The Efficacy of Jobelyn (Sorghum Bicolor Extract)in the Treatment of Sickle Cell Anemia
Condition: Sickle Cell Anemia
MeSH terms: Anemia; Anemia, Sickle Cell
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Paludrine + Folic Acid; Paludrine + Folic Acid + Jobelyn
Intervention type(s): Drug; Dietary Supplement
Intervention description(s): This is the combination of routine drugs for treating sickle cell disease; Combination of routine drugs + Jobelyn
Other intervention name(s): Routine drugs; 1. Routine Drugs, i.e. Paludirine + Folic Acid; 2. Sorghum bicolor extract (Jobelyn)
Intervention MeSH terms: Folic Acid; Vitamin B Complex; Proguanil
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Care Provider)
Primary purpose: Treatment
Keywords: Sorghum bicolor; sickle cell anaemia; haematological parameters