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- Milk Thistle (Silybum marianum)
- Silymarin
- Desferrioxamine
- β-Thalassemia Major
| Date: 05-31-2010 | HC# 021024-401 |
Re: Oral Silymarin Is Proven Effective in β-Thalassemic Major Patients under Conventional Chelation Therapy
Gharagozloo M, Moayedi B, Zakerinia M, et al. Combined therapy of silymarin and desferrioxamine in patients with β-thalassemia major: a randomized double-blind clinical trial. Fundam Clin Pharmacol. 2009;23: 359-365.
Silymarin
is a flavonolignan complex isolated from the fruits of milk thistle (Silybum marianum) endowed with strong antioxidant,
hepatoprotective, and iron-chelating properties. Silymarin is clinically used
for the treatment of liver diseases with degenerative necrosis and functional
impairment.1 One of its active components, silybin, shows strong
iron-chelating properties: oral administration of silybin protects against
iron-induced hepatic toxicity in vivo, suggesting its possible use in the
chelation therapy of chronic iron overload disorders, such as β-thalassemia
major. 2,3
β-Thalassemia
is a single gene disorder characterized by absence or decreased production of
the β chain of hemoglobin, resulting in anemia and requiring regular blood
transfusions. The excess transfusional iron builds up in different organs
leading to functional disruption and organ failure.4 Iron chelation
with subcutaneous (s.c.) or intravenous desferrioxamine is widely used to overcome
body iron over-storage, prevent iron-induced cardiac disease, and improve
survival in chronically transfused patients. As reactive oxygen species and
iron overload play an important role in the pathophysiology of thalassemia,
co-administration of desferrioxamine with silymarin may be an effective therapy
given silymarin's antioxidant, cytoprotective, and iron-chelating properties.
This randomized,
double-blind, placebo-controlled, 3-month trial was designed to investigate the
therapeutic activity of orally administered silymarin in patients with β-thalassemia
major under conventional iron chelation
therapy. Sixty β-thalassemia major patients aged 12 years or older (mean 19.5 ±
5.4 years) with serum ferritin levels above 1000 µg/L over the previous 6
months were selected from referrals to Dastgheib Clinic of Thalassemia (Shiraz
University of Medical Sciences; Iran).
All patients had homozygous β-thalassemia major, were regularly transfused to
maintain hemoglobin levels above 9.5 g/dL at a mean transfusional interval of
17 days, and chelated with s.c. desferrioxamine (mean dose 40-50 mg/kg per infusion
over 8-12 h, 5-6 days per week). Patients were randomized to receive either
placebo or a 140 mg silymarin tablet (Legalon®; Madaus Pharma;
Padova, Italy) at least an hour before food, 3 times daily, in addition to
conventional desferrioxamine (Novartis Pharma AG; Basel, Switzerland) therapy.
Chelators' efficacy
was assessed by serum ferritin measurements. Patients were evaluated at the beginning,
middle, and end of each treatment period for clinical laboratory parameters: regular
laboratory tests were performed including full blood count and liver and renal
function. The mean of difference values in the silymarin group was compared
with placebo using t-test of 2 independent samples. ANOVA repeated measure
analysis was used to examine the changes of serum ferritin level between
baseline, end of 1.5 months, and 3 months. Results were expressed as the mean ±
SD. All tests were two-tailed and a significance level of 0.05 was applied.
Fifty-nine
patients completed the study (silymarin, n = 29; placebo, n = 30). There were
no significant differences between groups in initial serum ferritin levels,
age, sex distribution, desferrioxamine dose, or amount of blood transfused. There
were no significant differences in hemoglobin, hematocrit (HCT), mean
corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), and mean
corpuscular hemoglobin concentration (MCHC) levels, as well as red blood cells
(RBC), platelet, lymphocyte, monocyte, eosinophil, and neutrophil counts at
baseline and end of the treatments in both groups. No significant variations were
registered in serum chemicals (calcium, phosphorus, and fasting blood sugar)
and electrolytes (blood urea nitrogen, creatinine, sodium, and potassium) after
3 months of silymarin or placebo treatment.
However, a significant
decrease in serum alkaline phosphatase (ALP) was observed in patients receiving
silymarin. Reduced glutathione (GSH) concentration of RBC was significantly greater
in silymarin-treated patients compared to the placebo group. An ANOVA repeated
measure analysis demonstrated a significant decrease in serum ferritin levels
at baseline, 45, and 90 days of silymarin therapy using Wilks’ Lambda test [F =
4.69, d.f. (degrees of freedom) = (2; 55), P = 0.014]. A fall in serum ferritin
was noted in 22/29 patients (75.8%) after 45 days, and in 25/29 (86.2%) after 90
days of silymarin therapy. However, the serum ferritin levels of 20/30 patients
(66.6%) decreased after 45 days, and 21/30 (70.0%) patients after 90 days of
desferrioxamine treatment. The decrease in serum ferritin levels was not
significant in the placebo group. On the other hand, ANOVA repeated measure analysis
demonstrated no significant difference in serum ferritin levels between
silymarin and placebo groups after 45 and 90 days of treatment, as evidenced by
the Wilks’ Lambda [F = 0.53, d.f. = (1; 56), P = 0.82] with the observed power
of 0.06.
The significant
decrease in ALP levels in silymarin-treated patients highlights silymarin's
hepatoprotective activity: ALP is a liver enzyme whose concentration is
abnormally elevated in chronic liver diseases affecting thalassemic patients as
a consequence of iron overload caused by the regular transfusion regimen.5,6
The key mechanisms that ensure hepatoprotection appear to be free radical
scavenging, reduction of oxidative stress via restoration of intracellular GSH
deficiency of RBC, and increased synthesis of ribosomal RNA resulting in
inducing liver regeneration.7
Concomitant
administration of silymarin and desferrioxamine can be safely used in treatment
of iron-loaded patients. In patients taking combined therapy (silymarin plus
desferrioxamine), the mean drop in serum ferritin was higher than in
desferrioxamine-treated patients, indicating that the combined therapy was more
effective than desferrioxamine in reducing serum iron overload. No significant difference
in serum ferritin levels was detected between silymarin and placebo groups,
probably due to the low observation power of the study (about 6%), caused by a sample
size insufficient to detect subtle changes in ferritin levels. Silymarin was
effective in reducing adverse side effects of conventional iron chelator
desferrioxamine and showed remarkable antioxidant, hepatoprotective activities,
and no sign of toxicity. The improvement in iron status resulting from the
combined therapy needs to be confirmed in larger studies with a longer follow-up
period.
—Silvia Giovanelli Ris
References
1Gazak R, Walterova D, Kren
V. Silybin and silymarin - new and emerging applications in medicine. Curr. Med. Chem. 2007;14:315-338.
2Borsari M, Gabbi C, Ghelfi F,
et al. Silybin, a new iron-chelating agent. J
Inorg. Biochem. 2001;85:123-129.
3Pietrangelo A, Borella F, Casalgrandi G, et al. Antioxidant activity of silybin in vivo
during long-term iron overload in rats. Gastroenterology. 1995;109:1941-1949.
4Rund D, Rachmilewitz E. Beta-thalassemia. N Engl J Med. 2005;353:1135-1146.
5Prati D, Maggioni M, Milani S, et al. Clinical and histological characterization of liver disease
in patients with transfusion-dependent beta-thalassemia. A multicenter study of
117 cases. Haematologica. 2004;89:1179-1186.
6Li CK, Chik KW, Lam CW, et al. Liver disease in transfusion dependent thalassaemia major. Arch Dis Child. 2002;86;344-347.
7Valenzuela A, Garrido A. Biochemical bases of the pharmacological action
of the flavonoid silymarin and of its structural isomer silibinin. Biol Res.
1994;27:105-112.
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