The Experts below are selected from a list of 399 Experts worldwide ranked by ideXlab platform

Nosratola D Vaziri - One of the best experts on this subject based on the ideXlab platform.

  • oxidative stress in uremia nature mechanisms and potential consequences
    Seminars in Nephrology, 2004
    Co-Authors: Nosratola D Vaziri
    Abstract:

    Oxidative stress has emerged as a constant feature of chronic renal failure (CRF). The presence of oxidative stress in CRF is evidenced by an overabundance of lipid, carbohydrate, and protein oxidation products in the plasma and tissues of uremic patients and animals. We recently have shown that oxidative stress in CRF animals is associated with and, in part, owing to up-regulation of superoxide-producing enzyme, nicotinamide-adenine dinucleotide phosphate (NAD(P)H) oxidase, and down-regulation of superoxide dismutase (SOD). The functional significance of these findings was confirmed by favorable response to administration of the cell-permeable SOD-mimetic agent, tempol, in CRF rats. Oxidative stress in CRF plays an important role in the pathogenesis of the associated hypertension (oxidation of NO and arachidonic acid and vascular remodeling), cardiovascular disease (oxidation of lipoproteins, atherogenesis), neurologic disorders (nitration of brain proteins, oxidation of myelin), anemia (reduction of Erythrocyte Lifespan), inflammation (nuclear factor κ B activation), fibrosis, apoptosis, and accelerated aging. The CRF-induced oxidative stress is aggravated by diabetes, uncontrolled hypertension, and autoimmune diseases, which independently increase production of reactive oxygen intermediates, and frequently are associated with CRF. In addition, dialysis treatment (blood interaction with dialyzer membrane and dialysate impurities), acute and chronic infections (blood access infection, hepatitis, and so forth), and excessive parenteral iron administration intensify CRF-associated oxidative stress and its adverse consequences in patients with end-stage renal disease. The problem is compounded by limited intake of fresh fruits and vegetables (K + restriction), which contain numerous natural phytochemicals and antioxidant vitamins.

Krishnan, Sheeja M - One of the best experts on this subject based on the ideXlab platform.

  • Modeling The Population Dynamics Of Erythrocytes To Identify Optimal Drug Dosages For The Treatment Of Hepatitis C Virus Infection
    2012
    Co-Authors: Krishnan, Sheeja M
    Abstract:

    The current treatment for hepatitis C virus (HCV) infection – combination therapy with pegylated interferon and ribavirin – elicits sustained responses in only ~50% of the patients treated. Greater cumulative exposure to ribavirin increases response to interferon-ribavirin combination therapy. A key limitation, however, is the toxic sideeffect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of Erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases Erythrocyte Lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in Erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced Erythrocyte Lifespan in patients and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones. A small fraction of the population (~30%) with polymorphisms in the ITPA gene shows protection from ribavirin-induced anemia. The optimum dosage of ribavirin that can be tolerated is then dependent on the ITPA polymorphisms. Coupled with a previous population pharmacokinetic study, our model yields a facile formula for estimating the optimum dosage given a patient’s weight, creatinine clearance, pretreatment hemoglobin levels, and ITPA polymorphism. The reduced Lifespan we predict is in agreement with independent measurements from breath tests as well as estimates derived from in vitro studies of ATP depletion. The latter estimates also agree with the extent of ATP depletion due to ribavirin that we predict from a detailed analysis of the nucleoside metabolism in Erythrocytes. Our model thus facilitates in conjunction with models of viral kinetics the rational identification of treatment protocols. Our formula for optimum dose presents an avenue for personalizing ribavirin dosage. By keeping anemia tolerable, the predicted optimal dosage may improve adherence, reduce the need for drug monitoring, and increase response rates

  • Ribavirin-Induced Anemia in Hepatitis C Virus Patients Undergoing Combination Therapy
    Public Library of Science, 2011
    Co-Authors: Krishnan, Sheeja M, Dixit, Narendra M
    Abstract:

    The current standard of care for hepatitis C virus (HCV) infection - combination therapy with pegylated interferon and ribavirin - elicits sustained responses in only similar to 50% of the patients treated. No alternatives exist for patients who do not respond to combination therapy. Addition of ribavirin substantially improves response rates to interferon and lowers relapse rates following the cessation of therapy, suggesting that increasing ribavirin exposure may further improve treatment response. A key limitation, however, is the toxic side-effect of ribavirin, hemolytic anemia, which often necessitates a reduction of ribavirin dosage and compromises treatment response. Maximizing treatment response thus requires striking a balance between the antiviral and hemolytic activities of ribavirin. Current models of viral kinetics describe the enhancement of treatment response due to ribavirin. Ribavirin-induced anemia, however, remains poorly understood and precludes rational optimization of combination therapy. Here, we develop a new mathematical model of the population dynamics of Erythrocytes that quantitatively describes ribavirin-induced anemia in HCV patients. Based on the assumption that ribavirin accumulation decreases Erythrocyte Lifespan in a dose-dependent manner, model predictions capture several independent experimental observations of the accumulation of ribavirin in Erythrocytes and the resulting decline of hemoglobin in HCV patients undergoing combination therapy, estimate the reduced Erythrocyte Lifespan during therapy, and describe inter-patient variations in the severity of ribavirin-induced anemia. Further, model predictions estimate the threshold ribavirin exposure beyond which anemia becomes intolerable and suggest guidelines for the usage of growth hormones, such as erythropoietin, that stimulate Erythrocyte production and avert the reduction of ribavirin dosage, thereby improving treatment response. Our model thus facilitates, in conjunction with models of viral kinetics, the rational identification of treatment protocols that maximize treatment response while curtailing side effects

Junichi Fujii - One of the best experts on this subject based on the ideXlab platform.

  • elevated oxidative stress in Erythrocytes due to a sod1 deficiency causes anaemia and triggers autoantibody production
    Biochemical Journal, 2007
    Co-Authors: Yoshihito Iuchi, Futoshi Okada, Kunishige Onuma, Tadashi Onoda, Hironobu Asao, Masanobu Kobayashi, Junichi Fujii
    Abstract:

    Reactive oxygen species are involved in the aging process and diseases. Despite the important role of Cu/Zn SOD (superoxide dismutase) encoded by SOD1, SOD1−/− mice appear to grow normally under conventional breeding conditions. In the present paper we report on a novel finding showing a distinct connection between oxidative stress in Erythrocytes and the production of autoantibodies against Erythrocytes in SOD1−/− mice. Evidence is presented to show that SOD1 is primarily required for maintaining Erythrocyte Lifespan by suppressing oxidative stress. A SOD1 deficiency led to an increased Erythrocyte vulnerability by the oxidative modification of proteins and lipids, resulting in anaemia and compensatory activation of erythropoiesis. The continuous destruction of oxidized Erythrocytes appears to induce the formation of autoantibodies against certain Erythrocyte components, e.g. carbonic anhydrase II, and the immune complex is deposited in the glomeruli. The administration of an antioxidant, N-acetylcysteine, suppressed Erythrocyte oxidation, ameliorated the anaemia, and inhibited the production of autoantibodies. These data imply that a high level of oxidative stress in Erythrocytes increases the production of autoantibodies, possibly leading to an autoimmune response, and that the intake of antioxidants would prevent certain autoimmune responses by maintaining an appropriate redox balance in Erythrocytes.

Ter Heine Rob - One of the best experts on this subject based on the ideXlab platform.

  • Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa
    'Springer Science and Business Media LLC', 2021
    Co-Authors: Van Beek, Stijn W., Svensson, Elin M., Tiono, Alfred B., Okebe Joseph, D’alessandro Umberto, Gonçalves, Bronner P., Bousema Teun, Drakeley Chris, Ter Heine Rob
    Abstract:

    Background Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. Methods A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established Erythrocyte Lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. Results The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2–8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin 

  • Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa
    'Springer Science and Business Media LLC', 2021
    Co-Authors: Van Beek, Stijn W., Tiono, Alfred B., Okebe Joseph, Gonçalves, Bronner P., Bousema Teun, Drakeley Chris, Svensson Elin, D'alessandro Umberto, Ter Heine Rob
    Abstract:

    Background Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. Methods A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established Erythrocyte Lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. Results The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women >= 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. Conclusions This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient

Bosman G.j.c.g.m. - One of the best experts on this subject based on the ideXlab platform.

  • The red cell revisited--matters of life and death.
    2004
    Co-Authors: Werre J.m., Willekens F.l.a., Bosch F.h., L.d. De ,haans, Vegt, S.g. Van Der, Bos, A.g. Van Den, Bosman G.j.c.g.m.
    Abstract:

    An Erythrocyte-fractionating method combining volume and subsequent density separation is described. Iron isotope (59Fe)-validation proved this combination of methods to be complementary. By deploying HbA1c as cell age marker, obtained fractions demonstrated that circulating Erythrocytes lose 20% of hemoglobin and membrane by shedding vesicles. Vesiculation from older cells proved to be facilitated by the spleen. Animal studies revealed that such vesicles are rapidly removed from the circulation by scavenger receptors on Kupffer cells with phosphatidylserine acting as the principal ligand. These studies reveal the existence of an alternative pathway of Erythrocyte breakdown. This means that the premortal substrate of 20% of any Erythrocyte is at our disposal. As this kind of vesiculation takes place during the entire Erythrocyte Lifespan, loss and sometimes reutilisation of marker substances limits the usefulness of isotope studies to the first half of the Erythrocyte Lifespan, thereby putting the dogmatic Lifespan of 120 days into question. Furthermore, these studies add to the understanding of hemoglobin A1c (HbA1c) metabolism and the origin of the wide variation of Erythrocyte parameters in peripheral blood. Removal of old Erythrocytes from the circulation and from donor blood may open new ways into the treatment of both bilirubin and secondary iron overload

  • The red cell revisited--matters of life and death.
    2004
    Co-Authors: Werre J.m., Willekens F.l.a., Bosch F.h., L.d. De ,haans, Vegt, S.g. Van Der, Bos, A.g. Van Den, Bosman G.j.c.g.m.
    Abstract:

    Item does not contain fulltextAn Erythrocyte-fractionating method combining volume and subsequent density separation is described. Iron isotope (59Fe)-validation proved this combination of methods to be complementary. By deploying HbA1c as cell age marker, obtained fractions demonstrated that circulating Erythrocytes lose 20% of hemoglobin and membrane by shedding vesicles. Vesiculation from older cells proved to be facilitated by the spleen. Animal studies revealed that such vesicles are rapidly removed from the circulation by scavenger receptors on Kupffer cells with phosphatidylserine acting as the principal ligand. These studies reveal the existence of an alternative pathway of Erythrocyte breakdown. This means that the premortal substrate of 20% of any Erythrocyte is at our disposal. As this kind of vesiculation takes place during the entire Erythrocyte Lifespan, loss and sometimes reutilisation of marker substances limits the usefulness of isotope studies to the first half of the Erythrocyte Lifespan, thereby putting the dogmatic Lifespan of 120 days into question. Furthermore, these studies add to the understanding of hemoglobin A1c (HbA1c) metabolism and the origin of the wide variation of Erythrocyte parameters in peripheral blood. Removal of old Erythrocytes from the circulation and from donor blood may open new ways into the treatment of both bilirubin and secondary iron overload