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Siliphos^® Bioavailable silybin

From Silybum marianum (L.) Gaertn. a new natural preventive targeted at the liver

The fruit of the milk thistle (Silybum marianum, Family Asteraceae) contains complex flavonoids endowed with clinically-validated liver protection activity^(1-2). Silymarin, the active ingredient of the plant, is a mixture of at least seven flavolignans and one flavonoid. The most abundant and potent costituents in silymarin are two diastereoisomeric compounds (silybin A and silybin B) known as silybin (also called silibinin)
Silymarin has been shown to be effective in the treatment of liver diseases of various kinds, including hepatitis, cirrhosis, fatty infiltration of the liver (alcoholic- and non-alcoholic fatty liver), and inflammation of the bile ducts^(3-6). The antioxidant properties of silymarin substantially boost the liver resistance to toxic insults⁽⁷⁾. Unfortunately, silymarin, and even more silybin, have a poor intestinal absorption, that limits their benefits. For this reason, many studies on liver-protectant flavolignans, have used phospholipid-complexed ingredients made through the Phytosome^®s technology, like Silymarin Phytosome^®, Silipide^® or Siliphos^®, the pharmacokinetically equivalent of Silipide^® for healthfood applications.

To overcome the poor bioavailability of silybin, Indena has complexed it with soy phospholipids exploiting the Phytosome^® technology.
As demonstrated by comparative pharmacokinetic studies, Silipide^® represents the most absorbable oral form of silybin known. 

In rats, after oral administration of 200 mg/kg of silybin, the plasma levels of silybin and its conjugated metabolites were below the analytical detection limit, while, after oral administration of Silipide® (200 mg/kg as silybin) the plasma levels of silybin (free and total) were easily measurable, being well absorbed within minutes when in phytosomal form(8).

Plasma levels of total silybin after oral Silipide® and silybin in rats, where Silipide® (200 mg/kg as silybin) and silybin (200 mg/kg) were administered by gavage as aqueous suspensions to 6 male rats

In another study on rats, the pharmacokinetic of Silipide^® and silymarin were compared⁽⁹⁾. Silybin given as Silipide^® at 200 mg/kg was detectable in the plasma within minutes, peaked after 1 h, and its plasma levels remained elevated for over 6 hours. The AUC value of free silybin after Silipide^® intake was more then 400% higher than after intake of silymarin. Silipide^® was also shown to rapidly reach the liver, cross the liver cells, and appear in the bile within 2 h. The amount of silybin reaching the bile after Silipide^® dosing was at least 6.5 times higher than that from non-complexed silybin administered as silymarin.

Mean plasma levels of unconjugated flavolignans after a single oral dosage of Silipide® and silymarin (both dosed at 200 mg/kg as silybin) in rats

Mean plasma levels of total flavolignans (silybin + isosilybin + silydianin + silychristin) after a single oral dosage of Silipide® and silymarin (both dosed at 200 mg/kg as silybin) in rats

The pharmacokinetics of Silipide^® in healthy human subjects showed that complexation with phosphatidylcholine improved the oral bioavailability of silybin 4.6 fold compared with silymarin, presumably because of a facilitated passage across the gastrointestinal mucosa⁽¹⁰⁾. 

The good bioavailability of Siliphos^® was confirmed in a human pharmacokinetic study in prostate cancer patients. The study employed high dosages, and was aimed at getting information on toxicity and phase II dosage of the product. Siliphos^® at a daily oral dose of 13 g in 3 divided doses, was well tolerated in all patients, and this dosage was recommended for the phase II study⁽¹¹⁾.The results, including the optimal tolerability obtained in these “extreme” clinical situations, provide strong support for the use of Siliphos^® also in less severe pathologies associated with liver damage.

In a recent randomized, controlled, double-blind study⁽¹²⁾ conducted in 50 children undergoing a standard chemotherapy treatment known to induce hepatic toxicity (vincristine, MTX, 6-MP) participants were randomized to receive either Siliphos^® or a placebo orally for 28 days. Liver function tests were performed during the study. 
The study investigated liver toxicity by measuring amino alanine transferase (ALT), aspartate amino transferase (AST) or total bilirubin (TB) at day 0, day 28 and day 56. At day 56, patients receiving Siliphos^® had a significantly lower AST and TB, and a trend toward a significantly lower ALT. No differences in side effects, incidence and severity of toxicities, or infections were observed between groups.

 
A pilot study on the liver protective effect of Silipide^® in patients with chronic active hepatitis (CAH) found that Silipide^® improved the liver function tests related to hepatocellular necrosis and/or increased membrane permeability⁽¹³⁾. 
The iron chelating properties of Silipide^® were also investigated during a 12 week study on 37 patients with 
chronic hepatitis C and Batts–Ludwig fibrosis. Treatment with silybin–phosphatidylcholine complex was clearly associated with a reduction in iron stores in patients with advanced fibrosis⁽¹⁴⁾. Hepatitis C infection was also improved by a combination of silybin-phospholipids and vitamin E complex (SPV complex)⁽¹⁵⁾. 
In another study, the role of SPV complex for the treatment of non alcoholic fatty liver disease (NAFLD) was 
investigated⁽¹⁶⁾. A significative correlation with the decrease of various indexes of fibrosis, body mass, insulinemia, plasma levels of transforming growth factor-β, tumor necrosis factor-α, degree of steatosis and γ-glutamyl transpeptidase was observed. 
The reduction in ultrasonographic scores for liver steatosis and the improvement of liver enzyme levels, hyperinsulinemia and indexes of liver fibrosis strongly suggest that the SPV complex could be used as a complementary approach to the treatment of patients with chronic liver damage. 
The addition of increasing concentrations of Silipide^® to isolated rat hepatocytes caused a dose-dependent inhibition of lipid peroxidation induced by cumene hydroperoxide, concluding that Silipide^® acted as potentially useful protective agent against free radical mediated toxic liver injury⁽¹⁷⁾.
Prompted by these observations, a phase II randomized open clinical trial to evaluate the dose response relationship of Silipide^® in patients with viral or alcoholic hepatitis was carried out, finding a dose-dependent improvement⁽¹⁸⁾.
In a pilot study on eight patients with chronic active hepatitis B and/or C, treatment with Silipide^® at 240 mg silybin for two months, reduced significantly the liver enzymes alanine aminotransferase (ALT) and alanine aminotransferase (AST), while the levels of glutamyltranspeptidase (GGT) and those of malondialdehyde (MDA), a by-product of lipid peroxidation, were not statistically improved⁽¹⁹⁾.
Healthy volunteers (total number not disclosed) receiving 360 mg Silipide^® three times daily for three weeks did not show any adverse effect⁽²⁰⁾, while treatment of 232 patients with liver disorder for up to four months with either 240 or 360 mg Silipide^® daily showed an excellent tolerability. Minor adverse effects (nausea, heartburn, dyspepsia, transient headache) were reported only in 12 patients (5.2% of the total studied), compared with 8.2% of patients who received uncomplexed silybin and 5.1% of patients treated with the placebo. In this study, Silipide^® produced no clinically relevant blood changes, and its efficacy was evaluated by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltranspeptidase (GGT). Besides antioxidant activity, Silipide^® has also the ability to scavenge ethanol-derived free radicals, and has therefore the potential to prevent liver damage from alcohol abuse⁽²¹⁾. Silipide^® was also able to scavenge free radicals generated by CCl₄ or INH⁽²²⁾, and was investigated in rodents in various models of liver damage. After oral administration, Silipide^® exhibited a significant and dose related protective effect against hepatotoxicity induced by CCl₄, acetaminophen, ethanol and galactosamine⁽²³⁾. A controlled clinical study on the effect of Silipide^® in chronic persistent hepatitis was also carried out⁽²⁴⁾. The drug treatments available for this condition have limited efficacy, do not work at all for many patients, and have major adverse effects. In this study, patients were randomized to receive either 240 mg Silipide^® (n=31) or a placebo (n=34) twice daily for three months. The Silipide^® group showed significant lowering of both serum ALT and AST, while in the placebo group these markers worsened. The Silipide^® treatment was well tolerated, with even fewer adverse events than for the placebo group, and no patient discontinued the trial due to adverse effects.

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