtualities 10 < Q2 < 5000 GeV2. The data were taken at the ep collider HERA with centre-of-mass energy sqrt(s) = 318 GeV using the ZEUS detector and correspond to an integrated luminosity of 82.2 pb-1. Jets were identified in the Breit frame using the k_T cluster algorithm in the longitudinally invariant inclusive mode. Measurements of differential dijet and trijet cross sections are presented as functions of jet transverse energy E_{T,B}{jet}, pseudorapidity eta_{LAB}{jet} and Q2 with E_{T,B}{jet} > 5 GeV and -1 < eta_{LAB}{jet} < 2.5. Next-to-leading-order QCD calculations describe the data well. The value of the strong coupling constant alpha_s(M_Z), determined from the ratio of the trijet to dijet cross sections, is alpha_s(M_Z) = 0.1179 pm 0.0013(stat.) {+0.0028}_{-0.0046}(exp.) {+0.0064}_{-0.0046}(th.)Comment: 22 pages, 5 figure

Measurement of (anti)deuteron and (anti)proton production in DIS at HERA

The first observation of (anti)deuterons in deep inelastic scattering at HERA has been made with the ZEUS detector at a centre-of-mass energy of 300--318 GeV using an integrated luminosity of 120 pb-1. The measurement was performed in the central rapidity region for transverse momentum per unit of mass in the range 0.3<p_T/M<0.7. The particle rates have been extracted and interpreted in terms of the coalescence model. The (anti)deuteron production yield is smaller than the (anti)proton yield by approximately three orders of magnitude, consistent with the world measurements.Comment: 26 pages, 9 figures, 5 tables, submitted to Nucl. Phys.

Measurement of the open-charm contribution to the diffractive proton structure function

Production of D*+/-(2010) mesons in diffractive deep inelastic scattering has been measured with the ZEUS detector at HERA using an integrated luminosity of 82 pb^{-1}. Diffractive events were identified by the presence of a large rapidity gap in the final state. Differential cross sections have been measured in the kinematic region 1.5 < Q^2 < 200 GeV^2, 0.02 < y < 0.7, x_{IP} < 0.035, beta 1.5 GeV and |\eta(D*+/-)| < 1.5. The measured cross sections are compared to theoretical predictions. The results are presented in terms of the open-charm contribution to the diffractive proton structure function. The data demonstrate a strong sensitivity to the diffractive parton densities.Comment: 35 pages, 11 figures, 6 table

Photoproduction of D∗±D^{*\pm} mesons associated with a leading neutron

The photoproduction of $D^{*\pm} (2010)$ mesons associated with a leading neutron has been observed with the ZEUS detector in $ep$ collisions at HERA using an integrated luminosity of 80 pb$^{-1}$. The neutron carries a large fraction, {$x_L>0.2$}, of the incoming proton beam energy and is detected at very small production angles, {$\theta_n<0.8$ mrad}, an indication of peripheral scattering. The $D^*$ meson is centrally produced with pseudorapidity {$|\eta| 1.9$ GeV}, which is large compared to the average transverse momentum of the neutron of 0.22 GeV. The ratio of neutron-tagged to inclusive $D^*$ production is $8.85\pm 0.93({\rm stat.})^{+0.48}_{-0.61}({\rm syst.})\%$ in the photon-proton center-of-mass energy range {$130 <W<280$ GeV}. The data suggest that the presence of a hard scale enhances the fraction of events with a leading neutron in the final state.Comment: 28 pages, 4 figures, 2 table