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)

Severe hemolysis or myolysis occurring during pathological states, such as sickle cell disease, ischemia reperfusion, and malaria results in high levels of free heme, causing undesirable toxicity leading to organ, tissue, and cellular injury. Free heme catalyzes the oxidation, covalent cross-linking and aggregate formation of protein and its degradation to small peptides. It also catalyzes the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Heme being a lipophilic molecule intercalates in the membrane and impairs lipid bilayers and organelles, such as mitochondria and nuclei, and destabilizes the cytoskeleton. Heme is a potent hemolytic agent and alters the conformation of cytoskeletal protein in red cells. Free heme causes endothelial cell injury, leading to vascular inflammatory disorders and stimulates the expression of intracellular adhesion molecules. Heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure. Heme offers severe toxic effects to kidney, liver, central nervous system and cardiac tissue. Although heme oxygenase is primarily responsible to detoxify free heme but other extra heme oxygenase systems also play a significant role to detoxify heme. A brief account of free heme toxicity and its detoxification systems along with mechanistic details are presented.
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PMID:Free heme toxicity and its detoxification systems in human. 1591 43

Fosfructose is a cytoprotective natural sugar phosphate under development by Questcor (formerly Cypros) for the potential treatment of cardiovascular ischemia, sickle cell anemia and asthma. It acts by stimulating anaerobic glycolysis which generates adenosine triphosphate under ischemic conditions. It is in phase III trials for sickle cell anemia [309234] and is in phase II/III trials for cardiovascular ischemia resulting from bypass surgery [337683]. The company has also commenced preclinical trials of fosfructose for asthma [337683]. In September 1999, the FDA granted fosfructose Fast Track designation for the treatment of the acute complications associated with coronary artery bypass graft surgery [340368].
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PMID:Fosfructose (Questcor). 1593 72

Ischaemia-related tissue injury is the leading cause of death in developed countries. Drugs that can reduce ischaemic injury would be beneficial in treatment of myocardial infarction (MI), surgical trauma and stroke. Fructose-1,6-diphosphate (FDP) is a key intermediate in anaerobic glycolysis and is the product of the major regulatory enzyme in the pathway (phosphofructokinase). Preclinical and clinical data suggest that FDP has substantial cytoprotective effects in a variety of ischaemia-reperfusion injury scenarios. Evidence indicates that FDP has a direct effect on ATP pools, reduces ischaemia-induced tissue damage and has positive inotropic effects on heart function. The clinical data suggest that FDP may be a useful drug in a variety of ischaemic and inflammatory clinical settings where acute management of tissue injury is desired. Potential uses include: iv. administration for the reduction of ischaemic injury in sickle cell anaemia, bypass surgery, congestive heart failure, myocardial infarction, as well as organ preservation in transplants.
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PMID:Potential therapeutic applications of fructose-1,6-diphosphate. 1599 98

The authors report a case of a young patient with a recent decrease in unilateral vision. He had homozygote sickle cell disease with multiple general complications. Fundus examination was normal apart from a mild alteration of the macular reflect in the left eye, but fluorescein angiography showed multiple arteriolar macular occlusions, explaining the decrease in vision in the left eye. After erythropheresis, vision acuity improved and fluorescein angiography showed reperfusion. This case suggests that transfusional exchange may improve acute macular ischemia secondary to sickle cell disease.
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PMID:[Recovery of sickle cell disease ischemic maculopathy after erythropheresis: a clinical case study]. 1614 31

CPC-111 is a cytoprotective drug under development by Cypros for the potential treatment of cardiovascular ischemia, sickle cell anemia and adult respiratory distress syndrome (ARDS). It acts by stimulating anaerobic glycolysis which generates adenosine triphosphate under ischemic conditions. Large phase III trials were planned for mid-1998, at 20 to 30 centers in Europe and the US, in patients at risk of ischemic complications resulting from coronary bypass surgery. In June 1998, the company began recruiting for a pivotal phase III trial of CPC-111 in sickle cell patients. The double-blind, placebo-controlled trial is expected to enroll 280 patients at 30 centers in the US. Study endpoints will include pain reduction, length of hospital stay, length of vaso-occlusive episode and amount of narcotic use. The drug has repeatedly demonstrated statistically significant improvements in a wide variety of endpoints in coronary artery bypass graft (CABG) patients treated with the drug, including measures of heart damage and recovery of post-operative heart function. CPC-111-treated patients also appear to require less post-operative care.
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PMID:CPC-111 (Cypros Pharmaceutical Corp). 1618 Jan 74

Hemolytic episodes such as sickle cell disease, malaria and ischemia-reperfusion occurrence are often associated to the statement of an inflammatory response which may develop or not to a chronic inflammatory status. Although these pathological states are triggered by distinct etiological agents, all of them are associated to high levels of free heme in circulation. In this review, we aim to focus the very recent achievements that have led to the statement of free heme as a proinflammatory molecule, which may play a central role during the onset and/or persistence of inflammation during these pathologies.
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PMID:Heme and innate immunity: new insights for an old molecule. 1641 Sep 72

In human and murine models of sickle cell disease (SCD), heme oxygenase-1 (HO-1) is induced in the kidney, an organ commonly involved in SCD. The present study assessed the role of HO-1 by using a competitive inhibitor of HO activity, tin protoporphyrin (SnPP), in protocols affording a composite, clinically relevant analysis of the kidney in SCD under unstressed and stressed conditions. Whereas short-term administration of SnPP exerted comparable renal hemodynamic effects in wild-type and sickle mice, chronic administration of SnPP exerted divergent effects: SnPP provoked tubulointerstitial inflammation and up-regulation of injury-related genes in wild-type mice, whereas in sickle mice SnPP reduced expression of injury-related genes and vascular congestion without provoking tubulointerstitial inflammation. SnPP also protected against the heightened sensitivity to renal ischemia observed in sickle mice, preventing ischemia-induced worsening of renal injury in sickle mice above that observed in wild-type mice. Effective and comparable inhibition of HO activity by SnPP in wild-type and sickle mice was confirmed. These findings suggest that induction of HO-1, at least as assessed by this approach, may contribute to renal injury in this murine model of SCD and uncover an experimental maneuver that protects the kidney in murine SCD.
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PMID:Anomalous renal effects of tin protoporphyrin in a murine model of sickle cell disease. 1681 58

Sickle cell disease is characterized by vaso-occlusive episodes, mainly in the small vessels, resulting in tissue ischemia, multi-organ failure, and, occasionally, death. Hydroxyurea (HU) is an agent with important and effective role in the treatment of patients suffering from this disease. The purpose of this study was to estimate the effect of HU on the deformability of the red blood cell's membrane (RBCM) in an effort to possibly improve the rheological properties of the RBCs of patients with sickle cell anemia (SCA), as well as to investigate the mechanical and rheological properties of these cells using micropipette and filtration techniques. The rigidity index, IR, which is a measure of cell rigidity and the elastic shear modulus, mu, which is a measure of cell's membrane deformability (CMd), of the RBCs from normal subjects, used as normal controls, were found significantly lower as compared to those of patients with SCA, regardless the treatment with HU. Patients under treatment with HU exhibited values better than those of untreated patients, in both, IR as well as mu, although still worse than the values of normal controls.
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PMID:Effect of hydroxyurea on the deformability of the red blood cell membrane in patients with sickle cell anemia. 1689 45

Following the generation of transgenic mouse models of sickle cell disease, pre-clinical trials have shown the beneficial effects of various potential therapeutic molecules for the acute or chronic manifestations of the disease. Several molecules are upon evaluation in phase I to phase III clinical trials. These therapeutic approaches target: 1) membrane cation transport systems and channels involved in sickle cell dehydration; 2) adherence of erythrocytes to endothelium; 3) activation of circulating and endothelial cells participating in the vasoocclusive events and local ischemia. The Gardos channel (calcium activated potassium channel KCNN4) is inhibited by the clotrimazole metabolite ICA17043, in phase III trial. The K-Cl co-transport (KCC1/3/4) activated by the depletion of erythrocyte magnesium is inhibited by Magnesium pidolate; dipyridamole inhibits ion transports upon deoxygenation. Sulfasalazyne (inhibitor of the NF-jB pathway) inhibits the abnormal activation of endothelial cells. Nitric oxide (NO) is the most potent vasodilator. It prevents the activation of leucocytes, platelets and endothelial cells in patients with sickle cell disease and vascular remodelling. The L-arginine, the NO precursor, provides could be beneficial in sickle cell patients.
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PMID:[Clinical trials of new therapeutic pharmacology for sickle cell disease]. 1744 60

Sickle cell disease results from the presence of abnormal beta globin chains within hemoglobin and may be manifested in anemia, vaso-occlusion, and superimposed infection. The gene that causes sickle cell disease is particularly prevalent in populations of African origin; approximately 8% of African Americans and 40% of the members of some African tribes carry the gene for hemoglobin S. Over time, the disease produces various musculoskeletal abnormalities as a result of chronic anemia; these include marrow hyperplasia, reversion of yellow marrow to red marrow, and, occasionally, extramedullary hematopoiesis. Familiarity with the imaging features of sickle cell disease is important for the diagnosis and management of complications. Ischemia and infarction are common complications that may have long-term effects on the growth of bone; these conditions have characteristic radiographic appearances. Infection may be more difficult to identify. Both infection and infarction may occur in muscle and soft tissue alone, without involving bone. However, osteomyelitis must be diagnosed early and treated immediately to prevent bone destruction and deformity; therefore, care must be taken to achieve an accurate diagnosis by identifying or excluding bone involvement. The clinical and radiographic features of acute osteomyelitis may be particularly difficult to distinguish from those of bone infarction. In that context, magnetic resonance (MR) imaging may be useful. At MR imaging, findings of cortical defects, adjacent fluid collections in soft tissue, and bone marrow enhancement are suggestive of infection.
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PMID:Musculoskeletal manifestations of sickle cell disease. 1762 Apr 64


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