Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension

Benoit Deschamps1, Naomi Musaji2, John A Gillespie21SFBC Anapharm, Montreal, Canada; 2Strativa Pharmaceuticals, a division of Par Pharmaceutical, Inc., Woodcliff Lake, NJ, USAObjective: Megestrol acetate oral suspension (MAOS) is an appetite stimulant indicated for cachexia in patients with AIDS. It is available in its original formulation, Megace® (MAOS), and as a nanocrystal dispersion, Megace® ES (MA-ES). Three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions.Methods: An open-label, crossover trial was conducted in 24 healthy males randomized to MA-ES 625 mg/5 mL given with a high-calorie, high-fat meal, or after an overnight fast. Blood samples were drawn at multiple time points and pharmacokinetic parameters were determined. Two separate, open-label reference studies evaluated MAOS 800 mg/20 mL in 40 fed or 40 fasting healthy male volunteers.Results: In fasting MA-ES subjects, the average maximum concentration (Cmax) was 30% less than the fed Cmax value. For MAOS, fasting Cmax was 86% less than fed Cmax. In fasting subjects, the area under the curve was 12,095 ng⋅h/mL for MA-ES, and 8,942 ng⋅h/mL for MAOS. In fed subjects, the absorption of the two formulations was comparable.Conclusion: Bioavailability and absorption are greater for MA-ES than MAOS in fasting subjects. MA-ES may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced.Keywords: megestrol acetate, bioavailability, cachexia, nanocrystal technology, appetite stimulan

Pembuatan Pendeteksi Gas Beracun Portable Untuk Penggali Sumur Berbasis Mikrokontroler

Pembuatan sumur timba memiliki resiko atau bahaya yang sangat tinggi. Hal ini dapat mengakibatkan penggali sumur keracunan udara yang terdapat di dalam tanah karena di dalam tanah yang akan digali memiliki beberapa gas beracun diantaranya gas CO, CO2, CH4 dan H2S. Dan yang paling berbahaya adalah gas CO dan CH4, karena jika gas tersebut terhirup melebihi ambang batas, maka akan menyebabkan sulit bernafas, tidak sadarkan diri, hingga kematian. Dari permasalahan tersebut maka dibuatlah alat pendeteksi gas beracun portable untuk penggali sumur berbasis mikrokontroler yang dapat mendeteksi adanya kadar gas beracun yang ditempatkan pada badan penggali sumur. Jika gas beracun terdeteksi oleh sensor gas MQ-7 untuk pendeteksi gas CO dan sensor gas MQ-4 untuk pendeteksi gas CH4, maka buzzer dan led menyala sebagai indikator, kemudian RF 433 mHz mengirimkan data ke LCD (Liquid Crystal Display) yang ada diatas sumur sebagai media penampil informasi. Hasil akhir dari alat ini yaitu ketika ppm mencapai angka lebih dari 500 atau melebihi ambang batas, maka indikator buzzer akan berbunyi, led akan menyala dan pada layar LCD akan menampilkan gas beracun yang terdeteksi ======================================================================================================================== Dipper well construction risk or danger is very high. This can result in well-digging poisoning the air contained in the ground as in the soil to be excavated have some toxic gases including CO gas, CO2, CH4 and H2S. And the most dangerous is the gas CO and CH4, because if the gas is inhaled exceeds the threshold, it will cause difficult breathing, unconsciousness, and death. Of the problems it is made portable toxic gas detection equipment for digging wells based microcontroller that can detect the presence of high levels of toxic gas that is placed on the bodydigging. If a toxic gas is detected by a gas sensor MQ-7 for the detection of CO gas and gas sensors MQ-4 for detecting CH4, then the buzzer and the LED lights up as an indicator, then RF 433 MHz transmit data to LCD (Liquid Crystal Display) that are above the well as a media viewer information. The final result of this tool is when ppm reached more than 500, or exceeds the threshold, the indicator buzzer will sound, and the LED will light up on the LCD screen will display the toxic gases were detecte

Comparing In-Person and Telepractice Service Delivery for Spoken Language Production and Comprehension Using the National Outcomes Measurement System

The American Speech-Language-Hearing Association (ASHA) developed the National Outcomes Measurement System for aggregating standardized patient outcomes. Outcomes are standardized using Functional Communication Measures (FCM), scales designed to describe communicative function across specific areas of clinical need. This investigation compared in-person and telepractice service delivery for children in elementary school settings who received treatment targeting the FCM categories of either “spoken language production” or “spoken language comprehension.” De-identified cases were secured from ASHA’s NOMS database and the database of a private e-learning provider that implemented the NOMS format. There were minimal significant differences in the median change scores between the traditional and telepractice interventions. These results support comparable treatment outcomes between in-person service delivery and telepractice for treatment of children exhibiting impaired spoken language production or spoken language comprehension in an elementary school settin

Pathway of Toll-Like Receptor 7/B Cell Activating Factor/B Cell Activating Factor Receptor Plays a Role in Immune Thrombocytopenia In Vivo

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti-platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP

Antigenic Complementarity in the Origins of Autoimmunity: A General Theory Illustrated With a Case Study of Idiopathic Thrombocytopenia Purpura

We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria

Experimental models of autoimmune thrombocytopenia in the mouse

De nombreux travaux antérieurs ont indiqué que la reconnaissance du soi par le système immunitaire joue un rôle fonctionnel. Cependant, en cas de dérégulation, ce type de réponse immunitaire normale peut conduire au développement de maladies auto-immunitaires. Parmi les facteurs qui transforment une réponse auto-immune en une pathologie auto-immune, les facteurs environnementaux, et particulièrement les virus, sont très souvent impliqués. De nombreux rapports cliniques ont en effet associé des infections virales avec la progression de maladies auto-immunes. Cependant, peu de modèles expérimentaux ont permis l’étude de la modulation de pathologies auto-immunes pré-existantes par des infections virales. Les principaux objectifs de ce travail étaient de développer un modèle murin de purpura thrombocytopénique auto-immune (AITP) humain et d’étudier les mécanismes effecteurs de la modulation d’une telle pathologie par un virus, en l’occurrence le « lactate dehydrogensase-elevating virus » (LDV). Un modèle d’AITP a donc été développé chez la souris par immunisations répétées avec les plaquettes de rat. La production d’auto-anticorps dirigés contre les plaquettes de souris a été analysée par ELISA, Western blots et cytométrie en flux. L’immunisation a induit une thrombocytopénique transitoire chez des souris CBA/Ht, leurs plaquettes étant opsonisées par des auto-anticorps cross-réagissant avec les plaquettes normale de rat et de souris. Par contre, des souris BALB/c immunisées de la même manière avec des plaquettes de rat, n’ont pas développé de thrombocytopénie. La spécificité de la réponse anticorps induite chez ces deux souches de souris était profondément différente, un antigène plaquettaire de souris de 145 – 155 kDA , correspondant à la glycoprotéine plaquettaire Ib (CD42b) étant reconnu chez le souris CBA/Ht, mais pas chez les BALB/c. Des expériences de déplétion par du clodronate ont montré que les macrophages étaient les cellules effectrices responsables de la destruction des plaquette couvertes d’anticorps. Nous avosn égelament montré que le LDV seul induisait une thrombocytopénie transitoire dans les 6 premiers jours qui suivent l’infection. Les plaquettes sont détruites par des macrophages qui ne se situent pas dans la rate. Au contraire de l’interféron-gamma, le M-CSF a pu être impliqué dans cette thrombocytopénie transitoire induite par le LDV, car des souris infectées par ce virus et traitées par des anticorps anti-M-CSF avaient des taux plaquettaires significativement plus élevés que des animaux non traités. Afin d’analyser la modulation par le LDV d’une AITP expérimentale, des modèles plus simples de thrombocytopénie ont été utilisés. Dans ces modèles la pathologie auto-immunitaire est induite par un transfert passif d’auto-anticorps monoclonaux anti-plaquettes de souris dérivés de souris F1 NZBxBXSB, d’anticorps polyclonaux obtenus de lapins immunisés ou d’anticorps monoclonaux commerciaux produit chez le rat. Nous avons montré dans ces modèles d’AITP qu’une infection viral peut augmenter la pathogénicité de réponses auto-immunes pré-existantes. L’infection conduisait à une augmentation importante de la destruction des plaquettes induite par les auto-anticorps, ce qui aboutissait au développement d’une thrombopénie mesurable et de symptômes cliniques, comme des pétéchies. L’infection virale induisait une augmentation de la phagogytose des plaquettes couvertes d’auto-anticorps. La pathogénicité des auto-anticorps nécessitait le présence de leur fraction Fc, suggérant l’implication de récepteurs pour cette . fraction Fc ou pour le complément, exprimés sur ces macrophages. Le rôle crucial des macrophages et de l’interféron-gamma dans cette destruction de plaquettes couvertes d’auto-anticorps induite par un virus a pu être mis en évidenceMany reports in the literature indicate that self recognition by the immune system has a physiological role. However, when deregulated, this normal type of immune response can lead to autoimmune diseases. Among factors that drive autoimmune response to autoimmune pathology, environmental factors, and especially viruses, play one of the most important roles. Many clinical reports have indeed associated viruses with autoimmune disease progression. However, few experimental models have addressed the question of the modulation of pre-existing autoimmune pathology by viruses. The main objectives of this work were to develop a mouse model of human idiopathic autoimmune thrombocytopenic purpura (AITP) and to study the effector mechanisms of viral modulation exemplified by lactate dehydrogenase-elevating virus (LDV). A mouse ITP model was developed by repetitive active immunizations of mice with rat platelets. Anti-mouse platelet autoantibody responses were analyzed by ELISA, Western blots and flow cytometry. Immunized CBA/Ht mice showed a transient thrombocytopenia. Platelets were opsonized by cross-reactive autoantibodies to both rat and mouse normal platelets. In contrast, BALB/c mice similarly immunized with rat platelets did not develop thrombocytopenia. The specificity of the antibody response elicited in these two mouse strains differed markedly, with a 145-155 kDa mouse platelet antigen, corresponding to platelet glycoprotein Ib (CD42b) recognized in CBA/Ht, but not in BALB/c animals. In clodronate-depleting experiments, macrophages were shown to be the effector cells responsible for antibody-coated platelet destruction. LDV infection alone was shown to induce a transient thrombocytopenia in the first 6 days after infection. Platelets are destroyed by macrophages that are not resident in the spleen. In contrast to IFN-gamma, M-CSF was shown to be involved in LDV-induced transient thrombocytopenia since LDV-infected mice treated with anti-M-CSF antibodies showed significantly higher platelet counts than their untreated counterparts. In order to study the modulation effects of LDV on experimentally-induced AITP, more simplified mouse experimental models of ITP were established. In these models, the autoimmune pathology is mimicked by a passive transfer of monoclonal autoantibodies, derived from NZWxBXSB F1 mice as well as by a passive transfer of either polyclonal (obtained from an immunized rabbit) or monoclonal (commercial antibody derived from the rat) antibodies. It was shown in experimental models of AITP, that a viral infection may enhance the pathogenicity of pre-existing autoimmune responses. The virus was found to largely increase the platelet destruction induced by anti-platelet autoantibodies, leading to the development of measurable thrombopenia and of clinical symptoms (petechiae). Viral infection triggered an enhancement of phagocytosis of autoantibody-coated target cells (platelets). The pathogenicity of the autoantibodies required the presence of their Fc portion, suggesting that macrophage Fc and/or complement receptor expression is involved. Macrophages and IFN-gamma secretion also played a pivotal role in this virally-induced destruction of autoantibody-coated thrombocytes.Thèse de doctorat en sciences biomédicales (SBIM 3)--UCL, 200

The development of the translation movement /

The development of the translation movement in Islamic history was a long, intricate movement which encompassed a large number of people over a long period of time. It is the objective of this paper to assess the historical setting which gave rise to this movement as well as to evaluate why it was embraced. Moving onward, the paper will then move to a more detailed examination of six translators, in an effort to evaluate their contribution to the movement. While doing this, an inventory will be conducted of the works which were translated in the three disciplines of astrology, philosophy, and medicine by these translators in an attempt to answer the question of why the selection process was so specific and what perhaps were the criteria for these choices