UGT1A1 Mediated Drug Interactions and its Clinical ...

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UGT1A1 Mediated Drug Interactions and its Clinical Relevance Chong Ping Goon1,2, Ling Zhi Wang*1,3, Fang Cheng Wong1, Win Lwin Thuya1,2, Paul Chi-Lui Ho2 and Boon Cher Goh1,3,4 1

Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599; 2Department of Pharmacy, National University of Singapore, Singapore 117543; 3Department of Pharmacology, National University Health System, Singapore 117597; 4Department of Haematology-Oncology, National University Health System, Singapore 119228 Abstract: The administration of multiple drugs for the treatment of diseases is an integral aspect of modern medicine. Though its purpose is to create the intended therapeutic effect, the unintended consequences of drug interactions can cause severe side effects and subsequent economic losses. Likewise, herbal extracts and supplements with pharmacologically active moieties also have the potential to interact with medications. This is a cause of concern given that the use of herbal supplements has also become more widespread even in western countries such as the Ling Zhi Wang United States. There are many possible mechanisms on how these moieties could potentially interact, one of which is mediated by modulation of the activity of metabolizing enzymes. One such enzyme of high clinical significance is uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphism of UGT1A1 has been found to affect the plasma concentrations of many drugs, and may even be linked to treatment outcome. This mini-review summarized the potential in vitro and in vivo interactions mediated by UGT1A1. Firstly, literature search was conducted using the Web of Knowledge database. No date limitation was applied to the search. Following which, the interactions were stratified into 3 main categories based on its clinical significance. The 3 categories were “Likely to be clinically significant”, “Unlikely to be clinically significant”, and “Inconclusive over its clinical significance”. Both herbal and pharmacological drug moieties are covered within the scope of this mini-review. We hope that this secondary literature can broaden and update the perspective of clinicians, pharmacists and academics on the interactions mediated by UGT1A1.

Keywords: Clinical relevance, drugs, drug interactions, herbal supplements, Phase II, UGT1A1. 1. INTRODUCTION When two or more drugs are administered to patients, they can potentially interact with each other and lead to detrimental outcomes. The administration of multiple drugs, also known as polypharmacy, is a common feature in the management of patients with complex medical issues [1]. Though the different drugs can be intentionally administered together by physicians to create the intended therapeutic effect, the unintended consequences of drug interactions can cause severe side effects and subsequent economic losses, and even mortality. It was previously estimated that drug interactions had caused an economic loss of $76.6 billion annually in the United States alone [2]. The incidences of drug interactions also correlate with the length of a patient’s hospital stay and the treatment cost incurred [3]. More importantly, serious drug interactions have also accounted for 4% of deaths in cancer patients [4]. Herbal supplements, through its pharmacologically active moieties, have the potential to interact with medications. The use of herbal supplements have also become more widespread even in the western countries like the United States, in which 18.4% of the patients on prescription medication are also consuming herbal supplements and vitamins [5]. There are many possible mechanisms on how these moieties could potentially interact, one of which is mediated by modulation of the activity of metabolizing enzymes. Metabolism of xenobiotics involves Phase I and II reactions. Phase I metabolism, which involves CYP450 enzymes, serves as a common pathway for many clinically significant interactions for drugs of different indications, such as antipsychotics [6], antiviral [7], and lipid-lowering agents [7]. In recent years, the clinical importance of Phase II metabolism is increasingly recognized. In fact, around 10%

of the top 200 medications prescribed in the United States is metabolized by uridine diphosphate glucuronosyltransferases (UGTs) [8]. The UGTs is thus one important family of the Phase II metabolizing enzymes. Similar to CYP450 enzymes, the majority of UGTs are inducible and inhibitable by xenobiotics, potentially affecting the metabolism of other concurrent medications. These UGTs are widely distributed in liver and extrahepatic tissues such as the stomach, lung, kidney, and intestines [9], and can be classified into 2 broad sub-families – UGT1 and UGT2 subfamilies (Fig. 1). Out of the members in these two subfamilies, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B4, UGT2B7, UGT2B15 and UGT2B17 are likely to cause UGTmediated human drug interaction [10-12]. Besides, the genetic polymorphism of UGT1A1 is also found to affect the concentrations of many drugs, and may even be linked to treatment outcome [13]. Given that the UGT1A1 mediated metabolism is of high clinical significance, it is essential to comprehensively review the potential drug interactions mediated by UGT1A1. This review summarizes the potential drug interactions mediated by UGT1A1 in published literature. Herbal supplements and drug interactions are also covered in this review, as increasing number of patients include herbal drugs as complementary medicines in their treatment. An overview of the reported drug-drug interactions and herbal supplement-drug interactions will be timely and clinically relevant. This review aims to update clinicians, pharmacists, and academics of the latest progress in this field of the research.

*Address correspondence to this author at the Cancer Science Institute of Singapore, National University of Singapore, P.O. Box: 117599, Singapore, Singapore; Tel: ++65-65168925; Fax: +65-68739664; E-mail: [email protected]

2. METHODS The literature search was conducted using the Web of Knowledge database (http://apps.webofknowledge.com.libproxy1.nus.edu. sg). The database contains 2.6 million of records [14]. The topic phrase “("UGT1A1") AND ("interact*") AND ("drug")” was

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Fig. (1). Structure of UGT family with xenobiotic-metabolizing enzymes The human UGT superfamily is comprised of 2 families, known to be UGT1 and UGT2. While UGT1 has only one type of subfamily, UGT1A, UGT2 contains two subfamilies, which are UGT2A and UGT2B. Majority of the UGT1A enzymes are involved in the glucuronidation reaction such as UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A7, UGT1A8, UGT1A9 and UGT1A10 but only four members in the UGT2 family are capable of initiating the glucuronidation of different drugs, such as UGT2B4, UGT2B7, UGT2B15 and UGT2B17. These enzymes are thus known as xenobiotic metabolizing enzymes, which are contained in the blue box. The rest of the members highlighted in purple are non-xenobiotic metabolizing enzymes, namely UGT1A5, UGT2A1, UGT2A2, UGT2A3, UGT2B10, UGT2B11 and UGT2B28.

searched. The articles were then screened for its relevance to UGT1A1-mediated in-vitro interactions. Another search was conducted on the same database with the topic phrase “("UGT") AND ("interact*") AND ("drug")”. The articles were then screened for its relevance to UGT-mediated in-vitro and in-vivo interactions. No date limitations were applied to both searches and all articles retrieved were dated from year 1996 to year 2014. Additional relevant literatures that were cited in the retrieved manuscript have also been reviewed. The scope of the review was limited to English language articles only. 3. RESULTS AND DISCUSSION Based on the search method described, 157 articles were retrieved with the topic phrase “("UGT1A1") AND ("interact*") AND ("drug")”. 256 articles were retrieved with the topic phrase “("UGT") AND ("interact*") AND ("drug")”. The articles were screened for its relevance and the relevant drug and herbal supplements interactions were then stratified into 3 main categories based on its clinical significance. The 3 categories were “Likely to be clinically significant”, “Unlikely to be clinically significant”, “Inconclusive over its clinical significance” which were summarized in Table 1, Table 2 and Table 3 respectively. The interactions were then classified into either 1 of the 3 categories based on the opinions of the original authors, as otherwise there was no scientific method of performing classification due to the variation of the study designs in all original studies. 3.1. Drug/Herbal Extracts Interactions that are Likely to be Clinically Significant Tyrosine kinase inhibitors of epidermal growth factor receptors have been used for the treatment of cancer. In particular, erlotinib is FDA-approved for the treatment of metastatic non-small cell lung cancer while nilotinib is approved for treatment of Chronic Myelogenous Leukemia (CML) [24-25]. Both compounds are found to be inhibitors of UGT1A1 in vitro. The concentration of SN-38 (7Ethyl-10-hydroxy-camptothecin), an active metabolite of the colorectal cancer medicine irinotecan, was found to be elevated when incubated with erlotinib and nilotinib [16-17]. This interaction may be of clinical significance as all the three drugs involved are used for the treatment of cancer, and SN-38 in particular has a narrow

therapeutic window [26]. Another study found that the level of 4-MU (4-methylumbelliferone), which is used in bile therapy that is also a known non-specific inhibitor of UGT1A1, is elevated when incubated with erlotinib [15]. The notion that nilotinib is a clinically significant UGT1A1 inhibitor also provides a possible explanation to why UGT1A1 polymorphism is correlated to the risk of nilotinib-induced hyperbilirubinemia [27]. Protease inhibitor is a class of antiviral agents that is often employed to treat Human Immunodeficiency Virus (HIV). Atazanavir and indinavir, both protease inhibitors, are 2 of the 204 pharmaceuticals that are found in the World Health Organization List of Essential Medicines which are of widespread use [28]. Both atazanavir and indinavir have been shown to inhibit UGT1A1 (in vitro Ki is 1.9 μM and 47.9 μM respectively) [18]. This increases the plasma concentration of bilirubin, an endogenous compound, which would otherwise be glucuronidated by UGT1A1 and eliminated from the circulation [29]. When prescribing HIV protease inhibitors to patients who are also diagnosed with hyperbilirubinemia (due to the genetic disorders such as Gilbert’s Syndrome), clinicians should exercise caution. For instance, it has also been found that atazanavir elevated serum bilirubin level clinically in patients, though such phenomena was largely asymptomatic and only less than 2% of the patients stop the medication due to this interaction [22]. Apart from that, the combination of lopinavir and ritonavir, which are both protease inhibitors, was found to cause a 204% increase in SN38 AUC in a clinical study involving 8 patients [23]. The suggested mechanism that lopinavir-ritonavir serves as an UGT1A1 inhibitor of SN-38 metabolism was supported by an in vitro study in which the IC50 of lopinavir and ritonavir was found to be 3.9 μM and 6.3 M respectively [18]. As myelosuppression is one of the adverse reactions of irinotecan [30], patients are more prone towards fungal infections. Clinicians should be aware that ketoconazole, a well-established antifungal agent, elevates the concentration of SN-38 in vitro via UGT1A1 inhibition [19]. The inhibition of UGT1A1 by ketoconazole provides a plausible explanation to the observation that plasma SN-38 level is elevated when ketoconazole is administered to humans [31]. Phenobarbital, an anti-epileptic agent, is a known inducer of UGT1A1. In another study, it was found that the increased enzyme activity will decrease the concentration of pharmacologically active

UGT1A1 Mediated Drug Interactions and its Clinical Relevance

Table 1.

Current Drug Metabolism, 2016, Vol. 17, No. 1

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Interactions involving UGT1A1 that are likely to be clinically significant

Drug or herbal extracts that interact via UGT1A1

Whether interaction is in vitro or in vivo

Elaboration

Ref

Erlotinib

4-MU

in vitro

Erlotinib (100 μM) inhibited UGT1A1 activity, reducing 4-MU glucuronidation by 88.3% (P < 0.01).

[15]

Erlotinib

SN-38

in vitro

Using predictive models, AUC of SN-38 may increase up to 28% with erlotinib administration of 50 mg/day or at higher doses.

[16]

Nilotinib

SN-38

in vitro

Estimated AUC of SN-38 will be twice as high with nilotinib than without it. AUC was estimated from Ki values.

[17]

Atazanavir

Bilirubin

in vitro

In vitro-in vivo scaling suggests that interaction is possible. Hence, atazanavir may cause hyperbilirubinemia.

[18]

Indinavir

Bilirubin

in vitro

In vitro-in vivo scaling suggests that interaction is possible. Hence, indinavir may cause hyperbilirubinemia.

[18]

Ketoconazole

SN-38

in vitro

Interaction between ketoconazole and irinotecan is also established, and paper supports that it is due to UGT1A1 inhibition.

[19]

Phenobarbital

SN-38

in vitro

Induction of UGT1A1 leads to a 1.6 fold increase in UGT1A1 activity after 2 days treatment, and 2.6 fold increase after 6 days treatment.

[20]

Scutellarein (metabolite of Scutellarin from Scutellaria barbata and Scutellaria lateriflora)

4-MU

in vitro

Scutellarein is presented in natural products in low quantity. Therefore the results have to be interpreted with caution, even though IC50 of scutellarein was found to be 0.02 μM in this study

[21]

Atazanavir

Bilirubin

in vivo

Hyperbilirubinemia occurs in 22-47% of the patients on atazanvir.

[22]

Lopinavir-ritonavir combination therapy

SN-38

in vivo

Lopinavir-ritonavir combination is found to inhibit UGT1A1 which led to a 204% increase in SN38 AUC.

[23]

Ketoconazole

SN-38

in vivo

In presence of ketoconazole, the relative exposure to the pharmacologically active metabolite SN-38 increased by 109% (p=0.004).

[31]

4-MU: 4-methylumbelliferone, SN-38: 7-Ethyl-10-hydroxy-camptothecin

SN-38, resulting in subtherapeutic effects. The induction effect caused by phenobarbital was investigated in 3 common UGT variants (-53(TA)6>7, -3156G>A and -3279T>G ). The results demonstrated that the basal and induced activities were correlated with 53(TA)6>7 and with -3156G>A (p=0.001) [20]. Scutellarin is a herbal extract that is used for treatment of cardio-cerebrovascular diseases for the past 30 years [21]. As an UGT1A1 inhibitor, scutellarein (its main bioactive form in plasma) is found to elevate the level of 4-MU in vitro. Cmax/Ki is a parameter that is used to predict the possibility of clinical drug interaction. When Cmax/Ki is more than 100%, it suggests that the drug interaction is significant. For this study, the Cmax/Ki was found to be 3500%. It is hence important to monitor the treatment outcome if scutellarin is co-administered with drugs metabolized by UGT1A1. 3.2. Drug/Herbal Extracts Interactions that are Unlikely to be Clinically Significant Corylin is present in the seeds of Fructus Psoraleae, a medicine that is listed in the Chinese Pharmacopeia. It is also established that

corylin has pharmacological activities [32]. Using 4-MU as a probe, it is found that corylin does not exhibit any inhibitory effects on UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A10 and UGT2B4 [32]. Another herbal extract, DA9801, which is indicated for diabetic neuropathy and undergoing Phase II trial in South Korea, has a clinically insignificant IC50 of 226 μg/ml with BE (17-Estradiol) used as a probe [33]. The complexities of analyzing the in vitro interactions of herbal extracts deserve attention. Depending on the extraction techniques employed, different quantities of the active moieties may be extracted from the original herbs. Even if the extraction techniques have been validated, the environmental factors that the herbs are exposed to (for example sunlight and rainfall) may affect the composition of the studied moieties within the herbs inherently. Dolutegravir, a viral integrase inhibitor, is a FDA-approved medicine for the treatment of HIV. Unlike atazanavir and indinavir (which are also HIV medication), it was found that dolutegravir was not an inhibitor of UGT1A1 at clinically relevant dose when 7-HFC (7-hydroxyltrifluromethyl coumarin) is used as the probe [34]. However, it should be noted that the author of the study was associ-


Table 2.

Goon et al.

Interactions involving UGT1A1 that are unlikely to be clinically significant



Elaboration

Ref

Corylin (herbal extract)

4-MU

in vitro

No potent inhibition was found with UGT1A1. However, complexities of herbal medication require us to be cautious in extrapolating results to clinical setting.

[32]

DA-9801 (herbal extract)

BE

in vitro

The inhibition is clinically insufficient due to high IC50 of 226 μg/ml of DA-9801.

[33]

Dolutegravir

7-HFC

in vitro

Dolutegravir in vitro inhibition of UGT1A1 is weak.

[34]

Gefitinib

4-MU

in vitro

Even when gefitinib is administered at maximum dose of 700 mg/day, AUC increase of 4-MU is less than 30%.

[15]

Levetiracetam

Ethinyloestradiol

in vitro

Levetiracetam shows insignificant inhibition of enzyme.

[35]

Glimepiride

4-MU

in vitro

UGT1A6 is expected to be the key route for glimepiride Phase II metabolism.

[36]

4-MU: 4-methylumbelliferone, BE: 17-Estradiol, 7-HFC: 7-hydroxyltrifluromethyl coumarin, SN-38: 7-Ethyl-10-hydroxy-camptothecin

ated with GlaxoSmithKline (GSK), the pharmaceutical firm that markets dolutegavir (Tivicay ®) [37]. Gefitinib is a tyrosine-kinase inhibitor indicated for Non-SmallCell Lung Carcinoma. When administered at maximum dose of 700 mg/day, AUC of 4-MU is increased by less than 30%. Hence, it is concluded that gefitinib does not have any clinically significant drug interactions via UGT1A1. Interestingly, this contrasts with the other tyrosine kinase inhibitors, such as erlotinib and nilotinib, which actually do interact with UGT1A1 substrates and is clinically significant [15-17]. Levetiracetam, a commonly used antiepileptic drug (AED) does not inhibit UGT1A1 to a clinical significant extent. In in vitro, Levetiracetam inhibits UGT1A1 by less than 6% at clinically relevant doses with ethinyloestradiol as the probe. This is concordant with clinical observations that levetiracetam does not have any significant pharmacokinetic interactions with other AEDs [38], and therefore is commonly used to suppress seizures where multiple concurrent medications are needed [39]. Glimepiride is a medicine under the class of sulfonylureas that is used to treat Type 2 Diabetes Mellitus. Glimepiride does not have any significant interaction via UGT1A1, as its glucuronidation is mainly mediated by UGT1A6 [36]. The clinical significance of glimepiride’s UGT1A6 inhibition is not within the scope of this discussion. 3.3. Drug/Herbal Extracts Interactions that Clinical Significance is Inconclusive Many herbal extracts and its purified compounds have the potential to interact with substrates of UGT1A1. However, there are potential issues with extrapolating results to the clinical setting as previously explained. Some of the herbal products may have poor oral bioavailability (such as flavonoids [41]) or unknown absorption profile (such as kampo [47]). The absorption kinetics is of imperative significance as herbal products are mostly consumed orally. Further in vivo studies may be required to quantitatively determine the clinical significance of the interactions with better accuracy. Efavirenz is a viral reverse transcriptase inhibitor which is used for the treatment of HIV. Though apparently it shows strong inhibition of UGT1A4 or UGT1A9, it can also inhibit UGT1A1 (Ki=40.3 μM) [50]. This raises the possibility that interactions via inhibition of UGT1A1 are relevant and further studies are needed.

Levothyroxine (L-thyroxine) is used to treat hypothyroidism, and is also on WHO’s list of essential medicines [28]. L-thyroxine inhibits UGT1A1 in a dose-dependent manner, resulting in increased level of 4-MU [51]. This is supported by another study which concluded that UGT1A1 polymorphism is correlated to treatment dose of L-thyroxine [55]. Both gemfibrozil and simvastatin are lipid-lowering agents, and are commonly prescribed together for their complementary effects. Gemfibrozil as a UGT1A1 inhibitor reduces the metabolism of simvastatin -hydroxy acid (the active metabolite of simvastatin) in vitro. This is postulated to be the reason for elevated simvastatin hydroxyl acid when it is administered with gemfibrozil in dogs [52]. Tacrolimus is an immunosuppressive agent and is found to elevate 4-MU via inhibition of recombinant human UGT1A1 [53]. However, tacrolimus is even a stronger inhibitor of UGT1A3. In an in vivo environment where tacrolimus is exposed to the different UGT isoforms, its inhibition of UGT1A1 may be weaker since it has higher affinity for UGT1A3. Hence, the clinical significance of this interaction is inconclusive. Raltegravir is a viral integrase inhibitor that is used for the treatment of HIV. It is established that raltegravir does not induce or inhibit hepatic CYP enzymes [54]. However, raltegravir is also a substrate of UGT1A1 [56] and share similar metabolism pathway as SN-38. Hence, it is inconclusive if there is any drug interaction between SN-38 and raltegravir [54]. 4. CONCLUSION As it is with any review papers, this periodical has its own limitations. Firstly, the gold standard of determining if a drug interaction is significant is to conduct retrospective studies or clinical trials in humans. However, majority of the literature available are in vitro studies. Extrapolating from in vitro results to the clinical setting may not be accurate. Secondly, the in vitro study designs of the cited literatures are substantially different. For example, the source of UGT1A1 may be from recombinant human DNA, and/or human microsomes, and/or dog microsomes. Some of the studies had also tested for in vitro interactions at drug concentrations which are not clinically relevant. Thirdly, it must be emphasized that any 2 drugs that do not interact via UGT1A1 may still interact via other mechanisms. This review paper does not provide an exhaustive list of drug interactions. Lastly, due to the risk involved in drug interac-

UGT1A1 Mediated Drug Interactions and its Clinical Relevance

Table 3.

Current Drug Metabolism, 2016, Vol. 17, No. 1

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In vitro interactions involving UGT1A1 that clinical significance is inconclusive



Elaboration

Ref

20(S)- Protopanaxatriol (ppt)

4-MU

in vitro

Complexities of herbal medication require us to be cautious in extrapolating results to clinical setting.

[40]

Monohydroxyflavone(3HF, 7HF, 4'HF) and Trihydroxyflavone (3,7,4'THF)

Monohydroxyflavone(3HF, 7HF, 4'HF) and Trihydroxyflavone (3,7,4'THF)

in vitro


[41]

Andrographis paniculata and Orthosiphon stamineus Extracts

4-MU

in vitro


[42]

Bavachalcone

4-MU

in vitro


[32]

Chrysin (inducer)

BE

in vitro

Complexities of herbal medication require us to be cautious in extrapolating results to clinical setting. Induction of UGT1A1 in human hepatocytes is 1.2 fold whereas in HepG2 cell is 11-fold.

[43]

Corydaline

BE

in vitro


[44]

Demethylzeylasteral

4-MU

in vitro


[45]

Isoliquiritigenin

4-MU

in vitro


[46]

Kampo

SN-38 and BE

in vitro

It is unclear on how Kampo is absorbed and what are its plasma concentrations in humans, making it difficult to extrapolate results to clinical setting.

[47]

Liquiritigenin (herbal extract)

4-MU

in vitro


[48]

Liquiritigenin (herbal extract)

BE

in vitro


[48]

trans-Resveratrol (originates from plant source)

7-HFC

in vitro


[49]

trans-Resveratrol (originates from plant source)

SN-38

in vitro


[49]

Efavirenz

BE

in vitro

Lack of extrapolation of results to in vivo

[50]

L-Tyroxine

4-MU

in vitro


[51]

Simvastatin

Gemfibrozil

in vitro

Studies in dogs confirm that gemfibrozil significantly affects concentration of simvastatin hydroxyl acid. UGT interaction is a possible explanation.

[52]

Tacrolimus

4-MU

in vitro


[53]

Raltegravir

SN-38

in vivo

Although both compounds are substrates of UGT1A1, they neither act as an inducer or inhibitor.

[54]

4MU: 4-methylumbelliferone, BE: 17-Estradiol, SN-38: 7-Ethyl-10-hydroxy-camptothecin, 7-HFC: 7-hydroxyltrifluromethyl coumarin

tion studies, the human subjects recruited in in vivo studies are often small in sample size. Nonetheless, this paper can serve as a starting point for future investigative in vivo studies or the initiation of retrospective drug interaction studies involving patients. Given that certain drugs and herbal extracts mentioned are found to interact via UGT1A1

in vitro, it should be of interest to researchers to conduct further studies. Other than that, extensive pharmacokinetic interaction studies for newly approved drugs are as important when polypharmacy is a common occurrence. The usage of animal models as surrogates to confirm its clinical significance may be preferred, as many clinically relevant interactions involved drugs that are toxic to humans.


In conclusion, clinicians and academics can use this secondary literature to have a broad and updated perspective of the interactions mediated by UGT1A1. This review article has also highlighted few studies on the interaction or potential interaction of drug/herbal extracts with bilirubin. However, the interactions of drugs/herbal extracts with endogenous substances, such as estradiol (3-OH) and T4 via the UGT1A1 pathway, are not sufficiently understood [57]. This would warrant further clinical studies to discern its clinical significance in the near future.

Goon et al. [15]

[16]

[17]

[18]

CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. [19]

ACKNOWLEDGEMENTS The study was sponsored by the National Research Foundation of Singapore (Experimental Therapeutics Program), National Medical Research Council of Singapore (NMRC/CSA/021/2010) and National University of Singapore (NUS). The authors thank the NUHS Medical Publications Support Unit, Singapore, for assistance in the preparation of this manuscript.

[20]

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Received: March 18, 2015

Revised: September 14, 2015

Accepted: October 30, 2015

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