PHYTOTHERAPY RESEARCH Phytother. Res. 29: 1046–1053 (2015) Published online 7 April 2015 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ptr.5345
Effect of Silymarin Administration on Cisplatin Nephrotoxicity: Report from A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial Foroud Shahbazi,1 Sanambar Sadighi,2 Simin Dashti-Khavidaki,3* Farhad Shahi,2 Mehrzad Mirzania,2 Alireza Abdollahi4 and Mohammad-Hossein Ghahremani1 1
Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran 4 Vali-e-Asr Hospital, Tehran University of Medical Sciences, Tehran, Iran 2 3
Despite several introduced preventive modalities, cisplatin nephrotoxicity remains a clinical problem. Some in vitro and in vivo studies have addressed the protective effects of silymarin against cisplatin nephrotoxicity. This study evaluated the effects of silymarin administration on cisplatin nephrotoxicity as the first human study. During this pilot, randomized, double-blinded, placebo-controlled clinical trial, the effect of oral silymarin 420 mg daily in three divided doses starting 24–48 h before the initiation of cisplatin infusion and continuing to the end of three 21-day cisplatin-containing chemotherapy courses on cisplatin-induced renal electrolytes wasting and kidney function were assessed. Cisplatin-associated acute kidney injury (AKI) occurred in 8% of the patients. Urine neutrophil gelatinase-associated lipocalin to urine creatinine ratio (NGAL/Cr) and urinary magnesium and potassium wasting increased significantly after cisplatin infusion in both groups. Significant positive correlation was found between cumulative dose of cisplatin and urine NGAL/Cr after three courses of cisplatin infusion. Incidence of AKI and the magnitude of urinary magnesium and potassium wasting did not differ between silymarin and placebo groups. No adverse reaction was reported by silymarin administration. Prophylactic administration of conventional form of silymarin tablets could not prevent cisplatin-induced urine electrolyte wasting or renal function impairment. Copyright © 2015 John Wiley & Sons, Ltd. Keywords: cisplatin; milk thistle; nephrotoxicity; silymarin.
INTRODUCTION Cisplatin, one of the most commonly used anti-neoplastic agent, is routinely administered to manage many solid tumors including head, neck, gastrointestinal, testis, and ovarian cancers (Abu-Surrah and Kettunen, 2006). Cisplatin is mainly eliminated via glomerular filtration and about 50% of the drug is eliminated within the first 24 h of administration (Litterst et al., 1977). Because the kidney is the principle site of cisplatin concentration and excretion, cisplatin nephrotoxicity is common and sometimes is the major dose limiting toxicity (Madias and Harrington, 1978; Arany and Safirstein, 2003; Dos Santos et al., 2012; Miller et al., 2010; Launay-Vacher et al., 2008). Kidneys reuptake cisplatin through organic acid transporter 2 (OCT2) more than other organs. The S3 segment of the proximal tubule accumulates the highest amount of cisplatin followed by the distal collecting tubule and the S1 segment of the proximal tubule (Arany and Safirstein, 2003; Dos Santos et al., 2012; Miller et al., 2010). Clinical and laboratory manifestations of cisplatin nephrotoxicity include renal function impairment, hypomagnesemia, salt-wasting nephropathy, anemia, Fanconilike syndrome, and rarely thrombotic microangiopathy (Miller et al., 2010; Launay-Vacher et al., 2008). Supportive * Correspondence to: Simin Dashti-Khavidaki, Nephrology Research Center, Tehran University of Medical Sciences, Tehran, Iran. E-mail: [email protected]
Copyright © 2015 John Wiley & Sons, Ltd.
treatments such as hydration and electrolytes replacement are usually employed to minimize cisplatin nephrotoxicity (Launay-Vacher et al., 2008). Even in the era of good supportive care, about 10–30% of treated patients experience increase in serum creatinine and nephrotoxicity (Arany and Safirstein, 2003; Dos Santos et al., 2012; Miller et al., 2010; Launay-Vacher et al., 2008). Serum creatinine concentration usually increases 3–5 days following cisplatin injection and peaks after 7–10 days, then declines and partially returns to baseline values after three weeks (Launay-Vacher et al., 2008). Because serum creatinine is a late marker of acute kidney injury (AKI), recently, several urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), cystatin-C, and kidney injury molecule-1 (KIM-1) have been introduced for early detection of AKI (De Geus et al., 2012). Neutrophil gelatinase-associated lipocalin has also been used to detect cisplatin nephrotoxicity (Gaspari et al., 2010). Milk thistle, also known as Silybum marianum, is a well-known traditional herb known for its hepatoprotective effects. This medicinal herb contains flavonoids (taxifolin and quercetin) and flavonolignans (silybin, silydianin, and silychristin) (Saller et al., 2001). Silymarin is the extract of milk thistle that is standardized to contain 70–80% silymarin flavonolignans (silybin A, silybin B, isosilybin A, isosilybin B, silydianin, and silychristin A and silychristin B) and 20–30% undefined fractions such as polymeric and oxidized polyphenolic compounds. Silybin or silibinin is considered the most active constituent of silymarin (Saller et al., 2001; Javed et al., 2011). Received 07 November 2014 Revised 07 February 2015 Accepted 11 March 2015
SILYMARIN AGAINST CISPLATIN NEPHROTOXICITY
Silymarin has been clinically studied as a hepatoprotective agent against chemotherapeutic agents-induced liver toxicity without antagonizing or even potentiating their anticancer effects (Ladas et al., 2010). Several in vitro and in vivo studies have addressed the promising protective effects of silymarin flavonolignans and flavonoids against cisplatin-induced nephrotoxicity. Silymarin-treated animals and cell cultures showed lower cisplatin nephrotoxicity as measured by urinary electrolyte wasting, kidney histologic changes, tissue caspase activity and inflammatory markers, and proteinuria without complicating chemotherapy (Gaedeke et al., 1996; Bokemeyer et al., 1996; Karimi et al., 2005; Agarwal et al., 2006; Yousef et al., 2011; Sanchez-Gonzalez et al., 2011). Cisplatinassociated nephrotoxicity is mediated in part by inflammatory and oxidative stress, therefore antiinflammatory and antioxidant agents including silymarin have been proposed to prevent cisplatin nephrotoxicity (Miller et al., 2010; Gaedeke et al., 1996; Bokemeyer et al., 1996; Karimi et al., 2005; Yousef et al., 2011; Sanchez-Gonzalez et al., 2011). The aim of the present study was to evaluate the effects of silymarin administration on cisplatin nephrotoxicity as the first human study.
METHODS This study was a pilot, randomized, double-blinded, placebo-controlled clinical trial conducted during early August 2013 to April 2014 at the Cancer Institute, Imam Khomeini Hospital Complex affiliated to Tehran University of Medical Sciences.
Patient population. Included in this study were hospitalized adult patients who received cisplatin and met the following criteria: Karnofsky performance status >70%, glomerular filtration rate (GFR) >45 ml/min (based on modification of diet in renal disease (MDRD) formula), and the ability to take oral medication. Patients with active infection, heart failure, abnormal liver enzymes, uncontrolled thyroid diseases, or using other nephrotoxic drugs (e.g. aminoglycoside, amphotericin) within the previous 72 h were excluded from the study. Because of the uncertainty about the mode of nephrotoxicity, patients who received fractionated doses of cisplatin were excluded (Hartmann et al., 2000). To minimize possible drug-herb or drug-laboratory tests interactions, patients on warfarin (Brantley et al., 2010), angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers were also excluded (Nielsen et al., 2010).
Ethics. The study protocol was approved by the local Ethics Committee of Tehran University of Medical Sciences and was registered at the Iranian Registry of Clinical Trials (IRCT201207013043N6) and clinicaltrial. gov (NCT01829178). All participants signed written, informed consent forms.
Study protocol. Patients were allocated to receive either silymarin or identical placebo tablets (Amin Pharmaceutical Company, Isfahan, Iran) according to computerized Copyright © 2015 John Wiley & Sons, Ltd.
random number generator software. Treatment group received conventional silymarin tablets (Liverherb® containing 140 mg active ingredient based on silymarin flavonolignans including silybin, silychristine, silydianin, 2,3-dehydrosilybin, and 2,3-dihydrosilychristin.) three times daily that started 24–48 h before the initiation of cisplatin infusion and continued consecutively to the end of the three 21-day cisplatin-containing chemotherapy courses to evaluate the long-term effects of silymarin on cisplatin-induced nephrotoxicity. To improve patients’ compliance, tablets were administered with daily meals. All patients were hydrated with 2 L of normal saline on the day before cisplatin administration and 1 L after cisplatin infusion. Exactly before cisplatin infusion, all patients received 8 mEq of magnesium (as magnesium sulfate) and 20 mEq of potassium (as potassium chloride) in 1 L of normal saline as routine ward protocol. Urine and serum samples were collected before cisplatin administration, six and 24 h after 2-hour cisplatin infusion, and daily thereafter up to patients’ discharge from the hospital after each chemotherapy course. Samples were immediately centrifuged at 10 000 RPM for 5 min. Serum and urine electrolytes and creatinine concentrations were measured at the day of sample collection. Remaining samples were stored at80 °C until other assays. During the study period, patients were followed for drug administration compliance and adverse drug reactions. Patients were considered to be adherent to their treatment if they consumed more than 80% of their administered drug/placebo by pill counting (Ho et al., 2009). Sample size. All previous studies on the renoprotective effects of silymarin against cisplatin-induced nephrotoxicity have been performed in animals or cell cultures that could not be used for sample size calculation. In one human study, urinary NGAL concentration increased by 1700% (standard error of mean of 390%) following cisplatin infusion (Gaspari et al., 2010). Assuming silymarin may decrease urinary NGAL level equal to variance of urinary NGAL changes following cisplatin injection (390%), α error of 5%, and study power of 80% (β = 0.20), the sample size was 16 patients in each silymarin and placebo group according to the following formula: 2 2 Z 1 α2 þ Z ð1 βÞ σ2 n¼ d2 This sample size was chosen to provide preliminary data to inform design of future randomized controlled trial to prevent cisplatin-induced nephrotoxicity. Measurements and calculations. Urine NGAL concentrations were measured by ELISA method (Bioassay Technology laboratory, Shanghai Crystal Day Biotech Co., Ltd., Shanghai, China) with detection limit of 5–600 ng/mL and inter-assay and intra-assay coefficient of variation of 2% and clinical pictures of polyuria, hypovolemia, and hyponatremia (Hamdi et al., 2010). Common Terminology Criteria for Adverse Events (CTCAE) version 4 was used to assess adverse events (CTCAE, 2013).
Statistical methods. Intention to treat analysis of data was done using SPSS software (SPSS Inc., Chicago, IL, USA) version 14. Results have been shown as mean ± standard deviation (SD) or median (Inter quartile range (IQR)) for normally and non-normally distributed continuous variables, respectively and number (percentages) for nominal variables. Shapiro-Wilk’s test was used to assess the normality of the variables distributions. To assess the equality of variance, Fisher’s F test and Levene’s test were used. Correlation between data was evaluated by Pearson or spearman rank coefficient tests. Independent sample t-test and Mann–Whitney U-test were used, respectively to compare normally and non-normally
distributed variables between the two groups at the initiation and at the end of the study. ANOVA tests were applied to assess the significance of changes of the repeated measures. Bonferroni correction was used for multiple comparisons. Fisher exact test was used to compare proportions between the groups; p < 0.05 was considered as significant.
RESULTS Of the 86 screened patients, 30 subjects were eligible to be enrolled in the study according to the inclusion/exclusion criteria. Twenty four patients (12 patients in each arm) completed the study (Fig. 1). Seventy-five percent of the patients suffered upper gastrointestinal cancer, followed by ovarian cancer in 20.9%, and mesothelioma in 4.1% of the patients. All patients received cisplatin-containing chemotherapy regimen at least once before the study inclusion (range from one to five chemotherapy courses). As shown in Table 1, except for the GFR, there were no significant differences between silymarin and placebo groups at the beginning of the study regarding demographic and clinical parameters (including cisplatin dosage) and laboratory findings. At the initiation of the study, patients in the silymarin group had a significantly lower GFR (p = 0.03). Both groups were also comparable regarding cancer types and chemotherapy regimens (Table 2).
86 patients screened Exclusion for: Low performance status (N=10) Fractionated cisplatin (N=15) ClCr 0.05). Cr, creatinine; NGAL/Cr, urine neutrophil gelatinase-associated lipocalin to urine creatinine concentration; AKI, acute kidney injury. Copyright © 2015 John Wiley & Sons, Ltd.
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Table 5. Adverse reactions in the study population based on CTCAE (N = 24) Severity Grade 1 Adverse reaction Gastrointestinal Nausea Vomiting Mucositis Diarrhea Hematologic Decreased Hemoglobin Decreased WBC Decreased Platelets Dermatologic Rash Hair loss Liver function tests Increased Liver enzymes Increased Total bilirubin Increased ALP
2 7 8 9
2 6 5 7
0.99 0.99 0.41 0.66
10 2 4 3
10 3 2 4
0.99 0.99 0.67 0.99
7 8 7
8 9 5
0.99 0.99 0.63
2 2 2
3 2 3
0.99 0.99 0.99
3 7 3
5 4 4
0.66 0.41 0.99
Grades 4 and 5 reactions were not seen during the study. CTCAE, common terminology criteria for adverse events; ALP, alkaline phosphatase; WBC, white blood cells.
than 25% increase in serum creatinine concentration (Gaspari et al., 2010;Lin et al., 2013). Five patients (20.8%) would be categorized as suffering cisplatinassociated AKI if we considered the previous definition (Gaspari et al., 2010; Lin et al., 2013) of AKI. Serum creatinine is a late indicator of cisplatin associated nephrotoxicity (Launay-Vacher et al., 2008; Moon et al., 2011). Several novel biomarkers such as NGAL, cystatin-C, and KIM-1 have been proposed for early detection of cisplatin associated AKI. Although conflicting, it seems that urine NGAL may be the best marker among them [Gaspari et al., 2010;Lin et al., 2013; Nan-Ya et al., 2014; Mishra et al., 2004; Kos et al., 2013a, 2013b]. Therefore, we assessed urine NGAL in this study. Neutrophil gelatinase-associated lipocalin is used as early marker of tubular toxicity (Gaspari et al., 2010; Lin et al., 2013). Because urinary NGAL concentration may be confounded by urine output and patient’s hydration status, it has been recommended to be standardized by urine creatinine concentration as urine NGAL/Cr (Devarajan, 2014). In the present study, urine NGAL/Cr significantly increased 24 h after cisplatin infusion in all three cisplatin-containing chemotherapy courses in both silymarin and placebo groups. Previous clinical data indicated that urine NGAL concentration or urine NGAL/Cr increase 12–24 h after cisplatin administration in patients with AKI (Gaspari et al., 2010; Lin et al., 2013). In the present study, the median of urine NGAL/Cr was higher in AKI-experienced subjects, although not as high as 1700% increase that was reported by Gaspari et al. (2010). Results of our study were more compatible with Lin et al. findings (Lin et al., 2013). Although GFR was significantly higher in the placebo group at the initiation of the study, however, ANCOVA test that adjusted patients’ kidney functions based on their baseline values in each group showed that this difference did not affect the occurrence of AKI and NGAL/Cr changes. Copyright © 2015 John Wiley & Sons, Ltd.
Cisplatin-induced urinary magnesium wasting is common and if not corrected, up to 90% of patients will experience hypomagnesemia (Miller et al., 2010; Moon et al., 2011; Blachley and Hill, 1981; Lajer and Daugaard, 1999); therefore, regular serum magnesium monitoring following cisplatin infusion and administering supplemental magnesium have been recommended (Launay-Vacher et al., 2008). Results from animal studies have shown that pretreatment with silymarin flavonolignans may improve cisplatin-induced tubular and glomerular dysfunctions (Gaedeke et al., 1996; Bokemeyer et al., 1996; Karimi et al., 2005; Yousef et al., 2011; Sanchez-Gonzalez et al., 2011). Although this seems to be clinically non-significant, compared with pre-cisplatin-treatment values, our patients had significantly higher urinary magnesium and potassium wasting after three cisplatin-containing chemotherapy courses; nevertheless, the difference between silymarin and placebo group did not reach statistical significance. No patient developed hyponatremia during our study period. This finding is consistent with previous data about rarity of cisplatin associated salt wasting (Hamdi et al., 2010). In this study, positive significant correlation was found between cumulative cisplatin dose and NGAL/Cr ratio, but not with the development of AKI. We continued silymarin administration for three cisplatin-containing chemotherapy courses to prevent chronic cisplatin nephrotoxicity, but we were not able to detect difference between silymarin and placebo group in term of cisplatin nephrotoxicity. This result may be explained by this evidence that cisplatin-induced chronic kidney injury is a delayed effect in nature and may occur even years after completion of chemotherapy without significant increase in serum creatinine levels during chemotherapy courses (Cvitkovic, 1998). Cisplatin is mainly eliminated through OCT2 in basolateral membrane of S3 segment. Organic acid transporter 2 down regulation or administration of Phytother. Res. 29: 1046–1053 (2015)
F. SHAHBAZI ET AL.
substrate that reduces cisplatin uptake results in lower cisplatin nephrotoxicity without compromising anticancer effects (Miller et al., 2010; Sprowl et al., 2013). Several mechanisms such as induction of cell death via apoptosis and necrosis, inflammation, and generation of reactive oxygen species have been suggested for cisplatin nephrotoxicity (Dos Santos et al., 2012; Miller et al., 2010). To date, no study has shown that silymarin is a substrate or inhibitor of OCT2,whereas animal studies described its antiinflammatory and antioxidant properties (Gaedeke et al., 1996; Bokemeyer et al., 1996; Karimi et al., 2005; Yousef et al., 2011; SanchezGonzalez et al., 2011). On the other hand, conventional formulation of silymarin tablet was used in this study. Extensive metabolism, low permeability across intestinal epithelial cells, low water solubility, and rapid excretion in bile might make this formulation unsuitable (Javed et al., 2011). Low silymarin bioavailability was even reported with modified formulation in soy phosphatidyl choline that had been assumed to be able to improve its bioavailability (Ladas et al., 2010). In the present study, urine and serum silymarin concentrations were not measured. Some studies had indicated that only low amount of silymarin flavonolignans, which are responsible for the potential renoprotective effects of silymarin, were recovered in urine by conventional silymarin formulation (Calani et al., 2012; Hawke et al., 2010). Therefore, urine silymarin concentrations were expected to be low in this study, while animal and cell culture studies have used higher doses or concentrations of silymarin (Gaedeke et al., 1996; Bokemeyer et al., 1996; Karimi et al., 2005; Yousef et al., 2011; Sanchez-Gonzalez et al., 2011).
Our study suffered several limitations: First, the sample size of our study was small because of the hard inclusion and exclusion criteria that were unavoidable for the first clinical trial. Second, we did not measure serum and urine concentrations of silymarin. Third, most cisplatin adverse effects including AKI and hypomagnesemia may occur more than 4 days after cisplatin infusion and at that time most of our patients were discharged from hospital and did not accept to comeback to be monitored.
CONCLUSION This study showed that conventional form of silymarin tablets at daily dose of 420 mg in three divided doses is not effective against cisplatin nephrotoxicity. Larger clinical and pharmacokinetic studies with higher silymarin doses or modified silymarin formulations with better oral absorption are recommended to clarify the potential role of silymarin on cisplatin nephrotoxicity.
Acknowledgements This study was part of an Iranian BCPS thesis supported by Tehran University of Medical Sciences (grant No: 18878).
Conflict of Interest The authors have declared that there is no conflict of interest.
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