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)

Sickle hemoglobin (HbS), as a result of its polymer-related and oxidant effects, damages the sickle erythrocyte, provokes inflammation, and causes endothelial injury. All these elements cause the phenotype of sickle cell disease. Novel treatments inhibit HbS polymerization by inducing fetal hemoglobin expression, prevent or repair erythrocyte dehydration by slowing cellular potassium and water loss, and replace HbS-producing erythroid progenitors by stem cell transplantation. Future treatment prospects include gene therapy, interruption of the interaction of sickle cells with the endothelium, inhibition of oxidative damage, and protection of an injured endothelium.
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PMID:Pathophysiological-based approaches to treatment of sickle cell disease. 1235 29

A prominent feature of sickle cell anemia is the presence of dehydrated red blood cells (RBCs) in circulation. Loss of potassium (K(+)), chloride (Cl(-)), and water from RBCs is thought to contribute to the production of these dehydrated cells. One main route of K(+) loss in the RBC is the Gardos channel, a calcium (Ca(2+))-activated K(+) channel. Clotrimazole (CLT), an inhibitor of the Gardos channel, has been shown to reduce RBC dehydration in vitro and in vivo. We have developed a chemically novel compound, ICA-17043, that has greater potency and selectivity than CLT in inhibiting the Gardos channel. ICA-17043 blocked Ca(2+)-induced rubidium flux from human RBCs with an IC(50) value of 11 +/- 2 nM (CLT IC(50) = 100 +/- 12 nM) and inhibited RBC dehydration with an IC(50) of 30 +/- 20 nM. In a transgenic mouse model of sickle cell disease (SAD), treatment with ICA-17043 (10 mg/kg orally, twice a day) for 21 days showed a marked and constant inhibition of the Gardos channel activity (with an average inhibition of 90% +/- 27%, P <.005), an increase in RBC K(+) content (from 392 +/- 19.9 to 479.2 +/- 40 mmol/kg hemoglobin [Hb], P <.005), a significant increase in hematocrit (Hct) (from 0.435 +/- 0.007 to 0.509 +/- 0.022 [43.5% +/- 0.7% to 50.9% +/- 2.2%], P <.005), a decrease in mean corpuscular hemoglobin concentration (MCHC) (from 340 +/- 9.0 to 300 +/- 15 g/L [34.0 +/- 0.9 to 30 +/- 1.5 g/dL], P <.05), and a left-shift in RBC density curves. These data indicate that ICA-17043 is a potent inhibitor of the Gardos channel and ameliorates RBC dehydration in the SAD mouse.
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PMID:ICA-17043, a novel Gardos channel blocker, prevents sickled red blood cell dehydration in vitro and in vivo in SAD mice. 1243 90

Total body irradiation(TBI) is being used as a method of preparation for bone marrow transplantation(BMT). In TBI, the dose calculation is based on dosimetry using a phantom. We measured the basic dose with a phantom using a 10 MV X-rays. We confirmed the accuracy of the dose calculation performed in our facilities and investigated a method of more accurate dosimetry. We measured the variation in dose according to the size of the phantom and the depth using a tough water phantom, and examined the difference in TMR according to SCD, field size, and size of the phantom. Consequently, the dose has been changed regardless of the size of the phantom at larger than 80 x 30 x 30 cm(3), and it is about 1% larger than 30 x 30 x 30 cm(3). Also TMR has changed according to various conditions, including the size of the phantom, field size, and SCD. Therefore, it was found that dosimetry using the 30 x 30 x 30 cm(3) phantom leads to underestimation in dose calculation, and there is no difference in dose between the field size of 151.5 x 160 cm(2) and 151.5 x 80 cm(2). It is also necessary to consider the effect of the vertical size of the phantom.
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PMID:[Dosimetry with phantom for total body irradiation(TBI)]. 1246 36

The effects of warmth stimulation and/or supplementation with vitamin E (300 mg/day for 6 weeks) on forearm blood flow (FBF) and forearm vascular resistance (FVR) were measured in 8 sickle cell anaemia (SCA) (mean age = 22.8 + 0.8 years) and 11 non sickle cell anaemia (NSCA) subjects (mean age = 23.2 + 1.1 years) of both sexes. Warmth stimulation was induced by immersing the left foot in warm water at 400C for 2 minutes. Forearm blood flow was measured with the venous occlusion plethysmography method. Warmth increased FBF (p <0.01 in each group) and reduced FVR (p <0.05) in NSCA subjects. The change in FBF was greater (p < 0.05) in the NSCA subjects than in the SCA subjects. Supplementation with vitamin E reduced systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MAP) (p < 0.001 in each case) in the NSCA subjects but had little or no effect on the SCA subjects. Vitamin E increased FBF in NSCA subjects (p < 0.05) and SCA subjects (p < 0.01) and decreased FVR in both groups (p < 0.05 in NSCA and p < 0.01 in SCA subjects). The change in FVR seen in the NSCA subjects was less (p < 0.01) than the change in SCA subjects. After supplementation with vitamin E, warmth further decreased SBP (p < 0.01 in each group) and FVR (p < 0.01 in each case) and increased FBF in both groups (p < 0.01 respectively). The changes caused by warmth after vitamin E supplementation on the blood pressure parameters, FBF and FVR were similar in the two groups of subjects.
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PMID:The effect of warmth or/and vitamin E supplementation on forearm blood flow and forearm vascular resistance in sickle cell and non sickle cell anaemia subjects. 1271 57

The question is, does the isoform hSK4, also designated KCNN4, represent the small conductance, Ca2+-activated K+ channel (Gardos channel) in human red blood cells? We have analyzed human reticulocyte RNA by RT-PCR, and, of the four isoforms of SK channels known, only SK4 was found. Northern blot analysis of purified and synchronously growing human erythroid progenitor cells, differentiating from erythroblasts to reticulocytes, again showed only the presence of SK4. Western blot analysis, with an anti-SK4 antibody, showed that human erythroid progenitor cells and, importantly, mature human red blood cell ghost membranes, both expressed the SK4 protein. The Gardos channel is known to turn on, given inside Ca2+, in the presence but not the absence of external Ko+ and remains refractory to Ko+ added after exposure to inside Ca2+. Heterologously expressed SK4, but not SK3, also shows this behavior. In inside-out patches of red cell membranes, the open probability (Po) of the Gardos channel is markedly reduced when the temperature is raised from 27 to 37 degrees C. Net K+ efflux of intact red cells is also reduced by increasing temperature, as are the Po values of inside-out patches of Chinese hamster ovary cells expressing SK4 (but not SK3). Thus the envelope of evidence indicates that SK4 is the gene that codes for the Gardos channel in human red blood cells. This channel is important pathophysiologically, because it represents the major pathway for cell shrinkage via KCl and water loss that occurs in sickle cell disease.
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PMID:The hSK4 (KCNN4) isoform is the Ca2+-activated K+ channel (Gardos channel) in human red blood cells. 1277 23

Homozygous HbC gene results only in mild hemolytic anemia. In HbSC disease red cells contain equal levels of HbS and HbC. It is a paradox that HbSC exhibit a moderately severe phenotype in spite of being a mixture of HbS trait and HbC trait, neither of which has significant pathology. Why does the combination of these two Hbs result in a serious disease? The short answer is that HbC enhances, by dehydrating the SC red cell, the pathogenic properties of HbS, resulting in a clinically significant disorder, but somewhat milder that sickle cell anemia (SCA). Nevertheless, retinnitis proliferans, osteonecrosis, and acute chest syndrome have equal or higher incidence in HbSC disease compared to SCA. This pathogenic trick is accomplished by HbC inducing, by mechanisms not fully understood, an increase in the activity of K:Cl cotransport that induces the lost of K(+) and consequently of intracellular water. This event creates a sufficient increase of MCHC, so that the lower levels of HbS found in SC red cells can polymerize rapidly and effectively. This situation offers a unique opportunity: if we could inhibit the effect of HbC on K(+) transport we can cure the disease.
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PMID:The paradox of hemoglobin SC disease. 1281 27

The conversion of red cells of patients with sickle cell anemia (S-S) from biconcave disk to sickle shape by removal of oxygen was found to increase the fraction of medium trapped in cells packed by centrifugation from 0.036 (S.E. 0.003) to 0.106 (S.E. 0.004). The fraction of water in the cells (corrected for trapped medium) was not affected by this shape transformation. Cation transport, however, was changed profoundly. S-S cells incubated in N(2) rather than O(2) showed net K loss with acceleration of both influx and outflux. That this change in K transport was due to the process of sickling was indicated by (1) the persistence of the effect in the absence of plasma, (2) the absence of the effect in hypoxic S-S cells in which sickling was inhibited by alkali or carbon monoxide, (3) the reversal of the effect when sickling was reversed by exposure to O(2), and (4) the independence of the effect from such potentially important factors as age of the cell population. The acceleration of K transport by sickling is probably mediated by modification of the cell surface rather than the cell interior since concentrated sickle hemoglobin solutions in O(2) or N(2) did not show selective affinity for K. In molecular terms, the effect of sickling on K transport can be explained by presuming that the shape change (1) opens pathways for the free diffusion of K, and (2) accelerates K transport by a non-diffusion carrier process. The evidence for the former mechanism included (a) dependence of K influx into sickled cells on the concentration of K in the medium, and (b) increase in the total cation content of sickled cells with increasing pH. Observations suggestive of a carrier process included (a) the failure of sickled cell K concentration to become equal to external K concentration even after 48 hours, (b) the deviation of the flux ratio from that characteristic of diffusion, and (c) the dependence of K influx on glycolysis.
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PMID:The effects of sickling on ion transport. I. Effect of sickling on potassium transport. 1325 34

Bone injury occurs in human hemolytic disorders associated with thrombosis, such as beta-thalassemia and sickle cell disease. Exposure of rats to 2-butoxyethanol (BE) has been associated with hemolytic anemia, disseminated thrombosis, and infarction in multiple organs including bone. This rat model apparently mimics acute hemolysis and thrombosis in humans. To elucidate the extent of bone injury, male and female Fischer F344 rats were given 4 daily doses of 250 mg BE/5 ml water/kg of body weight. Tail vertebrae were studied by histopathology and magnetic resonance imaging (MRI). Thrombosis and infarction were seen in both sexes, but females were more severely affected. Lesions were characterized by extensive medullary fat necrosis, granulomatous inflammation, fibroplasia, growth plate degeneration, and new woven bone formation adjacent to necrotic bone trabeculae. MRI mean and standard deviation tissue-density data for both sexes indicated a significant (P < or = 0.05) decrease following 4-days treatment and a significant increase (P < or = 0.05) following an additional 24 days without treatment. Thus, MRI was useful in revealing BE-induced bone injury, which was predominantly necrotic initially and subsequently regenerative with proliferation of connective tissue and bone following postischemia recovery.
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PMID:Osteonecrosis in a chemically induced rat model of human hemolytic disorders associated with thrombosis--a new model for avascular necrosis of bone. 1451 20

The anti-sickling activities of the extracts of the roots of a plant Cissus populnea L. (CPK) (a major constituent of a herbal formula Ajawaron HF used in the management of sickle cell disease in south-west Nigeria) has been examined. Phytochemical examination of the extract showed the presence of anthraquinone derivatives, steroidal glycosides and cardiac glycosides. Alkaloids and tannins were completely absent in the CPK extracts. Evaluation of the anti-sickling activity involved the use of both positive (p-hydroxybenzoic acid, 5 microg/mL) and negative control (normal saline) for each set of experiments aimed at the inhibition of sodium metabisulphite-induced sickling of the HbSS red blood cells obtained from confirmed non-crisis state sickle-cell patients. The chloroform and water partitioned fractions of the cold methanol extracts of CPK exhibited a 62.2% and 52.9% inhibition of sickling, respectively, at 180 min. The herbal formula (HF) aqueous extract showed the highest anti-sickling activity on a weight by weight basis of all the extracts and fractions tested, giving a 71.4% inhibition of sickling at the end of 180 min incubation when compared with the normal saline control. The maximum percentage inhibition of sickling exhibited by the p-hydroxybenzoic acid control was 46.0% at 90 min incubation.
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PMID:Anti-sickling potential of a Nigerian herbal formula (ajawaron HF) and the major plant component (Cissus populnea L. CPK). 1466 51

The primary hypothesis of the upcoming NIH-sponsored phase III infant hydroxyurea (BABY HUG) trial is that hydroxyurea can prevent chronic organ damage in infants with sickle cell anemia. Since hydroxyurea is currently commercially available only in capsules, a liquid formulation of hydroxyurea is needed for young patients. Hydroxyurea oral solutions were prepared by dissolving the contents of the capsules in water (room temperature or mildly heated) with vigorous stirring, filtering excipients, and adding flavored syrup to a final concentration of 100 mg/mL. Chemical stability was determined by measuring the hydroxyurea concentration using a standardized analytical colorimetric analysis, while functional stability was determined by measuring the inhibition of phytohemagglutinin-induced T lymphocyte proliferation. Hydroxyurea oral solutions prepared using room-temperature water had statistically equivalent spectrophotometric concentration and inhibition of T-lymphocyte proliferation for 3 to 6 months. Mild heating of the water to facilitate dissolution of the hydroxyurea capsule contents resulted in a reduced concentration and inhibitory activity of the preparations. Hydroxyurea oral solutions (100 mg/mL) prepared and maintained at room temperature have chemical and functional stability for several months. Hydroxyurea oral solutions prepared and dispensed monthly are suitable for use in the upcoming infant BABY HUG trial.
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PMID:Chemical and functional analysis of hydroxyurea oral solutions. 1512 10


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