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CYP3A4 and CYP2D6 inhibitory activities of Indonesian medicinal plants.

Abstract

Thirty samples of Indonesian medicinal plants were analyzed for their capacity to inhibit in vitro metabolism by human cytochrome P450 3A4 (CYP3A4) and CYP2D6 with a radiometric assay. The MeOH-soluble fractions of 25 samples, prepared from water extracts, demonstrated inhibitory activity more than 50% on the metabolism mediated by CYP3A4, and 21 samples on the metabolism mediated by CYP2D6. Among the MeOH-soluble fractions, Piper nigrum leaf showed the highest inhibitory activity against CYP3A4 (91.7%), and Punica granatum against CYP2D6 (98.1%). The water extracts of which MeOH-soluble fraction showed inhibitory activity more than 70% were fractionated with EtOAc. From the EtOAc-soluble fractions, Curcuma heyneana (67.0%), Pi. cubeba (75.0%), Pi. nigrum fruit (84.0%), Pi. nigrum leaf (85.8%), and Zingiber aromaticum (75.3%) demonstrated inhibitory activity more than 50% on the metabolism mediated by CYP3A4, but only Pi. nigrum fruit (72.8%) and Pi. nigrum leaf (69.1%) showed strong inhibitory activity against CYP2D6. For samples that showed more than 70% inhibition, their I[C.sub.50] values were determined. The most potent inhibitory activity against CYP3A4 (I[C.sub.50] value of 25 [micro]g/ml) was found for the extract of Pi. nigrum leaf, while that of Catharanthus roseus showed the most potent inhibitory effect against CYP2D6 (I[C.sub.50] value of 11 [micro]g/ml). These results should indicate once more the possibility of potential medicinal plant-drug interactions.

[c] 2005 Elsevier GmbH. All rights reserved.

Keywords: Cytochrome P450; Jamu; Drug interaction; Inhibition; CYP3A4; CYP2D6

Introduction

Cytochrome P450 (CYP) is the main enzyme which catalyzes the metabolism of drugs and other xenobiotics. CYP3A4, the major hepatic and intestinal CYP in humans, metabolizes more than 50% of clinically used drugs such as cyclosporine A, dihydropyridines, ethinylestradiol, midazolam, terfenadine, and triazolam (Rendic and DiCarlo, 1997). CYP2D6 catalyzes the metabolism of about 30% of all drugs including amitriptyline, imipramine, haloperidol, propranolol, and dextromethorphan (Clarke and Jones, 2002).

Recently, several reports have demonstrated that natural compounds and herbal products may cause pharmacokinetic interaction with western drugs used clinically when they are simultaneously administrated (Foster et al., 1999; Nebel et al., 1999; Taylor and Wilt, 1999). The use of medicinal herbs has particularly increased over the past few years among specific patient populations including HIV-infected patients. St. John's wort altered pharmacokinetics of the HIV protease inhibitor, indinavir in individuals on retroviral therapy (Piscitelli et al., 2000). Indeed, plasma concentrations of the HIV protease inhibitor, saquinavir, have been decreased in individuals exposed long-term to garlic supplements (Piscitelli et al., 2002). The increased clearance of saquinavir may be due to induction of hepatic and/or intestinal CYP3A4. The most widely studied natural product is grapefruit juice, which has been found to increase the bioavailability and/or to prolong the metabolic elimination of many drugs such as dihydropyridine-type calcium channel blockers, histamine-1 receptor antagonists (e.g., terfenadine), quinidine, benzodiazepines (e.g., midazolam), 17[beta]-estradiol, and caffeine (Ameer and Weintraub, 1997; Bailey et al., 1998).

Indonesia, a country in Southeast Asia, has many medicinal plants which are used as traditional medicines "Jamu" (Sastroamidjojo, 1997). Those medicinal plants have been used from the ancient time to now, and are largely consumed by people of different levels in villages and also in big cities. People could easily buy readymade "Jamu" which is packed in the form of powder, pills, capsules, drinking liquid, and ointment. There are still "Jamu" shops to sell only ingredients or to prepare the "Jamu" on spot by request. It is a common view across the country that some women are roaming the street to sell "Jamu", and many Indonesians start their day with drinking "Jamu". These traditional medicines are almost unregulated, and many patients do not inform their physician about the traditional medicines they consume. Therefore, interactions between traditional medicines and drugs prescribed clinically are becoming a concern. To the best of our knowledge, there have been no reports on the inhibitory potential of Indonesian medicinal plants against CYP. Thus, we chose 30 medicinal plants which are generally used in Indonesian traditional medicines (Sastroamidjojo, 1997; PT Eisai Indonesia, 1995) (Table 1) and evaluated their inhibitory activity against CYP3A4 and CYP2D6.

Materials and methods

Medicinal plants

Indonesian medicinal plants were obtained at GORO traditional market, Jakarta, Indonesia, in May 2002 and voucher samples are preserved at the Museum of Materia Medica, Research Center for Ethnomedicines, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan (Table 1).

Extraction and preparation of test solutions

Each medicinal plant (25-150 g) was cut into small pieces and extracted with water (150-400 ml, reflux, 2 h, x 2). The water solution was concentrated under reduced pressure and lyophilized to give a water extract. A part of the water extract (0.5 g) from each medicinal plant was extracted with MeOH (15 ml), followed by centrifugation to facilitate removal of the supernatant, to give a MeOH-soluble fraction. The MeOH-soluble fraction was evaporated and redissolved in 1.5 ml of MeOH and used as a test solution. The medicinal plants on which the MeOH-soluble fraction showed strong inhibition against CYP3A4 and/or CYP2D6, an EtOAc-soluble fraction was prepared from the water extract by extracting with EtOAc (15 ml), followed by centrifugation. The EtOAc-soluble fraction was evaporated and dissolved in 1.5 ml of MeOH and used as a test solution.

Chemicals

Quinidine sulfate dihydrate and ketoconazole were obtained from Wako Pure Chemicals Industry, Ltd. (Osaka, Japan). [N-methyl-[.sup.14]C]Erythromycin (55 mCi/mmol, >99% pure) and [O-methyl-[.sup.14]C]dextromethorphan (55 mCi/mmol, >99% pure) were purchased from American Radiolabeled Chemicals, Inc. (St. Louis, MO, USA). Human liver microsomes (HLM) were obtained from Xenotech, LLC (Kansas, KS, USA) and stored at -80 [degrees]C prior to use. [beta]-Nicotinamide adenine dinucleotide phosphate (NAD[P.sup.+], oxidized form), glucose-6-phosphate (G-6-P), and G-6-P dehydrogenase were purchased from Oriental Yeast Co., Ltd. (Tokyo, Japan). All other chemicals and solvents were of the highest grade available.

CYP inhibitory activity

Inhibitory activity against CYP3A4 was assayed by the method of Riley and Howbrook (1998) with a slight modification. Briefly, the assay was performed in a disposable culture tube of 13 x 100 mm (Iwaki, Tokyo, Japan). Tubes were designated as "control", "positive control", and "test". The control tube consisted of 2.5 [micro]l of MeOH; positive control consisted of 2.5 [micro]l of ketoconazole (100 [micro]M); and test tubes consisted of 2.5 [micro]l of samples (equivalent to 1.65 mg/ml of extract). To all tubes were added 150 [micro]l of phosphate buffer (pH 7.4), 197.5 [micro]l of ultrapure water, 50 [micro]l of [N-methyl-[.sup.14]C]erythromycin (0.1 [micro]Ci/incubation, 1 mM in 5% of MeOH), and 50 [micro]l of HLM (4 mg/ml). The total incubation volume was 500 [micro]l. After 5 min preincubation under shaking at 37 [degrees]C, the reaction was initiated by addition of 50 [micro]l of NADPH-generating system (4.20 mg/ml of NAD[P.sup.+], 100 mM of G-6-P, 100 mM of Mg[Cl.sub.2], and 10 U/ml of G-6-P dehydrogenase) and continued for 10 min under the same conditions. The reaction was stopped by the addition of 125 [micro]l of 10% trichloroacetic acid (Nacalai tesque, Inc., Kyoto; Japan). After centrifugation at 3000 rpm for 10 min at room temperature, the supernatant was applied to EnviCarb solid-phase extraction column (Supelco, PA, UK) and was eluted by ultrapure water (500 [micro]l x 2). After addition of 10 ml of Clear-sol I (Nacalai tesque, Inc.), the eluted radioactivity was quantified by liquid scintillation counting LS 6500 (Beckman, CA, USA). Correction was made for radioactivity eluted from the control in which HLM and NADPH-generating system were omitted. The assays were performed in duplicate for all samples. The inhibitory activity against CYP2D6 was also measured by the method of Rodrigues (1996) with a slight modification. The assay was done with the same procedure in the case of CYP3A4 using [O-methyl-[.sup.14]C]dextromethorphan (0.1 [micro]Ci/incubation, 100 [micro]M in 5% of MeOH) as a substrate and longer incubation time (20 min). Quinidine (100 [micro]M) was used as a positive control.

To calculate the I[C.sub.50] values (concentrations of sample causing 50% reduction in activity relative to the control) of the sample that showed more than inhibition 70%, the sample was added to the reaction mixture at a concentration range of 0-1.65 mg/ml. The relationship between the concentration of sample and the remaining activity was analyzed using software product WinNonlin Ver.3.1 (Pharsight Corp., Mountain View, CA, USA). I[C.sub.50] values were calculated by linear regression analysis of the sample concentration versus percentage control activity plots.

[FIGURE 1 OMITTED]

Results and discussion

All 30 samples of Indonesian medicinal plants were analyzed for their ability to inhibit CYP3A4-mediated metabolism of [N-methyl-[.sup.14]C]erythromycin and CYP2D6-mediated metabolism of [O-methyl-[.sup.14]C]-dextromethorphan. The amount of the test solution used was 1.65 mg/ml of extract according to Iwata et al. (2004), or equivalent to 2-10 mg of herbal powder which is 30 times smaller than the minimal amount of one time consumption of Indonesian traditional medicine, generally. The MeOH-soluble fractions of 14 samples (Alyxia reinwardtii, Andrographis paniculata, Curcuma heyneana, Cymbopogon nardus, Glycyrrhiza glabra, Piper cubeba, Pi. nigrum fruit, Pi. nigrum leaf, Pu. granatum, Rheum palmatum, Sanatalum album, Syzygium aromaticum, Tinospora crispa, and Zingiber aromaticum) showed inhibitory activity over 70% on the metabolism mediated by CYP3A4, and Pi. nigrum leaf revealed the strongest activity (91.7%) (Fig. 1). Twelve samples (Alpinia galanga, Alstonia scholaris bark, Amomum compactum fruit, Am. compactum rhizome, Ca. roseus, Cinnamomum burmani, Cu. aeruginosa, Cu. xanthorrhiza, Melaleuca leucodendron, Strychnos ligustrina leaf, St. ligustrina wood, and Z. cassumunar) showed inhibition between 30% and 70%. Other samples showed inhibition only less than 30%.

On the metabolism mediated by CYP2D6, 15 samples (Als. scholaris bark, An. paniculata, Ca. roseus, Ci. burmani, G. glabra, Pi. nigrum fruit, Pi. nigrum leaf, Pu. granatum, R. palmatum, Sa. album, St. ligustrina leaf, St. ligustrina wood, Sy. aromaticum, Ti. crispa, and Z. aromaticum) demonstrated inhibitory activity over 70% and 7 of them were more than 90%: An. paniculata (92.6%), Ca. roseus (96.4%), G. glabra (94.5%), Pi. nigrum leaf (90.9%), Pu. granatum (98.1%), R. palmatum (96.4%), and Sy. aromaticum (94.5%) (Fig. 1). The inhibitory activity more than 30% but less than 70% was found with Aly. reinwardtii, Am. compactum rhizome, Cu. aeruginosa, Cu. heyneana, Cu. xanthorrhiza, Cy. nardus, M. leucodendron, and Pi. cubeba. The remaining samples showed inhibition only less than 30%.

[FIGURE 2 OMITTED]

Then, the EtOAc-soluble fraction was prepared from the water extract whose MeOH-soluble fraction showed inhibition more than 70%. Among 19 EtOAc-soluble fractions, those of Pi. cubeba (75.0%), Pi. nigrum fruit (84.0%), Pi. nigrum leaf (85.8%), and Z. aromaticum (75.3%) demonstrated inhibitory activity over 70% on the metabolism mediated by CYP3A4 (Fig. 2). An. paniculata, Cu. heyneana, and Sy. aromaticum showed the inhibitory activity between 30% and 70%. Other samples showed inhibition only less than 30% against CYP3A4. On the other hand, only Pi. nigrum fruit (72.8%) demonstrated inhibitory activity over 70% on the metabolism mediated by CYP2D6 (Fig. 2), and the inhibition between 30% and 70% was found on Pi. nigrum leaf (69.1%).

The I[C.sub.50] values of the samples that showed inhibition more than 70% are listed in Table 2. All samples showed inhibitory activity on the metabolism mediated by CYP3A4 and CYP2D6 in a concentration-dependent manner. The potent inhibitory activity against CYP3A4 with I[C.sub.50] values less than 100 [micro]g/ml were found on Pi. cubeba (53 [micro]g/ml), Pi. nigrum fruit (29 [micro]g/ml), Pi. nigrum leaf (25 [micro]g/ml), and Pu. granatum (35 [micro]g/ml), while Ca. roseus was the most potent inhibitory activity against CYP2D6 with an I[C.sub.50] value of 11 [micro]g/ml.

These experiments have demonstrated that 63% of the selected samples of Indonesian medicinal plants significantly inhibited CYP3A4-mediated metabolism of [N-methyl-[.sup.14]C]erythromycin and CYP2D6-mediated metabolism of [O-methyl-[.sup.14]C]-dextromethorphan. Tsukamoto et al. (2002) reported five bisalkaloids, dipiperamides A-E, and a lignan, (-)-hinokinin, as potent CYP3A4 inhibitors of Pi. nigrum. In addition, (-)-hinokinin with two methylenedioxyphenyl groups in the molecule was also isolated from Pi. cubeba (Parmar et al., 1997). Methylenedioxyphenyl compounds were well known to inhibit CYP reaction through the formation of stable complexes with CYP enzymes (Marcus et al., 1985). Thus, the inhibitory activity of Pi. cubeba may be due to constituents like (-)-hinokinin. Surprisingly, Pi. nigrum also showed strong inhibition against CYP2D6 (>70%), suggesting the presence of other inhibitor(s). The dried roots of G. glabra have been consumed for the past 6000 years and are used as flavoring and sweating agents, demulcents, and expectorants in the Western world and as antiallergic and anti-inflammatory agents in Japan and China (Chandler, 1985; Mitschner et al., 1986). Licorice root extract, as well as its major isoflavan glabridin, is a potent antioxidant against LDL oxidation in mice and humans (Rosenblat et al., 1999), and Kent et al. (2002) reported that glabridin inactivates CYP3A4 in a time-, concentration-, and NADPH-dependent manner; i.e., mechanism-based inactivation. On the other hand, 2,4-dimethylglabridin did not show the inhibition on CYP3A4. Thus, the two hydroxyl groups on the 2 and 4 positions of the B ring should be important for the CYP3A4 inactivation. In our experiment, G. glabra also showed inhibitory activity over 70% on the metabolism by CYP2D6, indicating the possibility of the presence of other potent inhibitor against CYP2D6.

Fifteen samples from the MeOH-soluble fraction showed inhibitory activity more than 70% on the metabolism by CYP2D6. Hasegawa et al. (2002) identified o-methoxycinnamaldehyde from Cinnamomi cortex as a potent inhibitor against CYP1A2 and CYP2E1 in rat liver microsomes, but they showed weak inhibition against CYP2D6. Thus, CYP2D6-inhibitory constituent(s) in Ci. burmani, showing the inhibition more than 70% on CYP2D6, may be different from o-methoxycinnamaldehyde.

On the EtOAc-soluble fractions, Pi. cubeba, Pi. nigrum, and Z. aromaticum showed strong inhibitory activity on the metabolism by CYP3A4, but only Pi. nigrum inhibited CYP2D6. It should be noted here that Z. aromaticum, showing strong inhibition against CYP3A4, is the crude drug used mostly in Indonesian traditional medicines. The result of this study should clearly demonstrate the probability of interaction between Indonesian medicinal plants and concomitantly administrated conventional drugs. Further studies on these plants, including the identification of the active constituents and in in vivo system, are under progress and will be reported elsewhere.

Acknowledgements

A part of this work was supported by a Grant-in-Aid for the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

References

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T. Usia (a), H. Iwata (a,b), A. Hiratsuka (c), T. Watabe (a), S. Kadota (a), Y. Tezuka (a,d,*)

(a) Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630-Sugitani, Toyama 930-0194, Japan

(b) Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14-Sunayama, Ibaraki 314-0255, Japan

(c) Tokyo University of Pharmacy and Life Science, 1432-I-Horinouchi, Tokyo 192-0392, Japan

(d) 21st Century COE Program, Toyaina Medical and Pharmaceutical University, 2630-Sugitani, Toyama 930-0194, Japan

Received 22 December 2003; accepted 6 June 2004

*Corresponding author. Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630-Sugitani, Toyama 930-0194, Japan Tel.: 81 76 434 7627; fax: 81 76 434 5059.

E-mail address: tezuka@ms.toyama-mpu.ac.jp (Y. Tezuka).
Table 1. Indonesian medicinal plants, their families, parts used, local
names, therapeutic applications, and voucher specimen numbers

 Part
Plant name Family used Local name

Alpinia galanga (L.) SWARTZ Zingiberaceae Rhizome Laos
Alstonia scholaris (L.) R.BR. Apocynaceae Bark Pulai
Alstonia scholaris (L.) R.BR. Apocynaceae Leaf Pulai
Alyxia reinwardtii BL. Apocynaceae Bark Pulosari
Amomum compactum SOLAND ex Zingiberaceae Fruit Kapulaga
 MATON
Amomum compactum SOLAND ex Zingiberaceae Rhizome Kapulaga
 MATON
Andrographis paniculata Acanthaceae Aerial Sambiloto
 (BURM. F.) NEES part
Catharanthus roseus (L.) G. DON Apocynaceae Aerial Tapak dara
 part
Cinnamomum burmani NEES ex BL. Lauraceae Bark Kayu manis
Curcuma aeruginosa ROXB. Zingiberaceae Rhizome Temu ireng
Curcuma heyneana VAL & V. ZIJP Zingiberaceae Rhizome Temu giring
Curcuma xanthorrhiza ROXB. Zingiberaceae Rhizome Temu lawak
Cymbopogon nardus (L.) RENDLE Gramineae Aerial Sere
 part
Foeniculum vulgare MILL. Umbelliferae Seed Adhas
Glycyrrhiza glabra L. Leguminosae Stem Kayu legi
Melaleuca leucadendron L. Myrtaceae Leaf Kayu putih
Piper cubeba L. Piperaceae Fruit Kemuk us
Piper nigrum L. Piperaceae Fruit Marica putih
Piper nigrum L. Piperaceae Leaf Marica putih
Punica granatum L. Punicaceae Fruit Delima putih
Rheum palmatum L. Polygonaceae Root Klembak
Santalum album L. Santalaceae Wood Kayu cendana
Sericocalyx crispus (L.) BREMEK Acanthaceae Leaf Keji beling
Strychnos ligustrina BL. Loganiaceae Leaf Bidara laut
Strychnos ligustrina BL. Loganiaceae Wood Bidara laut
Syzygium aromaticum (L.) Myrtaceae Flower Cengkeh
MERR. & PERRY
Tamarindus indica L. Leguminosae Fruit Asem
Tinospora crispa (L.) DIELS Menispermaceae Stem Brotowali
Zingiber aromaticum VAL Zingiberaceae Rhizome Lempuyang
 wangi
Zingiber cassumunar ROXB. Zingiberaceae Rhizome Bengle

Plant name Therapeutic application TMPW No.

Alpinia galanga (L.) SWARTZ Stomachic, anorexia 22261
Alstonia scholaris (L.) R.BR. Fever, anorexia, nephritis, 22262
 diabetes, malaria,
 hypertension
Alstonia scholaris (L.) R.BR. Beri-beri, syphilis, 22263
 diabetes
Alyxia reinwardtii BL. Fever, gastritis, 22264
 albuminuria, whooping cough,
 carminative, leucorrhea,
 gonorrhea, menstrual
 disorder
Amomum compactum SOLAND ex Cough, tonsillitis, 22265
 MATON menstrual disorder, colic,
 influenza, gastritis
Amomum compactum SOLAND ex Tonic, fever 22266
 MATON
Andrographis paniculata Diabetes, gonorrhea, 22267
 (BURM. F.) NEES syphilis, tonsillitis,
 epilepsy, diphtheria, fever,
 typhus, tonic
Catharanthus roseus (L.) G. DON Diabetes, cancer, malaria, 22268
 hypertension
Cinnamomum burmani NEES ex BL. Diarrhea, malaria 22269
Curcuma aeruginosa ROXB. Anthelmintic, obesity, 22270
 scabies, rheumatism
Curcuma heyneana VAL & V. ZIJP Anthelmintic 22271
Curcuma xanthorrhiza ROXB. Anticonvulsant, hemorrhoid, 22272
 malaria, diarrhea, anorexia,
 gastritis, anemia, jaundice
Cymbopogon nardus (L.) RENDLE Diaphoretic, body warming 22273
Foeniculum vulgare MILL. Albuminuria, insomnia, 22274
 menstrual disorder
Glycyrrhiza glabra L. Hepatitis, tonic 22275
Melaleuca leucadendron L. Vertigo, anticonvulsant, 22276
 tooth-ache, rheumatism
Piper cubeba L. Dysentery, gonorrhea 22277
Piper nigrum L. Carminative, hypertension, 22278
 dyspnea
Piper nigrum L. Tooth-ache 22279
Punica granatum L. Leucorrhea, constipation, 22280
 diarrhea, dysentery
Rheum palmatum L. Tonic, stomach-ache 22281
Santalum album L. Dysentery, asthma, fever, 22282
 gonorrhea
Sericocalyx crispus (L.) BREMEK Diabetes, renal calculus, 22283
 vesical calculus
Strychnos ligustrina BL. Antidote, depurative, 22284
 stomachic
Strychnos ligustrina BL. Anthelmintic, boil, chancre, 22285
 depurative, antidote for
 snake poisoning
Syzygium aromaticum (L.) Cold, cough 22286
MERR. & PERRY
Tamarindus indica L. Fever, laxative 22287
Tinospora crispa (L.) DIELS Fever, diuretic, tonic, 22288
 diabetes
Zingiber aromaticum VAL Cholescystopathy, whooping 22289
 cough, jaundice, arthritis,
 anorexia, cold, cholera,
 anemia, malaria, rheumatism,
 abdominalgia
Zingiber cassumunar ROXB. Obesity, vertigo, 22290
 constipation, cold,
 jaundice, anticonvulsant,
 rheumatism

Table 2. I[C.sub.50] values of the Indonesian medicinal plants on the
metabolism mediated by CYP3A4 and CYP2D6

 I[C.sub.50] value ([micro]g/ml)
Plant name CYP3A4 CYP2D6

MeOH-soluble fraction
 Als. scholaris bark NT 222
 Aly. reinwardtii 447 NT
 An. paniculata 102 86
 Ca. roseus NT 11
 Ci. burmani NT 1203
 Cu. heyneana 271 NT
 Cy. nardus 370 NT
 G. glabra 345 515
 Pi. cubeba 53 NT
 Pi. nigrum fruit 29 315
 Pi. nigrum leaf 25 146
 Pu. granatum 35 32
 R. palmatum 467 385
 Sa. album 337 886
 St. ligustrina leaf NT 302
 St. ligustrina wood NT 637
 Sy. aromaticum 219 249
 Ti. crispa 428 488
 Z. aromaticum 102 693

EtOAc-soluble fraction
 Pi. cubeba 332 NT
 Pi. nigrum fruit 223 344
 Pi. nigrum leaf 240 NT
 Z. aromaticum 376 NT

NT not tested.
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Author:Usia, T.; Iwata, H.; Hiratsuka, A.; Watabe, T.; Kadota, S.; Tezuka, Y.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Article Type:Clinical report
Geographic Code:9INDO
Date:Jan 1, 2006
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