Arch Pharm Res Vol 34, No 11, 1773-1777, 2011DOI 10.1007/s12272-011-1121-0

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SHINBARO, a New Herbal Medicine with MultifunctionalMechanism for Joint Disease: First Therapeutic Application

for the Treatment of Osteoarthritis

Sung-Yeol Lee1, Hyoung-Keun Kwon1, and Sun-Mee Lee2

1Green Cross, 303 Bojeong-Dong, Giheung-Gu, Yongin 446-770, Korea and2School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Korea

Osteoarthritis (OA) is a chronic, degenerative dis-order with multifactorial etiology, characterized byloss of articular cartilage and periarticular bone re-modeling. It is the most common form of arthritis anda serious clinical concern in an aging population. OAalso causes joint pain, typically worse with weightbearing and activity, and stiffness after inactivity.There is no cure, and gradual, although slow, progres-sion is highly common. Goals of managing OA includecontrolling pain, maintaining and improving therange of movement and stability of affected joints, andlimiting functional impairment. These goals should beachieved with minimal toxicity. The ideal therapeuticagent for OA, in addition to decreasing pain and in-

flammation, should provide protection against car-tilage destruction. However, current pharmacologicaltherapies remain unsatisfactory (Farkouh et al., 2004).Therapeutic interventions conventionally employedfor OA include the use of physiotherapy and antidepres-sant therapies, patient education and weight control(Weinberger et al., 1989). In addition, drug therapyincludes non-opioid analgesics such as paracetamol,non-steroidal anti-inflammatory drugs (NSAIDs), top-ical analgesics, opioid analgesics, and intra-articularsteroid injection. NSAIDs have been used clinically forthe past few years in the treatment of arthritic dis-ease although gastrointestinal complications havebeen frequently reported with them. Cyclooxygenase-2(COX-2)-specific inhibitors might be beneficial for ad-verse effects on cartilage. Uncertainty about potentialincreased risk of cardiovascular events remains withCOX-2 inhibitors (Bombardier et al., 2000; Farkouh etal., 2007). This risk can be especially high in patientswith conventional cardiovascular risk factors (smoking,hypertension, diabetes mellitus, hyperlipidemia, and

Report on Investigational Drugs

Correspondence to: Sung-Yeol Lee, Green Cross, Yongin 446-770, KoreaTel: 82-31-260-9757E-mail: sylee@greencross.comEdited by Mi-Kyoung Kwak, College of Pharmacy, The CatholicUniversity of Korea, Bucheon 420-743, KoreaTel: 82-2-2164-6532E-mail: mkwak@catholic.ac.kr

SHINBARO is a purified extract from a mixture of 6 oriental herbs (Ledebouriellae Radix, Achyranthis Radix,Acanthopanacis Cortex, Cibotii Rhizoma, Glycine Semen, and Eucommiae Cortex) that have been used as atraditional medicine for treatment of several inflammatory diseases and bone disorders. We determined anti-inflammatory and antinociceptive activities of SHINBARO in adjuvant-induced (osteo)arthritis in rats. Thispotential anti-(osteo)arthritic property of SHINBARO can be due to the downregulation of inflammatory mediatorssuch as iNOS, COX-2, and TNF-α, the increase of pain threshold in the peripheral system, the activation ofalkaline phosphatase in osteoblasts, the suppression of proteoglycan degradation, and the inhibition of MMP-2 andMMP-9 activities as demonstrated by in vitro and in vivo experimental studies. We confirmed that SHINBARO isas effective as celecoxib, a selective COX-2 inhibitor, but it has the better safety profile in clinical trials. Finally,SHINBARO was approved as a New Herbal Medicine for treatment of osteoarthritis by Korean FDA on January25th, 2011.

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family history of premature cardiovascular disease ina first-degree-relative). Both NSAIDs and COX-2 in-hibitors may cause acute deterioration in renal func-tion, fluid retention and hypertension. Hence, conti-nuous development of new agents to treat arthritis isurgently required because, to date, conventional thera-peutic agents with a kind of toxicity can not meet tothe needs of the times, “Aging Society”. Many scientistshave been finding a new agent among traditionalherbal medicines because of the safety although theuse of herbal medicine provokes debate in its currentand future role in health care and evidence for bothefficacy and safety. However, more information onherbal medicine including preparation, standardiza-tion, identification of active ingredients, and toxicolo-gical evaluation needs to be accumulated. Thus, devel-opment of herbal medicine requires advanced interdis-ciplinary technology and methodology. Further experi-mental and clinical investigations will allow a betterunderstanding of mechanisms of action, therapeuticeffects, and the safety profile of herbal medicine. GreenCross have searched a good medicinal candidate fromtraditional therapeutic herbs for treatment of OA,developed it for several years, and finally proved atherapeutic advantage by clinical trials.

SHINBARO is a purified extract from a mixture of 6oriental herbs (Ledebouriellae Radix, AchyranthisRadix, Acanthopanacis Cortex, Cibotii Rhizoma, GlycineSemen, and Eucommiae Cortex) that have been used

as traditional medicine for the treatment of severalinflammatory diseases and bone disorders. Althoughactive ingredients of this mixture have not been com-pletely identified, recent studies have reported anal-gesic and/or anti-inflammatory effect of LedebouriellaeRadix (Kim et al., 2002), antioxidant activity and/oranti-inflammatory effect of Achyranthis Radix (Ida etal., 1998), and antioxidant activity and/or analgesiceffect of Eucommiae Cortex (Hong et al., 1988). ChineseTraditional Medicine Pharmacopeia described anti-inflammatory effect of Acanthopanacis Cortex, anal-gesic effect of Cibotii Rhizoma, and antiedemic effectof Glycine Semen (Fig. 1).

The safety of the 6 oriental herbs of SHINBAROwas well acknowledged during their long standinghistory of human use, but their use still lacks scientif-ic support. Therefore, we demonstrated the effect ofSHINBARO in the rodent preclinical toxicity and safetypharmacology studies. No changes were observed inbody weight, blood cell counts, and clinical chemistriesof enzymes such as hemoglobin, alkaline phosphatase,and creatine phosphokinase, which were in the nor-mal value range. No clinical signs were observed inthe central nervous, respiratory and gastrointestinalsystems in rats and beagle dogs (Kim et al., 2005; Leeet al., 2005).

We determined anti-inflammatory and anti-nocicep-tive activities of SHINBARO in adjuvant-induced OAin rats. SHINBARO significantly inhibited the incre-

Fig. 1. Composition of SHINBARO. SHINBARO is a purified extract from a mixture of 6 oriental herbs (LedebouriellaeRadix, Achyranthis Radix, Acanthopanacis Cortex, Cibotii Rhizoma, Glycine Semen, and Eucommiae Cortex) with anti-(osteo)arthritic properties.

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ase of acetic acid-induced vascular permeability inmice and the increase of carrageenan-induced swell-ing of the rat’s hind paw. SHINBARO significantlyinhibited the number of acetic acid-induced writhingin mice but increased the pain threshold in theRandall-Selitto test. In rabbit knee articular explants,SHINBARO inhibited proteoglycan degradation whichis the primary chemical change of osteoarthritis and isassociated with inflammation. In the histopathologicaland radiological examinations of monoiodoacetate-induced osteoarthritis rat model, anti-inflammatorypotential in osteoarthritic lesions and protective po-tential in knee joint were observed (Kim et al., 2005;Lee et al., 2005). This potential anti-arthritic mechani-sms of SHINBARO can be due to the inhibition of in-flammatory mediators such as inducible nitric oxidesynthase (iNOS), COX-2, and tumor necrosis factor-α(TNF-α), the increase of the pain threshold in the per-ipheral system, the activation of the alkaline phospha-tase (ALP) in the osteoblast, the suppression of pro-teoglycan degradation and the inhibition of matrixmetalloproteinase-2 (MMP-2) and MMP-9 activities,as shown by in vitro and in vivo experimental studies(data not shown) (Fig. 2).

The placebo-controlled, randomized, double-blind,multi-centers, phase II clinical study of SHINBAROwas undertaken to explore the appropriate dose fortreatment of OA patients. The patients were randomly

placed into one of the following four groups: placebo,600 mg (300 mg twice a day), 1200 mg (600 mg twicea day) or 2400 mg (1200 mg twice a day) for 12 weeks.The primary and second end-point was a change inpatient assessment of pain as measured using theWestern Ontario and McMaster Universities (WOMAC)scale and 100 mm Pain Visual Analogue Scope (VAS)on walking. The efficacy assessment was performed toevaluate differences in mean WOMAC (or 100 mmPain VAS) between baseline and week 12 in eachgroup as Per Protocol (PP) group. The 1200 mg groupof SHINBARO (28.0; p-value = 0.0782; n = 29) showedthe better efficacy compared with the placebo (17.0; n= 31), 600 mg (22.0; p-value = 0.3946; n = 29), or 2400mg group (23.0; p-value = 0.4913; n = 32). The resultsfrom 100 mm Pain VAS on walking was similar withthe WOMAC scale (data not shown). From this result,oral administration of 1200 mg SHINBARO (600 mgtwice a day) was selected to apply to the followingphase III clinical study.

A randomized, double-blind, double-dummy, phaseIII noninferiority clinical trial in 215 OA patients wasperformed to confirm if SHINBARO was as effectiveas celecoxib, a selective COX-2 inhibitor which is pre-ferred because of the lower gastrointestinal riskalthough co-treatment of conventional NSAIDs andgastroprotective agents are recommended as the firsttherapy. Data from 165 patients (SHINBARO, 1200

Fig. 2. Proposed pharmacological mechanism of SHINBARO. The potential anti-(osteo)arthritic property of SHINBARO canbe due to 1) anti-inflammation, 2) anti-nociception, 3) growth of osteoblast and, 4) the joint protection, shown by in vitro andin vivo experimental studies.

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mg/day, n = 80; celecoxib, 200 mg/day, n = 85) of PPgroup were used for efficacy assessment. The primaryand second end-point was a change in patient assess-ment of pain as measured using the WOMAC scaleand 100 mm Pain VAS on walking as used in the phaseII trial. The non-inferiority analysis was performed toassess differences in mean WOMAC (or 100 mm PainVAS) between baseline and week 12 in both studygroups. Pain intensity decreased significantly compar-ed with baseline as determined by WOMAC score21.26 in SHINBARO group and 20.50 in celecoxibgroup, but no significant difference was found betweenboth groups (p-value = 0.7944). SHINBARO was con-sidered non-inferior to celecoxib because the lowerlimit of the 1-sided 95% Confidence Interval (CI) forthe treatment difference was 4.47. Results from the100 mm Pain VAS assessment were similar as ofWOMAC. Pain intensity decreased significantly com-pared with baseline as determined by 100 mm PainVAS 27.91 in SHINBARO group and 29.92 in celecoxibgroup, but no significant difference was found betweenboth groups (p-value = 0.5763). Therefore, we confirm-ed again that SHINBARO was considered non-inferiorto celecoxib (Fig. 3).

Tolerability assessments were performed by a meta-analysis using data from Phase II study (SHINBARO,n = 39) and Phase III study (SHINBARO, n = 99;celecoxib, n = 99) of Intention-to-Treat (ITT) groups.Twenty two out of 138 (15.9%) in SHIBARO group and31 out of 99 (31.3%) in celecoxib group experienced ≥1drug-related Adverse Events (AE) (p-value = 0.0051).Tolerability assessments for gastrointestinal compli-cation, which is frequently reported in patients treat-

ed with NSAIDs, were performed by the same manner.Eighteen out of 138 (13.0%) in SHINBARO group and22 out of 99 (22.0%) in celecoxib group were reported(p-value = 0.0628) (Fig. 4).

These results suggest that SHINBARO has thera-peutic effects on osteoarthritis patients by multi-func-tional mechanism compared to celecoxib through thebone regeneration and protection; and it has bettersafety profile (Fig. 4). Therefore, SHINBARO can be agreat candidate for OA treatment. SHINBARO hasshown satisfactory inhibition of inflammation andpain, and improvement of cartilage, with no signifi-cant long-term side effects in the preclinical and clini-cal observations. Thus, SHINBARO was successfullyapproved as a New Herbal Medicine for treatment ofOA by Korean FDA (Food and Drug Administrations)on January 25th, 2011.

REFERENCES

Bombardier, C., Laine, L., Reicin, A., Shapiro, D., Burgos-Vargas, R., Davis, B., Day, R., Ferraz, M. B., Hawkey, C.J., Hochberg, M. C., Kvien, T. K., and Schnitzer, T. J.,Comparison of upper gastrointestinal toxicity of rofecoxiband naproxen in patients with rheumatoid arthritis.VIGOR Study Group. N. Engl. J. Med., 343, 1520-1528(2000).

Farkouh, M. E., Kirshner, H., Harrington, R. A., Ruland, S.,

Fig. 3. Efficacy results of phase III clinical trial. SHINBAROwas as effective as celecoxib for treatment of OA patients.Primary and secondary assessments (WOMAC and 100 mmVAS) were performed in the data from 165 patients (ppgroups; SHINBARO, n = 80; celecoxib, n = 85) in the phaseIII clinical trial. Two SHINBARO capsules (300 mg) weretreated twice a day and one Celecoxib capsule (200 mg) wastreated once a day for 12 weeks.

Fig. 4. Meta-analysis of tolerability assessments of phase IIand III clinical trials. Fewer drug-related adverse drugevents were reported in SHINBARO group compared withcelecoxib group. Meta-analysis of Tolerability assessmentswere performed in data from 39 patients (ITT group,SHINBARO, n = 39) in phase II clinical trial and 198patients (ITT groups, SHINBARO, n = 99; celecoxib, n = 99)in phase III clinical trial. Two SHINBARO capsules (300mg) were treated twice a day and one Celecoxib capsule (200mg) was treated once a day for 12 weeks.

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Verheugt, F. W., Schnitzer, T. J., Burmester, G. R., Mysler,E., Hochberg, M. C., Doherty, M., Ehrsam, E., Gitton, X.,Krammer, G., Mellein, B., Gimona, A., Matchaba, P.,Hawkey, C. J., and Chesebro, J. H., Comparison of lumi-racoxib with naproxen and ibuprofen in the TherapeuticArthritis Research and Gastrointestinal Event Trial(TARGET), cardiovascular outcomes: randomised controlledtrial. Lancet, 364, 675-684 (2004).

Farkouh, M. E., Greenberg, J. D., Jeger, R. V., Ramanathan,K., Verheugt, F. W., Chesebro, J. H., Kirshner, H., Hochman,J. S., Lay, C. L., Ruland, S., Mellein, B., Matchaba, P. T.,Fuster, V., and Abramson, S. B., Cardiovascular outcomesin high risk patients with osteoarthritis treated withibuprofen, naproxen or lumiracoxib. Ann. Rheum. Dis.,66, 764-770 (2007).

Hong, N. D., Rho, Y. S., Kim, J. W., Won, D. H., Kim, N. J.,and Cho, B. S., Studies on the general pharmacologicalactivities of Eucommia ulmoides Oliver. Kor. J. Pharm-acogn, 19, 102-110 (1988).

Ida, Y., Satoh, Y., Katsumata, M., Nagasao, M., Hirai, Y.,Kajimoto, T., Katada, N., Yasuda, M., and Yamamoto, T.,Two novel oleanolic acid saponins having a sialyl Lewis X

mimetic structure from Achyranthes fauriei root. Bioorg.Med. Chem. Lett., 8, 2555-2558 (1998).

Kim, H. W., Kwon, Y. B., Ham, T. W., Roh, D. H., Yoon, S. Y.,Han, H. J., Kang, S. K., Lee, H. J., Mar, W. C., Yang, I. S.,Beitz, A. J., and Lee, J. H., The antinociceptive and anti-inflammatory effect of ethylacetate extracts from Bang-Poong (Radix ledebouriellae) on the Freund's adjuvant-induced arthritis in rats. J. Vet. Sci., 3, 343-349 (2002).

Kim, S.-H., Lee, C.-H., Lee, J.-S., Cho, K.-H., Kim, S.-O.,Cho, S.-H., Cho, H.-K., and Lee, S.-M., Anti-InflammatoryActivities of a Herbal Preparation GCSB-5 on Acute andChronic Inflammation. Kor. J. Pharmacogn, 36, 311-317(2005).

Lee, C.-H., Kim, S.-H., Lee, J.-S., Cho, K.-H., Kim, J.-S., Cho,S.-H., and Lee, S.-M., Evaluation of the AntinociceptiveProperties of GCSB-5, a Herbal Formulation. Kor. J.Pharmacogn, 36, 299-304 (2005).

Weinberger, M., Tierney, W. M., Booher, P., and Katz, B. P.,Can the provision of information to patients with osteoar-thritis improve functional status? A randomized, controll-ed trial. Arthritis Rheum., 32, 1577-1583 (1989).

Sung-Yeol Lee

Managing Director of Head of Corporate Development, Green Cross Corp.Main Research Area

New Herbal Medicine: SHINBARO, GC7101 (reflux oesophagitis)Human Antihemophilic Factor: Green-geneVaccine Development: Seasonal influenza, Avian influenza

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