1Technological Innovation in Medicine Department, Federal University of Ceara, Brazil
2Pathology Department, Federal University of Ceara, Brazil
Submission: October 04, 2016; Published: October 24, 2016
*Corresponding author: Renata Mirian Nunes Eleutério, Technological Innovation in Medicine Department, Federal University of Ceara, Fortaleza, CE, Padre Antônio Tomás Avenue, number 3885, apartment 202, CEP: 60192-120, Brazil, Tel:+55 (85) 99637 6879;
How to cite this article: Eleuterio R, Nogueira N, Eleutério J, Araújo T, Lemes R. Arginine in the Treatment of Patients with Sickle Cell Disease: A Systematic Review. Adv Biotech & Micro. 2016; 1(4): 555566. DOI: 10.19080/AIBM.2016.01.555566
Introduction: Sickle cell anemia (SCA), a monogenic disease prevalent in Brazil, is characterized by a point mutation, generating abnormal hemoglobin, hemoglobin S (HbS). Hydroxyurea, the drug used to treat SCA, increases fetal hemoglobin and nitric oxide levels; however, it is both cytotoxic and genotoxic. Arginine has been studied as one option for managing the disease. Material and methods: A systematic review was performed on scientific literature located by searching databases using the keywords “arginine” and “sickle cell anemia.” Articles published within the last 10 years were included if written in Portuguese, English, or Spanish, and describing studies that used humans. The articles were evaluated and classifieds according to the recommendations of the Brazilian Medical Association. Results and discussion: The search resulted in 139 articles, of which 65 were published within the last ten years. Of these, seven met the remaining inclusion criteria. The results showed that arginine, with or without hydroxyurea, increased nitric oxide levels and improved patient clinical condition. Conclusion: It seems that arginine increased levels of nitric oxide, a potent vasodilator. These studies encourage new clinical trials to evaluate the use of arginine in SCA.
Sickle cell anemia (SCA) is a genetic disease caused by a point mutation at position six of the beta chain, resulting in hemoglobin S (HbS). Erythrocytes whose predominant content is HbS take on a sickle shape when HbS polymerizes. As a result, microcirculation becomes difficult and may result in obstruction of capillary blood flow .
Sickle cell anemia is the most prevalent monogenic disease worldwide. In Brazil, it is found in about 0.1% to 0.3% of the black population, and it is estimated that there are over two million carriers of HbS .
Patients with sickle cell disease have a heterogeneous clinical picture. The magnitude of their anemia ranges from mild to severe and may include high rates of morbidity and mortality of painful vaso-occlusive crises .
The treatment of SCA using oral hydroxyurea (HU) has
multiple direct effects on the pathophysiological mechanism.
Synthesis of fetal hemoglobin is increased, reducing infra-erythrocytes and HbS polymerization in deoxygenation conditions. At the same time, the number of neutrophils is decreased along with erythroid hydration and the expression of adhesion erythrocytes, and the synthesis of nitric oxide (NO) and its bioavailability is increased .
Unfortunately, HU is a chemotherapeutic agent that is both cytotoxic and genotoxic, so it is important to study other various SCA treatment options. In addition, some patients do not respond to treatment or suffer from male infertility and myelo suppression .
Arginine is an amino acid that is a substrate for the synthesis of NO, a potent vasodilator that is deficient in SCA. High consumption of the reactive oxygen species (ROS) and NO by free Hb in plasma leads to lower bioavailability of NO and a reduction of the availability of the substrate of the nitric oxide synthase .
In this context, the goal of this review was to assess the
articles that discuss using L-arginine in the treatment of patients
A systematic review of articles found in the scientific
literature was performed. PubMed, Lilacs, Embase, the Cochrane
library, and Google Scholar were used to locate the articles. Search
terms such as “arginine” and “sickle cell anemia” were used.
The main descriptors in the search strategy were: (“arginine”
[MeSH Terms] or “arginine” [All Fields]) and (“anemia, sickle
cell” [MeSH Terms] or (“anemia” [All Fields] and “sickle”[All
Fields] and “cell”[All Fields]) or “sickle cell anemia”[All Fields] or (“anemia”[All Fields] and “sickle”[All Fields] and “cell”[All
Fields]) or “anemia sickle cell” [All Fields]).
After evaluation, those reports published from 2006-2016
in Portuguese, English, or Spanish describing experiments
that were conducted only in humans were included. Narrative
reviews were excluded. The articles were then evaluated for
methodological quality. Only those approved were included in
Of the 139 articles resulting from the search, 65 were
published in the last ten years. Of these, seven articles met the
remaining inclusion criteria (Table 1).
The use of supplementation with L-arginine in SCA was
studied by Ogungbemi et al.  utilizing 28 patients who
were compared to a control group of 32 people. The authors
observed that oral supplementation with L-arginine increased
the availability of NO and improved heart rates in patients with
Morris et al.  conducted a double-blind randomized
placebo-controlled trial with inhaled L-arginine in 38 patients
with vessel occlusion, finding a significant reduction in pain and
in the use of opioids.
Elias et al. , in a clinical trial with 31 patients, evaluated
hematological parameters and demonstrated that NO increased
in patients with SCA. This demonstrates the action of oral
arginine associated with HU in increasing the availability of NO
with the intent of reducing pain and vessel oclusion.
In a Tanzanian case-control study between July 2007 and
June 2009, patients with SCA were evaluated for plasma amino
acids. No difference was found in hemolytic markers between a
group of young African patients and older Americans, possibly reflecting differences in cause of death and disease severity .
A phase II clinical trial conducted by Mc Mahon et al. 
treated patients with SCA and ulcers of the lower refractory
members with a standard treatment for at least 6 months. They
demonstrated that topical use of butyrate arginine cured 30% of
the patients at 12 weeks and 78% after 3 months.
In turn, Sullivan et al.  aimed to determine the
effect of oral arginine on NO levels in patients with sickle cell
disease with and without acute chest syndrome, using a group of
healthy people as a control. After arginine supplementation, the
NO increased in all groups to a similar degree, and lung function
and physiological parameters, such as blood pressure and heart
frequency, were minimally affected.
Little et al.  studied patients with SCA who used oral
L-arginine and sildenafil. L-arginine increased plasma ornithine
and arginine, but not citrulline. Thus, the author discusses
the possibility that arginase was offset by the plasma for NO
Using the studies meeting our inclusion criteria, it seems
that NO, a potent vasodilator, increases and leg ulcers heal when
arginine is used as part of the treatment. These studies encourage
further clinical trials to examine whether, in fact, there are
improvements in clinical and hematological parameters when
arginine is supplemented in patients with SCA.
Acknowledgment: This work was supported by the National
Council of Technological and Scientific Development (CNPq).