Though sickle cell anemia has no cure, extracts of local Nigerian plants and some nutritional supplements have

shown promise on alleviating the painful symptoms of the genetic disorder. CHUKWUMA MUANYA reports. THE unanimous verdict is that Sickle Cell Anaemia (SCA) is a genetic disorder and cannot be cured in the conventional sense. The affected individual and their families suffer a burden of anxiety, frequent pain crisis and financial cost needlessly aggravated by ignorance and palpable lack of appropriate services and research. However, recent studies have clearly demonstrated that plant-based antioxidants replete in Cajanus cajan (Pigeon pea in English, fio fio in Igbo), Fagara zanthoxyloides (Chewing stick in English, orin ata in Yoruba), fishes, fruits and vegetables, nuts and whole grains, and nutritional supplements can compensate for some inborn defect of sickle cell anaemia. The studies suggest that for people with Sickle Cell Disorder (SCD), it means healthier red blood cells, less anaemia and pain, and other improvement in health. Until now, numerous herbs and supplements have been suggested for people with sickle cell disease, including alpha-linolenic acid, beta-carotene, coenzyme Q10, folate, garlic, green tea, lipoic acid, magnesium, OPCs (oligomeric proanthocyanidins), suma, vitamin B2, vitamin B6, vitamin B12, vitamin C, and vitamin E, but as yet the supporting evidence for these treatments remains far too preliminary to be relied upon at all. But Nigerian researchers have reported a randomised single-blind placebo controlled study, which showed that the extract of Cajanus cajan reduced the frequency of painful crises and possibly ameliorated the adverse effects of SCA on the liver in children aged one to15 years. Cajanus cajan is a popular food in developing tropical countries and belongs to the plant family Fabaceae. Nutritious and wholesome, the green seeds (and pods) serve as vegetable. The results of this study by researchers at the College of Medicine University of Lagos (CMUL)/Lagos University Teaching Hospital (LUTH), Idi-Araba, published in the Journal of Tropical Paediatrics, are encouraging when viewed in the light of increasing concern about the benefit of new conventional therapies like Hydroxyurea in an African setting where limited resources make widespread use, monitoring of side effects, and toxicities virtually impossible. Considerable attention has thus been paid, particularly in Africa, to naturally occurring anti-sickling agents which offer the potential of being relatively safer, easily administered and potentially less costly than Hydroxyurea. The encouraging results of this study by A. O. Akinsulie, E. O. Temiye, A. S. Akanmu, F. E. A. Lesi, and C. O. Whyte need to be balanced by concerns over uncertainties of the effect of this product with long term use and the fact that the results of this study have not been confirmed by multi-centre studies. The authors of the study titled "Clinical evaluation of extract of Cajanus cajan in sickle cell anaemia" rightly stress the need to determine the mechanism of action of this extract, and further clinical studies with this product need to identify the predictive factors for response and non response to therapy among

SCA patients because this will influence how to optimise therapy with this product. Secondly, the effect of the product in pregnancy and on adults with SCA needs to be studied. Thirdly, it is unclear at this stage, what the effect of this product is with long term therapy even though it showed promising results at six months follow-up. A longer period of follow-up may reveal an uncommon effect or increases in an adverse outcome, and will provide the benefit of observing the effect of the product on the frequency of painful crises over a minimum of 12 months, which will cover the entire duration of the rainy season, which has been associated with an increase in the frequency of painful crises in individuals with SCA. Lastly, future studies will also need to examine how efficacy of this product compares with effectiveness in the general population of SCA patients. In summary, evidence from this study shows that the extract of Cajanus cajan appears to be safe, easily administered and efficacious in reducing painful crises and may offer increased benefit to patients with SCA in future. Its effect on ameliorating liver pathology needs to be further evaluated with studies which use ultrasonography to objectively assess hepatic changes. In more recent studies, a nutritional supplement made with Cajanus cajan (Ciklavit) was found in multicentre clinical trials conducted at six Nigerian university teaching hospitals and a Ghanaian university to lower the sickling of the red blood cells and relieve the intensity and duration of painful crisis associated with sickle cell disorder. The centres are: The University College Hospital (UCH), Ibadan; University of Ilorin Teaching Hospital (UITH), Ilorin; Ahmadu Bello University Teaching Hospital (ABUTH), Kaduna; University of Calabar Teaching Hospital (UCTH), Calabar; Lagos University Teaching Hospital (LUTH), Idi-Araba; Obafemi Awolowo University Teaching Hospital (OAUTH), Ife; and Khorle-Bu University, Ghana. Pigeon pea has many folk medicinal uses. In India and Java, the young leaves are applied to sores. Indochinese claim that powdered leaves help expel bladder stones. Salted leaf juice is taken for jaundice. In Argentina, the leaf decoction is prized for genital and other skin irritations, especially in females. Floral decoctions are used for bronchitis, coughs, and pneumonia. Chinese shops sell dried roots as an alexeritic, anthelminthic, expectorant, sedative, and vulnerary. Leaves are also used for toothache, mouthwash, sore gums, child-delivery, dysentery. Scorched seed, added to coffee, are said to alleviate headache and vertigo. Fresh seeds are said to help incontinence of urine in males, while immature fruits are believed of use in liver and kidney ailments. In Peru, the leaves are prepared in a infusion for anaemia, hepatitis, diabetes, urinary infections, and yellow fever. The flowers are prepared in an infusion for dysentery, and menstrual disorders; and the seeds are infused to use as a diuretic. In Brazilian herbal medicine, the leaves are infused for coughs, fevers and ulcers; the seeds are prepared in a tea for inflammation and blood disorders; and the flowers are prepared into a tea for upper respiratory infections and pain. In Argentina the leaves are used for genital and other skin irritations and the flowers are used for bronchitis, coughs, and pneumonia.

In several clinical studies scientists have reported that seed extracts of pigeon pea inhibit red blood sickling and may be beneficial for people with sickle cell anaemia. Laboratory studies with animals report that the seeds have some anti-nutritional qualities and reported to contain trypsin inhibitors and chymotrypsin inhibitors which reduce or inhibit pancreatic amylase and lipase. Roots of Fagara zanthoxyloides (orin ata in Yoruba), known as chewing sticks, are widely used for tooth cleaning in West Africa. The Nigerian Zanthoxylum is a common component of the rain forest vegetation of southern Nigeria. According to a study on the Nigerian Fagara zanthoxyloides by S. K. Adesina of the Drug Research & Production Unit, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, traditional healers throughout Nigeria have used species of the Zanthoxylum for the treatment of a wide range of disorders, including toothache, urinary and venereal diseases, rheumatism and lumbago. According to the study, which was published in the African Journal. Traditional, Complementary and Alternative Medicines metabolites isolated from Zanthoxylum species so far include alkaloids, aliphatic and aromatic amides, lignans, coumarins, sterols, carbohydrate residues. The interesting story of Fagara zathoxyloides probably started in Nigeria with the observation or chance discovery by El-Said and his team that the Fagara root extract possessed activity on the red cell membrane. El-Said and his collaborators reported that the extract of this plant, apart from being antibacterial preserved the colour of the blood within its zones of inhibitions when examined on blood agar plates. Sofowora and Isaacs later reported on the reversal of sickling and crenation in erythrocytes by the root extract of Fagara zanthoxyloides. Both authors and their associates have separately reported these effects at different scientific meetings. Sofowora and his team reported the isolation and characterisation of 2-hydroxymethyl benzoic acid as one of the anti-sickling agents of the plant. Though Honig et al, adopting a different methodology of evaluation and working on plant specimens purportedly collected in Ghana could not confirm these effects, Sophia Abu and his collaborators confirmed the antisickling effects of Fagara zanthoxyloides root extract. Since then, biological and chemical assays have been developed for the estimation of antisickling agents in the roots of many Nigerian Zanthoxylum species. In 1989, Osoba and his team studied the effect of the root extract of Fagara zanthoxyloides and some selected substituted benzoic acids on glucose-6-phosphate and 6-phosphogluconate dehydrogenases in HBSS red blood cells and found out that the antisickling fraction of the root of Fagara zanthoxyloides, vanillic acid, p-hydroxy benzoic acid and p-fluoro benzoic acid possessed antisickling inhibitory activity at low concentrations. The authors found out that p-fluorobenzoic acid was the most active. It was also noted that the agent did not affect the activities of glucose-6-phosphate and 6-phosphogluconate dehydrogenases while exhibiting antisickling activity nor disrupt the cell membrane to the extent of causing leakage to the media. The quest for ant-sickling agents continued in other laboratories with time. In preliminary assays carried out at the Universitty of Ibadan, Isaacs Sodeye noted that it seemed that zanthoxylol isolated from

Fagara zanthoxyloides in 1966 possessed antisickling activity. Zanthoxylol was modified chemically to 3,4dihydro-2,2-dimethyl-2H-1-benzopyran-6-butyric acid (DBA). This compound was found to efficiently prevent and reverse sickling. It also had no acute toxicity in male mice. Zanthoxylol has since been isolated and estimated from the root of Fagara zanthoxyloides the only Nigerian Zanthoxylum in which it was detected. Researchers have reported a potent anti-sickling compound code-named NX-06999 (The World Sickle Cell Foundation Inc., 1990). It was reported to be free from any toxic side effects and was already being subjected to preliminary clinical trials in Nigeria, Gabon and Panama. There is, therefore, no doubt that Zanthoxylum extracts and the "unknown antisickling candidate" coded NX-06999 had some promise as possible additions to the regime of managing SCD. Meanwhile, antioxidant nutrients have been shown to protect the body's cells from oxygen-related damage. Many studies show that sickle cell anemia patients tend to have low blood levels of antioxidants, including carotenoids, vitamin A, vitamin E, and vitamin C, despite adequate intake. Low blood levels of vitamin E in particular have been associated with higher numbers of diseased cells in children and with greater frequency of symptoms in adults. A small, preliminary trial reported a 44 per cent decrease in the average number of diseased cells in six sickle cell anemia patients given 450 IU vitamin E per day for up to 35 weeks. This effect was maintained as long as supplementation continued. In another preliminary trial, 13 patients with sickle cell anaemia were given two supplement combinations for seven to eight months each. The first combination included 109 mg zinc, 153 IU vitamin E, 600 mg vitamin C, and 400 ml (about 14 ounces) of soybean oil containing 11 grams of linoleic acid and 1.5 grams of alpha linolenic acid. The second combination included 140 IU vitamin E, 600 mg vitamin C, and 20 grams of fish oil containing 6 grams of omega-3 fatty acids. Reduction in diseased cells was observed only during the administration of the first protocol. The authors concluded that zinc was the important difference between the two combinations and may be a protector of red blood cell membranes. Fish oil alone has also been studied. In a double-blind trial, supplementation with menhaden oil, in the amount of 250 mg per 2.2 pounds of body weight per day for one year, reduced the frequency of severe pain episodes by approximately 45 per cent, compared with placebo. The zinc deficiency associated with sickle cell anemia appears to play a role in various aspects of the illness. For example, preliminary research has correlated low zinc levels with poor growth in children with sickle cell anemia. In a preliminary trial, 12 people with sickle cell anemia received 25 mg of zinc every four hours for three to 18 months. The number of damaged red blood cells fell from 28 per cent to 18.6 per cent. Addition of 2 mg of copper per day did not inhibit the effect of zinc. (Zinc supplementation in the absence of copper supplementation induces a copper deficiency.) Patients with the highest number of damaged red blood cells had a marked response to zinc, but those with lower levels of damaged cells (less than 20 per cent irreversibly sickled cells) had little or no response. Chronic leg ulcers occur in about 75 per cent of adults with sickle cell disease. In a controlled trial, sickle cell patients with low blood levels of zinc received 88 mg of zinc three times per day for 12 weeks. Ulcer healing rate was more than three times faster in the zinc group than in the placebo group.

People with sickle cell anaemia suffer from many nutrient deficiencies, but preliminary research on dietary habits shows that food and nutrient intake by sickle cell patients in general meets or exceeds recommendations and is not significantly different from healthy controls. This suggests the higher rate of nutrient deficiencies may be due to an increased need for many nutrients in sickle cell patients. The effectiveness of dietary interventions in supplying adequate nutrition to meet these higher demands has not been examined. In a preliminary study, individuals with pulmonary hypertension (a life-threatening complication of sickle cell anaemia) received L-arginine in the amount of 100 mg per 2.2 pounds of body weight, three times per day for five days. L-arginine treatment resulted in a significant improvement in pulmonary hypertension, as determined by a 15 per cent decline in the pulmonary artery systolic pressure. Longerterm studies are needed to confirm these preliminary results. Sickle cell anaemia may result in vitamin B12 deficiency. A study of children with sickle cell anemia found them to have a higher incidence of vitamin B12 deficiency than children without the disease. A study of 85 adults with sickle cell anemia showed more of them had vitamin B12 deficiency than did a group of healthy people. A subsequent preliminary trial demonstrated that for patients with low blood levels of vitamin B12, intramuscular injections of 1 mg of vitamin B12 weekly for 12 weeks led to a significant reduction in symptoms. Researchers do not know whether people with sickle cell anemia who are found to be deficient in vitamin B12 would benefit equally from taking vitamin B12 supplements orally. In a preliminary trial, 20 patients with sickle cell anemia were given either 1 mg of folic acid per day or folic acid plus 6 grams of aged garlic extract, 6 grams of vitamin C, and 1,200 mg of vitamin E per day for six months. Patients taking the combination had a significant improvement in their hematocrit (an index of anaemia) and less painful crises than those taking just folic acid. Preliminary research has found that patients with sickle cell anemia are more likely to have elevated blood levels of homocysteine compared to healthy people. Elevated homocysteine is recognised as a risk factor for cardiovascular disease. In particular, high levels of homocysteine in sickle cell anaemia patients have been associated with a higher incidence of stroke. Deficiencies of vitamin B6, vitamin B12, and folic acid occur more frequently in people with sickle cell anaemia than in others and are a cause of high homocysteine levels. A controlled trial found homocysteine levels were reduced 53 per cent in children with sickle cell anaemia receiving a 2-4 mg supplement of folic acid per day, depending on age, but vitamin B6 or B12 had no effect on homocysteine levels. A double-blind trial of children with sickle cell anemia found that children given 5 mg of folic acid per day had less painful swelling of the hands and feet compared with those receiving placebo, but blood abnormalities and impaired growth rate associated with sickle cell anemia were not improved. In the treatment of sickle cell anemia, folic acid is typically supplemented in amounts of 1,000 mcg daily. Anyone taking this amount of folic acid should have vitamin B12 status assessed by a healthcare professional. Iron deficiency is relatively common in people with sickle cell anemia, especially in pregnant women and in children. Iron deficiency in people with sickle cell anemia is best diagnosed with a laboratory test called serum ferritin.

During sickle cell crises, however, serum ferritin is no longer useful as an indicator of iron deficiency. The value of iron supplementation for people with sickle cell anaemia who are diagnosed with iron deficiency is unclear. Iron supplements have, in some reports, reduced the severity of anaemia as measured by laboratory tests; however, some reports suggest they may increase the symptoms of sickle cell anemia. Moreover, a state of iron deficiency has been shown to reduce sickling of red blood cells in the blood of people with sickle cell anaemia. A small trial of iron restriction in patients with sickle cell anaemia found improvement in anaemia and clinical symptoms, as well as decreased red blood cell breakdown during iron restriction. A doctor should be consulted before deciding to supplement or restrict iron in sickle cell anaemia. Low concentrations of red blood cell magnesium have been noted in patients with sickle cell anemia. Low magnesium, in turn, is thought to contribute to red blood cell dehydration and a concomitant increase in symptoms. In a preliminary trial, administration of 540 mg of magnesium per day for six months to sickle cell anaemia patients reversed some of the characteristic red blood cell abnormalities and dramatically reduced the number of painful days for these patients. The form of magnesium used in this trial, magnesium pidolate, is not supplied by most magnesium supplements; it is unknown whether other forms of magnesium would produce similar results. In test tube studies, vitamin B6 has been shown to have anti-sickling effects on the red blood cells of people with sickle cell anaemia. Vitamin B6 deficiency has been reported in some research to be more common in people with sickle cell anaemia than in healthy people. In a controlled trial, five sickle cell anemia patients with evidence of vitamin B6 deficiency were given 50 mg of vitamin B6 twice daily. The deficiency was reversed with this supplement, but improvement in anemia was slight and considered insignificant. Therefore, evidence in support of vitamin B6 supplementation for people with sickle cell anemia remains weak.