Pharmacy & Therapeutics - April 2008 - (Page 242) CONTINUING EDUCATION CREDIT ability to prolong or delay the time to polymerization of deoxyHb S.41 A phase 2, double-blind, placebo-controlled, six-month randomized crossover trial revealed that the frequency of sickle cell pain crisis in the Niprisan arm was significantly reduced.42 A phase 3 clinical trial is under way, and an investigational New Drug Application (NDA) is being prepared by Xechem for submission to the FDA. Nitric Oxide in daily narcotic usage. Overall, the oral administration of L-glutamine has shown a consistent and significant increase in red blood cell NADH and was well tolerated by the patients with no adverse effects.50 Magnesium Nitric oxide (NO), a potent vasodilator thought to be deficient in patients with SCD, has been suggested as a therapeutic option.43 Its proposed mechanism of action is its ability to limit the sickling of RBCs by preventing them from sticking to vessel walls or by dilating peripheral blood vessels.44 Studies by Head et al. suggested that NO increases the hemoglobin oxygen affinity in homozygous HbS (SS) erythrocytes either when RBCs are exposed to NO in vitro or during NO inhalation in low concentrations in vivo.45 It is not clear how low concentrations of NO enhance oxygen affinity of erythrocytes in SCD, compared with normal erythrocytes, but research suggests that NO modifies HbS, thereby reducing polymerization and increasing oxygen affinity in sickled RBCs. L-Arginine De Franceschi et al. suggested that a possible therapeutic strategy for SCD was based on reducing the cellular concentration of sickle cell hemoglobin (HbS) by preventing erythrocyte dehydration.51 The major determinant of sickle cell dehydration is the potassium chloride transporter, which is inhibited by increasing the erythrocyte magnesium content. Oral administration of magnesium showed considerable increases in sickle erythrocyte magnesium and potassium content and reductions in the number of dense sickle erythrocytes. In addition, the erythrocyte potassium chloride co-transport was reduced significantly, and the absolute reticulocyte count and the number of immature reticulocytes were greatly reduced. The authors concluded that oral magnesium reduced the number of dense erythrocytes and improved the erythrocyte membrane transport abnormalities of patients with SCD, thus reducing erythrocyte dehydration. Transient diarrhea was the only significant side effect and was noted in one of 10 patients in the study. The amino acid L-arginine is a required substrate for nitric acid synthesis by endothelial cells, platelets, and other cells. In addition to having a deficiency of NO, adults with SCD sometimes have significantly diminished arginine levels. This arginine deficiency may be the cause of PHTN in sickle cell patients; therefore, the infusion of L-arginine has been shown to reduce vascular resistance and improve blood oxygenation in infants with PHTN.46 In one study, L-arginine supplementation improved pulmonary artery pressures and hemodynamics in primary and secondary hypertension within one week of therapy. Overall, arginine was well tolerated with minimal adverse effects.47 L-Glutamine L-Glutamine is a precursor for nicotinamide adenine dinucleotide (NAD), which is deficient in patients with sickle cell anemia. A deficiency of glutamine may result in the possibility of skeletal muscle wasting, immunosuppression, and impaired wound healing.48 It is suggested that the deficiency in glutamine is a result of the rate of active transport of glutamate (a by-product of glutamine) in sickled RBCs. Oral L-glutamine therapy can be beneficial in patients with sickle cell anemia by increasing the activity of NAD synthesis, thus countering the oxidant-dependent pathophysiology of sickled RBCs.49 In a four-week study of seven patients with sickle cell anemia who were 19 to 60 years of age, Niihara and colleagues found that given 30 g of oral L-glutamine for four weeks brought about a significant increase in NADH (the reduced form of NAD) and NAD redox potential (the ratio of NADH to NAD+ plus NADH). These participants also experienced an overall improvement in energy, accompanied by an increased activity level and various degrees of decreases in chronic pain. Of the seven patients who participated in the study, six reported a decrease Conclusion Although bone marrow transplantation can cure SCD, it is an impractical solution for most Third World countries, which have a high disease burden. Even in the U.S., bone marrow transplantation is limited by the availability of donors. Pharmacological therapies are effective at reducing complications of SCD and are safe and easily administered, and they continue to prolong the life expectancy of patients. References 1. American Stroke Association. Sickle cell disease. Available at www.strokeassociation.org/presenter.jhtml?identifier=3034962. Accessed August 10, 2007. 2. Nietert PJ, Silverstein MD, Abboud MR. Sickle cell anemia: Epidemiology and cost of illness. Pharmacoeconomics 2002;20:357– 366. 3. Steiner C, Miller J. Sickle cell disease patients in U.S. hospitals, 2004. Healthcare Cost and Utilization Project (HCUP) Statistical Brief No. 21, December 2006. Rockville, Md: Agency for Healthcare Research and Quality. Available at: www.hcup-us.ahrq.gov/ reports/statbriefs/sb21.pdf. Accessed 2/24/2008. 4. Anemia, sickle cell. National Library of Medicine. Available at: www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection &rid=gnd.section.98. Accessed October 8, 2007. 5. Sickle cell anemia. ACP PIER & AHFS DI Essentials, 2007. American College of Physicians (Philadelphia, Pa.), Physician’s Information and Education Resource and American Hospital Formulary Service, Drug Information. Available at: http:/online.statref. com/titles/title infopage.aspx?titleid=92. Accessed December 14, 2007. 6. A brief history of sickle cell disease. Harvard University Information Center for Sickle Cell and Thalassemic Disorders. Available at: http://sickle.bwh.harvard.edu/scd_history.html. Accessed December 17, 2007. 7. Fosdal MB, Alexandrov AW. Events of hospitalization among children with sickle cell disease. J Pediatr Nurs 2007; 22:342–346. 8. Driscoll CM. Sickle cell disease. Pediatr Rev 2007;28:259–267. 242 P&T® • April 2008 • Vol. 33 No. 4 http://www.strokeassociation.org/presenter.jhtml?identifier=3034962 http://www.hcup-us.ahrq.gov/reports/statbriefs/sb21.pdf http://www.hcup-us.ahrq.gov/reports/statbriefs/sb21.pdf http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gnd.section.98 http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowSection&rid=gnd.section.98 http://online.statref.com/titles/titleinfopage.aspx?titleid=92 http://online.statref.com/titles/titleinfopage.aspx?titleid=92 http://sickle.bwh.harvard.edu/scd_history.html
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