Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Senicapoc, a novel Gardos channel inhibitor, limits solute and water loss, thereby preserving sickle red blood cell (RBC) hydration. Because hemoglobin S polymerization is profoundly influenced by intracellular hemoglobin concentration, senicapoc could improve sickle RBC survival. In a 12-week, multicenter, phase 2, randomized, double-blind, dose-finding study, we evaluated senicapoc's safety and its effect on hemoglobin level and markers of RBC hemolysis in sickle cell anemia patients. The patients were randomized into 3 treatment arms: placebo; low-dose (6 mg/day) senicapoc; and high-dose (10 mg/day) senicapoc. For the primary efficacy end point (change in hemoglobin level from baseline), the mean response to high-dose senicapoc treatment exceeded placebo (6.8 g/L [0.68 g/dL] vs 0.1 g/L [0.01 g/dL], P < .001). Treatment with high-dose senicapoc also produced significant decreases in such secondary end points as percentage of dense RBCs (-2.41 vs -0.08, P < .001); reticulocytes (-4.12 vs -0.46, P < .001); lactate dehydrogenase (-121 U/L vs -15 U/L, P = .002); and indirect bilirubin (-1.18 mg/dL vs 0.12 mg/dL, P < .001). Finally, senicapoc was safe and well tolerated. The increased hemoglobin concentration and concomitant decrease in the total number of reticulocytes and various markers of RBC destruction following senicapoc administration suggests a possible increase in the survival of sickle RBCs. This study is registered at http://clinicaltrials.gov as NCT00040677.
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PMID:Efficacy and safety of the Gardos channel blocker, senicapoc (ICA-17043), in patients with sickle cell anemia. 1843 67

The birth and mortality rates in the Democratic Republic of Congo (DRC), a former Belgian colony, are high, i.e., 48.9/1000 and 17/1000 respectively. The DRC also has one of the highest maternal death rates in the world, i.e., 1289/100,000 live births. Health conditions have not improved since independence. Access to drinking water is limited, living conditions are poor, and food availability in households is low. The mean health services utilization rate in the DRC is estimated to be 0.15 visits/inhabitant/year. The incidence of transmissible diseases is rising. This increase is observed even for illnesses that were under control before independence such as sleeping sickness, onchocerciasis, leprosy, and tuberculosis. One the main causes of mortality and morbidity in the population is malaria that is responsible for the deaths of 150,000 to 250,000 children under the age of 5 every year. The HIV prevalence rate is 4.5% with 1.19 million persons with AIDS and 930,000 orphans whose parents died of AIDS. Other potentially epidemic diseases including bubonic plaque and Ebola hemorrhagic fever are serious threats. Non-transmissible diseases are also on the rise including diabetes, systemic arterial hypertension, cancer and neglected diseases such as sickle cell anemia. To meet these challenges, the country's health authorities have established a program called the Strategy for Reinforcement of the Health System (SRHS). One goal of the SRHS is to develop health zones in order to improve access to quality health care for the whole population.
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PMID:[Medicine and health in the Democratic Republic of Congo: from Independence to the Third Republic]. 1822 27

Sickle cell disease (SCD) is a hereditary condition characterized by deformation of red blood cells (RBCs). This phenomenon is due to the presence of abnormal hemoglobin that polymerizes upon deoxygenation. This effect is exacerbated when dehydrated RBCs experience a loss of both water and potassium salts. One critical pathway for the regulation of potassium efflux from RBCs is the Gardos channel, a calcium-activated potassium channel. This paper describes the synthesis and biological evaluation of a series of potent inhibitors of the Gardos channel. The goal was to identify compounds that were potent and selective inhibitors of the channel but had improved pharmacokinetic properties compared to 1, Clotrimazole. Several triarylamides such as 10 and 21 were potent inhibitors of the Gardos channel (IC50 of <10 nM) and active in a mouse model of SCD. Compound 21 (ICA-17043) was advanced into phase 3 clinical trials for SCD.
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PMID:Novel inhibitors of the Gardos channel for the treatment of sickle cell disease. 1823 33

Clotrimazole, a poorly water-soluble antimycotic agent, is a promising therapeutic agent for various diseases including cancer and sickle cell anemia. The oral bioavailability and hepatic toxicity of clotrimazole were compared with its beta-cyclodextrin inclusion form which was prepared by the spray-drying method. The inclusion complex gave significantly higher initial plasma concentrations, Cmax and AUC than did clotrimazole alone, indicating that the drug from the inclusion compound could be more easily absorbed in rats. Furthermore, mice treated with the inclusion compound showed significantly higher GOT/GPT values compared to clotrimazole alone. The inclusion compound also induced hypertrophy of hepatic cells by fat accumulation and disappearance of hepatic sinusoids, indications of pathological changes of liver, suggesting that the inclusion compound could induce more severe tissue damage in the liver than clotrimazole alone. Thus, hepatotoxicity of clotrimazole seems to be correlated with the enhanced oral bioavailability by inclusion complexation. Our results suggest that, in the development of a novel oral product, appearance or enhancement of hepatic toxicity must be considered along with oral bioavailability.
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PMID:The effect of beta-cyclodextrin complexation on the bioavailability and hepatotoxicity of clotrimazole. 1823 80

Sickle cell anemia is associated with the mutant hemoglobin HbS, which forms polymers in red blood cells of patients. The growth rate of the polymers is several micrometers per second, ensuring that a polymer fiber reaches the walls of an erythrocyte (which has a 7-microm diameter) within a few seconds after its nucleation. To understand the factors that determine this unusually fast rate, we analyze data on the growth rate of the polymer fibers. We show that the fiber growth follows a first-order Kramers-type kinetics model. The entropy of the transition state for incorporation into a fiber is 95 J mol(-1) K(-1), very close to the known entropy of polymerization. This agrees with a recent theoretical estimate for the hydrophobic interaction and suggests that the gain of entropy in the transition state is due to the release of the last layer of water molecules structured around contact sites on the surface of the HbS molecules. As a result of this entropy gain, the free-energy barrier for incorporation of HbS molecules into a fiber is negligible and fiber growth is unprecedentedly fast. This finding suggests that fiber growth can be slowed by components of the red cell cytosol, native or intentionally introduced, which restructure the hydration layer around the HbS molecules and thus lower the transition state entropy for incorporation of an incoming molecule into the growing fiber.
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PMID:Determination of the transition-state entropy for aggregation suggests how the growth of sickle cell hemoglobin polymers can be slowed. 1828 Apr 99

Anisotropic protein interactions play a role in globular protein phase transitions, including the shape of fluid-fluid coexistence curves and the formation of hemoglobin polymer fibers in sickle cell disease. Also, the solvent has been shown to play an important role in the phase behavior of some aqueous protein solutions, through the release or trapping of water molecules upon crystallization. Both anisotropy and solvent effects have been treated separately in earlier theoretical studies. Here we propose and analyze a simple, composite model that treats both anisotropy and solvent effects. We find that this model qualitatively explains some phase behavior that has been observed in protein solutions, including normal and retrograde solubility curves and lower critical points.
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PMID:Effect of solvent on the phase diagram of a simple anisotropic model of globular proteins. 1853 89

Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.
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PMID:Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia. 1923 69

The parametric variational two-electron reduced-density-matrix (2-RDM) method is applied to computing electronic correlation energies of medium-to-large molecular systems by exploiting the spatial locality of electron correlation within the framework of the cluster-in-molecule (CIM) approximation [S. Li et al., J. Comput. Chem. 23, 238 (2002); J. Chem. Phys. 125, 074109 (2006)]. The 2-RDMs of individual molecular fragments within a molecule are determined, and selected portions of these 2-RDMs are recombined to yield an accurate approximation to the correlation energy of the entire molecule. In addition to extending CIM to the parametric 2-RDM method, we (i) suggest a more systematic selection of atomic-orbital domains than that presented in previous CIM studies and (ii) generalize the CIM method for open-shell quantum systems. The resulting method is tested with a series of polyacetylene molecules, water clusters, and diazobenzene derivatives in minimal and nonminimal basis sets. Calculations show that the computational cost of the method scales linearly with system size. We also compute hydrogen-abstraction energies for a series of hydroxyurea derivatives. Abstraction of hydrogen from hydroxyurea is thought to be a key step in its treatment of sickle cell anemia; the design of hydroxyurea derivatives that oxidize more rapidly is one approach to devising more effective treatments.
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PMID:Exploiting the spatial locality of electron correlation within the parametric two-electron reduced-density-matrix method. 2009 31

Liberal fluid intake is one of the key management strategies in sickle cell anaemia [SCA] patients in steady state, but less work has been done on the desire of patients to drink water. Using the Visual Analogue Scale we studied thirst perception [TP] in 20 euhydrated SCA patients and 28 control [HbA] subjects, as well as during dehydration in 13 SCA patients and 9 HbA subjects. Serum and urine samples were collected and analyzed for Na, K ions, creatinine concentrations and haematocrit and specific gravity of urine were determined. During euhydration, TP was significantly [P<0.05] higher in male SCA patients compared to the HbA subjects. In females, TP in SCA patient was not statistically significant compared with HbA subjects. After 13 hours of dehydration, TP was significantly [P<0.05] reduced in female. While dehydration increased TP in HbA subjects, it reduced TP in SCA patients. Fluid intakes after dehydration in SCA patients were not significantly different from the control HbA subjects in both male and female. It can be concluded that female SCA patients do not have normal response to dehydration with regards to TP after a period of dehydration. Since dehydration stimulates the release of vasoactive hormones like vasopressin, this may explain why female patients are less prone to crisis than their male counterparts.
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PMID:Thirst perception in dehydrated sickle cell disease patients in steady state. 2023 51

The process of hemoglobin polymerization and the consequent sickling of red blood cells that occurs in patients with sickle cell disease shortens the half-life of red blood cells. It causes vaso-occlusive complications, as well as pain and pulmonary and cardiovascular dysfunction. We evaluated an aquatic rehabilitation program used for patients with sickle cell anemia and examined the possible benefits that exercise in warm water has for the circulatory system, for relieving pain, and for increasing lung capacity. The patient was a 32-year-old female. The parameters that we used in this study include respiratory muscle strength (which was calculated by measuring maximum inspiratory pressures and maximum expiratory pressures), the McGill and Wisconsin pain questionnaires (in order to evaluate the patients' characterizations and descriptions of their pain), and the SF-36 Health Survey. The treatment included warm water exercises, stretching, aerobic exercise, and relaxation, during two sessions of 45 min per week for 5 weeks. The patient experienced a significant decrease in pain, a significant increase in the strength of respiratory muscles, and improved quality of life. We conclude that aquatic rehabilitation can be used to improve the clinical condition of sickle cell anemia patients, and we encourage more research on this new treatment regime, in comparison with other types of therapies.
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PMID:Benefits of kinesiotherapy and aquatic rehabilitation on sickle cell anemia. A case report. 2030 22


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