The Efficacy of Jobelyn (Sorghum Bicolor Extract)in the Treatment of Sickle Cell Anemia

Overview

The primary objective is to determine if there is a significant increase in the haematocrit value of patients on Jobelyn and standard therapy compared to those on standard therapy alone.

Sickle cell anaemia is an inherited haemoglobinopathy caused by a point missense mutation (GAG to GTG) in the beta globin gene that resulted in the substitution of an acidic amino acid ( glutamic acid) with a neutral and hydrophobic amino acid (valine) in the codon 6 of the beta globin chain. This genetic defect has a prevalence of 20% to 40% in Sub Saharan Africa, 7.8% in African Americans and to a lesser extent in the Middle East, Mediterranean and India. The higher frequency in the sub Saharan Africa is thought to be due to the selective advantage the gene confers on the traits (heterozygotes state) in malaria zone. Nigeria is the most populous country in this region with about 24% frequency of the mutant gene. The prevalence of sickle cell anaemia in Nigeria is about 20 per 1000 life births. This implies that Nigeria may have the highest burden of the disease in the world. The severity of sickle cell disease varies. The disease is more severe in patients with haemoglobin SS or haemoglobin S beta thalassaemia than in those with haemoglobin S beta+ thalassaemia or haemoglobin SC disease. The Arab - Indian haplotype produces a less severe disease than the African haplotype. Similarly, the coinheritance of one or two, alpha globin chain deletions or high fetal haemoglobin level in hereditary persistence of fetal haemoglobin are associated with mild disease, The severity is therefore higher in the Sub Saharan African sub region. However, the severity of the disease varies widely for unexplained reasons among patients with haemoglobin SS in this region. The beta S globin chain binds at the valine site with complementary hydrophobic effects on other beta globin chain. This triggers the formation of polymers of haemoglobin. The rate of polymerization is increased with increase in intracellular deoxy-haemoglobin. Factors that promote polymerisation are dehydration, acidosis, increase in the level of 2,3 diphosphoglycerate which may occur in infections. On the other hand, the association of haemoglobin 5 with other haemoglobin that have higher oxygen affinity-like haemoglobin F or haemoglobin A reduce the rate of polymerisation. The haemoglobin polymer forms a firm gel that damages the cellular membrane. The damaged membrane causes movement of potassium and water out of the cell thus leading to dehydration and more polymer formation. This damage also causes the negatively charged phosphatidylserine to move to the membrane surface and the red cell becomes deformed in shape, more rigid and more adherent to the vascular endothelium. The result of these are easy fragmentation of the membrane and extra vascular haemolysis, complement mediated lysis of the cell and intravascular haemolysis, shortened red cell survival to 4 to 25 days, trapping of rigid irreversible sickle cells in the post capillary venules which is promoted by leukocytosis, platelet activation and inflammatory cytokines. The release of intravascular haemoglobin mobs up nitric acid which has a vasodilatation effect. This aggravates the already deficient tissue perfusion. A vicious circle is formed that eventually leads to tissue hypoxia, sequestration of blood in organs with sinuses (spleen, liver, lungs and the penis). There is also a chronic haemolytic anaemia with insufficient increase in the production of erythropoietin due to the fact that the beta S globin chain has a lower affinity for oxygen and therefore releases oxygen easily to the tissue. To further reduce erythropoiesis is the increase of inflammatory cytokines that inhibit haemopoiesis i.e interleukin 1 and tumor necrotic factor. On the other hand an increase in the red cell mass tends to increase vascular occlusion and ischemic crises. The ideal stable haematocrit for sickle cell disease is therefore between 24% and 28%. At this range of haematocrit, tissue hypoxia is minimized and painful crises are easier to control. Factors that precipitate crises are dehydration, infection, extreme heat or cold and physical or emotional stress. These factors are prevalent in our environment. Early detection and preventive measures are very important in the management of sickle cell disease. To enhance red cell production, patients are offered regular folic acid. To prevent malaria, prophylactic paludrine is given and infection is treated with appropriate antibiotic. Among the anti sickling drugs, hydroxyurea, an inhibitor of ribonucleotide reductase, has been shown to decrease the rate of painful crises probably by reducing adhesion to the endothelium, increasing the proportion of fetal haemoglobin within the cell and reduction in the white blood cells and platelets. Other drugs on trial are butyrate compounds and analogues of azacytidine. Other modalities are blood transfusion, exchange blood transfusion, stem cell transplant and the possibility of gene therapy is realistic. These modalities are not without their side effects and high costs. A new drug added to the routine drugs might minimize tissue. Hypoxia, rate of sickling and haemolysis if the haematocrit is within the steady state range, white cells count are reduced and inflammatory cytokines are reduced. Available reports suggest that sickle cell erythrocytes are susceptible, to endogenous free radical mediated oxidative damage as indicated by marked increase in lipid peroxidation and superoxide dismutase level in haemoglobin SS patient. However there remain discrepancies in the status of anti oxidant enzymes and vitamins in the patients. Sorghum bicolor, a grain long used in Africa for its high nutritional value also exhibits strong antioxidant properties and antiinflammatory effects. The traditional preparation of Sorghum bicolor has an oxygen radical absorbance capacity (ORAC) OF 3,123 micro mole TE/g. This is much higher than other botanical preparations. Complementing the antioxidant properties, sorghum bicolor also exhibits anti inflammatory effects and demonstrated selective COX-2 inhibition, providing effective reduction in inflammation without residual side effects. Sorghum bicolor extract has been shown to increase the haematocrit and haemoglobin level and reduce the white cell count in trypanosome brucei brucei induced anaemia in experimental rabbits. These effects were conclusive within 49 days of experimentation. Animals sacrificed after the administration of lethal dose Jobelyn were shown to have congestion of the liver, kidneys and lungs. This might be as a result of direct effect on these organs or a sign of cardiotoxicity. However there is a wide therapeutic range. Jobelyn is the proprietary name for the product intended to treat sickle cell disease and it is currently marketed as a nutritional supplement. Jobelyn is marketed in 250mg capsules of Sorghum bicolor leaf extract. The product is widely marketed in many countries including Nigeria. Many of our sickle cell patients have been using it regularly for a long time without any report of adverse effect. The sorghum bicolor extract is expected to increase the haematocrit of' sickle cell anaemia within a short time, to reduce leukocytosis during sickling and therefore reduce vascular occlusion and improve tissue perfusion. The selective effect on COX 2 and the moderation of inflammatory cytokines is expected to reduce painful crises and inhibition of haemopoiesis.

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