<30385FBFCFB7E15FBAB8B9AE5FBBEABEF7C0C0BFEB5F484D D E687770>

Size: px

Start display at page:

Download "<30385FBFCFB7E15FBAB8B9AE5FBBEABEF7C0C0BFEB5F484D D E687770>"

지아 소
5 years ago
Views:

1 Korean Journal of Microbiology (2015) Vol. 51, No. 1, pp pissn DOI eissn Copyright c 2015, The Microbiological Society of Korea 보문 다양한약물과영양제가장내세균에미치는영향 박재은 이도경 하남주 송영천 * 삼육대학교약학과 The influence of various medicines and nutritional supplements against bacteria with gastrointestinal relevance Jae Eun Park, Do Kyung Lee, Nam Joo Ha, and Young Cheon Song* College of Pharmacy, Sahmyook University, Seoul , Republic of Korea (Received December 2, 2014; Accepted March 12, 2015) ABSTRACT: Recently, change of Western pattern diet and lifestyle is caused by various metabolic disorders and chronic diseases. These diseases need to take medicine regularly. Also, many people take health functional food, various vitamins and nutritional supplements in order to maintain a healthy life. But, there was no study about affects taking medicines against bacteria with gastrointestinal relevance. This study was performed by antibacterial activity test to evaluate the influence of a long time or commonly used medication. As a result, medicines of Vitamins & Minerals or Central nervous system show antibacterial activity against beneficial enteric bacteria and harmful enteric bacteria. Dexibuprofen of the Anti-inflammatory Drugs that acts on the central nervous system has shown high antibacterial activity at beneficial enteric bacteria strains (Lactobacillus casei, Lactobacillus rhamnosus) and harmful enteric bacteria (Staphylococcus aureus). Also, fenofibric acid of the antilipemic agents that acts on the Cardiovascular & Hematopoietic system has shown high antibacterial activity at beneficial enteric bacteria strains (Lactobacillus casei). Vitamins & Minerals appeared antibacterial activity against most intestinal bacteria. Vitamin B-Complex/with C and vitamin C were especially high with beneficial enteric bacteria strains (Bifidobacterium infantis) and harmful enteric bacteria (E. coli, E. aerogenes, S. flexneri, S. Typhimurium, S. aureus). Therefore, these results indicate that variously taking medicines have generally antibacterial activity against harmful enteric bacteria strains and beneficial enteric bacteria strains. Key words: antibacterial activity, beneficial enteric bacteria, harmful enteric bacteria 서구식식생활의변화로우리나라질병양상은비만, 고혈압, 당뇨등과같은만성질환의발병률이증가하여사회적문제로대두되었다. 이에따라다양한건강기능식품과영양제를찾는사람들이꾸준히늘고있다. 또한만성질환인경우지속적인관리와약물복용이요구된다. 2014년 OECD Health Date를비교분석한보건복지부의통계에따르면우리나라는 1인당의약품에지출하는비용이 19.8% 로 OECD평균 15.4% 보다높은양상을보이고있다. 또한우리나라의항생제소비량은국민 1,000명당하루 28.4DDD (Defined Daily Dose 일일상용량 ) 로 OECD 평균 (20.3DDD) 에비해높았다 (OECD Health Data 2014). 골관절염의치료에사용되고건강보조식 *For correspondence. alexsongsu@syu.ac.kr; Tel.: ; Fax: 품으로도인정받은글루코사민은부작용을일으킨다는연구결과가나왔다. 임상연구결과에서관찰된부작용으로는복통, 변비, 설사등의위장관계증상이다 (Tapadinhas et al., 1982). 또한진통제로사용되는덱시부프로펜의부작용은위장장애, 신장애, 간장애, 피부발진과특이적으로수막자극증상이있다. 아스피린계열의 Salicylate는소염진통제로많이사용되고있는데, 위장장애, 신장기능저하, 간기능저하, 알러지반응유발, 이독성난청등다양한부작용을유발한다고보고되었다 (Marchese-Ragona et al., 2008; Lee et al., 2010). 다양한약들이약이지닌본래의작용외에부수적으로발생되는작용인부작용을가지고있다. 그러나이러한작용들로인해장내세균에도영향을주는지에대한연구는보고된바없었다. 장내미생물들은장내생태계를구성하고소화기관내

2 62 Park et al. 의세균총환경유지에도이용되어면역반응을조절한다 (Kim, 2010; Kau et al., 2011). 하지만이러한장내미생물들의균형이깨진다면비정상적인면역반응을일으켜각종질환에노출될수있다. 따라서본연구에서는사람들이흔히사용하는다양한약물들이장내세균총 (Escherichia coli, Shigella flexneri, Salmonella Typhimurium, Enterobacter aerogenes, Enterococcus faecalis, Staphylococcus aureus와같은유해균과 Bifidobacterium logum, Bifidobacterium adolescentis, Bifidobacterium infantis, Lactobacillus ruminis, Lactobacillus casei와같은유익균 ) 에미치는영향을항균활성을통해측정하였다. 재료및방법 유익균인 Bifidobacterium logum KCTC3128, Bifidobacterium adolescentis KCTC3352, Bifidobacterium infantis KCTC3127 은 General anaerobic medium (Nissui) 에혐기배양하여균의농도가 McFarland No. 0.5가되도록준비하였다. 항균활성측정항균활성은 Clinical and Laboratory Standards Institute (CLSI) guideline의 disc diffusion methods를응용하여측정하였다 (CLSI, 2012). McFarland No.0.5의농도로준비된배양액을각각한천배양배지에도말한후각각의약물과영양제가 loading된 paper disc를올렸다. 장내유해균은호기성상태에서장내유익균은혐기성상태로 36에서 24시간배양하였다. 또한실험의 quality control을위해 gentamicin (Difco), ciprofloxacin (Difco), penicillin (Difco) 이함유된 disc를사용하였다. 실험재료 본실험에서는주변에서쉽게얻을수있는약물과흔히복용하고있는약물을다양한종류로수집하여사용하였다. 실험에사용된약품은약효및약리학적특성에따라위장관 & 간담도계, 심장혈관계 & 조혈기계, 호흡기계, 중추신경계, 근골격계, 전신감염치료제, 비뇨생식기계, 내분비및대사계, 비타민및미네랄, 영양제, 눈그리고알러지 & 면역계와같이총 12가지로분류하여실험하였다 (Table 1). Paper disc에 loading하기위하여각각의약물들은 Phosphate Buffered Saline (PBS) 로용해하여준비하였다. 장내세균총배양본실험에서는장내세균총중유해균인 E. coli ATCC 25922, Shigella flexneri ATCC9199, Salmonella Typhimurium ATCC13311, Enterobacter aerogenes ATCC39751, Enterococcus faecalis ATCC29212, Staphylococcus aureus ATCC6538p 모두 6가지장내유해균을사용하였다. Enterococcus faecalis ATCC29212을제외한장내유해세균은 Mueller Hinton broth (Difco) 에배양하고, E. faecalis ATCC29212는 Brain Heart Infusion broth (Difco) 에배양하여균의농도가 McFarland No. 0.5가되도록준비하였다. 그리고장내유익세균중 Bifidobacterium logum KCTC3128, Bifidobacterium adolescentis KCTC3352, Lactobacillus ruminis KCTC3601, Lactobacillus casei KCTC2180, Bifidobacterium infantis KCTC3127 모두 5 가지유익균을사용하였다. 장내유익균인 Lactobacillus ruminis KCTC3601, Lactobacillus casei KCTC2180은 Lactobacilli MRS broth (Difco) 에혐기배양 (CO 2 5%, H 2 5%, N 2 90%) 하고, 결과및고찰 총 12가지의효능으로분류된약물총 56가지중에서 27가지의약물은장내유해균및유익균모두에서성장저지환을형성하였다 (Table 2). 또한 27가지약물중비타민및미네랄과중추신경계에작용하는약물은유해균과유익균모두에서성장저지환이선명하게나타났다. 게다가유익균에서관찰되는성장저지환의크기는유해균에서관찰되는성장저지환의크기보다대체적으로크게나타났다. 대부분의장내유해균과유익균에서성장저지환이나타났던비타민및미네랄중 Vitamin B-Complex/with C, vitamin C 와 vitamin complex는장내유익균인 B. infantis과장내유해균인 E. coli, E. aerogenes, S. flexneri, S. Typhimurium, S. aureus 모두에서성장저지환이선명하게나타났다. 특히, vitamin C는장내유해균인 E. aerogenes와 S. Typhimurium 에서각각 27 mm, 22 mm의성장저지환이나타났으며 vitamin complex는장내유익균인 B. infantis에서 35 mm의성장저지환이나타났다 (Table 3, Fig. 1). 비타민의항산화작용이면역기능을향상시키고항균효과를일으킨다는보고가있다 (Masadeh et al., 2012). 따라서본연구에서도비타민복합제는장내유해균및유익균의증식에영향을미친것으로사료된다. 장내유해균인 E. faecalis은심혈관계 & 조혈기계에효능이있는 7가지약물에서모두성장저지환을형성하였다. 심혈관계, 조혈기계에작용하는약중고지혈증치료제의 fenofibric acid는장내유익균인 L. casei과 L. ruminis에각각 25 mm와 미생물학회지제 51 권제 1 호

3 약물과영양제가장내세균에미치는영향 63 Table 1. List of medicines and nutritional supplements used in this study Medicinal use Detailed medicinal use Generic name (abbreviation) (mg/ml) Famotidine (FAM) (4 mg/ml) Antacids, antireflux agents & antiulcerants Cimetidine (CIM) (40 mg/ml) Ranitidine (RAN) (15 mg/ml) GIT regulators, antiflatulents & antiinterflammatories Levosulpiride (LEV) (5 mg/ml) Antispasmodics Tiropramide hydrochloride (TIR) (20 mg/ml) Antidiarrheals Loperamide oxide (LOP) (0.2 mg/ml) Gastrointestinal & hepatobiliary system Cardiovascular & hematopoietic system Laxatives, purgatives Digestives Anorectal preparations Other gastrointestinal agents Cardiac drugs Anti-anginal drugs Beta-blockers Angiotensine Ⅱ antagonists Diuretics Peripheral vasodilators & cerebral activators Bisacody, senna powder, sennae fructus angustifoliae powder, sennae fructus angustifoliae extrct (BIS) (11 mg/ml) Lactitol monohydrate (LMH) (1 mg/ml) Pancellase SS, biodiastase 2000, lipase (saiken) 100, pancreatin enteric coated granule, panprosin SS, simethicone, ursodeoxycholic acid (PSS) (24.4 mg/ml) Dimethicone, hemicellulase, pancreatin, ursodeoxycholic acid (DIM) (52 mg/ml) Ginkgo biloba ext., heptaminol hydrochloride, troxerutin (GIN) (123 mg/ml) Mosapride citrate (MOC) (1 mg/ml) Flecainide acetate (FLA) (10 mg/ml) Isosorbidedinitrate (ISD) (24 mg/ml) Atenolol (ATE) (10 mg/ml) Olmesartan medoxomil (OLM) (4 mg/ml) Furosemide (FUR) (8 mg/ml) Hydrochlorothiazide (HYD) (5 mg/ml) Ginkgo biloba (GBI) (20 mg/ml) Atorvastatin calcium (ATC) (1 mg/ml) Antilipemic agents Fenofibric acid (FFA) (27 mg/ml) Simvastatin, ezetimibe (SIM) (20 mg/ml) Dyslipidaemic agents Omega 3 (OM3) (700 mg/ml) Anticoagulants Warfarin sodium (WAR) (0.4 mg/ml) Antiplatelets & fibrinolytics Aspirin (ASP) (20 mg/ml) Respiratory system Cough & cold preparations Ivy leaf 30% ethanol ext. (IVY) (7 mg/ml) Anxiolytics Melatonin (MEL) (0.5 mg/ml) Tofisopam (TOF) (8 mg/ml) Hypnotics & sedatives Zolpidem tartrate (ZOL) (5 mg/ml) Central nervous system Analgexics (Non-opioid) & antipyretics Acetaminophen (ACE) (10 mg/ml) Caffeine anhydrous, acetaminophen, ethenzamide (CAE) (80 mg/ml) Anti-inflammatory Drugs Dexibuprofen (DEX) (300 mg/ml) Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen (IBU) (80 mg/ml) Nootropics & neurotonics Choline alfoscerate (CHA) (80 mg/ml) Musculo-skeletal system Hyperuricemia & gout preparations Allopurinol (ALL) (20 mg/ml) Anti-infectives (systemic) Antivirals Entecavir (ENT) (0.1 mg/ml) Genito-urinary system Drugs for bladder & prostate disorders Finasteride (FIN) (1 mg/ml) Tamsulosin hydrochloride (TAH) (0.04 mg/ml) Korean Journal of Microbiology, Vol. 51, No. 1

4 64 Park et al. Table 1. Continued Medicinal use Detailed medicinal use Generic name (abbreviation) (mg/ml) Linagliptin (LIN) (1 mg/ml) Metformin hydrochloride (MET) (100 mg/ml) Endocrine & Antidiabetic agents metabolic system Acarbose (ACA) (10 mg/ml) Glimepiride (GLI) (0.4 mg/ml) Thyroid hormones Levothroxine sodium (LES) (0.02 mg/ml) Ascorbic acid, benfotiamine, biotin, calcium pantothenate, choline bitartrate, 0.1% cyanocobalamin, di-methionine, folic acid, inositiol, magnesim oxide, Vitamins &/or minerals nicotinamide, pyridoxine hydrochloride, riboflavin, tocopherolacteate 50%, ursodeoxycholic acid, zinc oxide, γ-oryzanol (ASA) (120 mg/ml) Vitamins & minerals Nutrition Eye Allergy & immune system Vitamin B-complex/with C Vitamin C Vitamins & minerals (Geriatric) Calcium/ with vitamins Enteral/Nutritional products Electrolytes Other eye preparations Immunosuppressants COQ 10 (100 mg/ml) Vitamin C, vitamin B (V.C, V.B)(173.6 mg/ml) Nicotinamide, vitamin B1, vitamin B12,vitamin B2, vitamin B6, vitamin B1, calcium pantothenate (V.B) (18.6 mg/ml) Vitamin C (powder) (V.C.P) (400 mg/ml) Vitamin C (V.C) (44 mg/ml) Ascorbic acid Gr. 90%, calcium phosphate hydroxide, chromic chloride, cupric oxide, ferrous fumarate, magnesium oxide (AAG)(219 mg/ml) Ca, Mg, V.D (CMV) (99.5 mg/ml) Yeast, keratin, thiamine mononitrate, L-cystine, p-aminobenzoic acid, calcium pantothenate (YEA) (16.67 mg/ml) Mg citrate (MGC) (20 mg/ml) Vacciniummyrtillus extract, vacciniummyrtillus fruit Dred Powder, riboflavin sodium phosphate, retinol palmitate (VAC) (60 mg/ml) Tacrolimus hydrate (TAH) (0.5 mg/ml) Microemulsion cyclosporine (MIC) (1 mg/ml) 18 mm로성장저지환이확인되었다. 중추신경계에작용하는약중소염진통제의 dexibuprofen 은장내유익균인 L. casei와 L. ruminis에각각 26 mm, 30 mm 의성장저지환이나타났으며, 장내유해균인 S. aureus에는 20 mm의성장저지환인나타났다 (Table 3, Fig. 1). 성장저지환의생성유무외에특이한점으로중추신경계의약효가있는 zolpidem tartrate와 melatonin의 disc 주변에서장내유해균인 S. Typhimurium가더잘자라는것을관찰할수있었다 (Fig. 2). 멜라토닌과살모넬라균의관계를다룬문헌을참고하면, 고농도의멜라토닌은살모넬라균이잘자라도록하여장염을유발할수있다는보고가있으며참고문헌의임상실험결과에따르면아연과갑상선호르몬에영향을미쳐살모넬라균의형성을돕는다고보고되었다 (Nisbet et al., 2008). 약물중에서내분비및대사계효능을지닌 acarbose은장내유해균모두에서성장저지환이관찰되었다. E. coli, E. aerogenes, S. flexneri, S. Typhimurium, E. faecalis, S. aureus의장내유해균에서각각 12 mm, 8 mm, 10 mm, 10 mm, 8 mm, 8 mm로성장저지환이확인되었다 (Table 3). 다양한종류의약물들과영양제들이장내유해균과유익균에어떠한메커니즘으로항균효과를나타냈는지에대한다각적인연구가필요하다. 또한장내환경을보호하기위해항생제는정장제와함께처방하여복용하는것과같이장기간약물을복용해야한다면장내유익균이영향을받지않게이를고려할수있는규정이마련되어야할것으로사료된다. 적요 최근우리나라는서구화된식생활과생활양식의변화로다양한대사성질환과만성질환이나타나고있다. 이러한질환들은지속적으로약물을복용해야한다. 또한많은사람들이건강한삶을유지하기위해건강기능식품과각종비타민, 영양제를복용한다. 하지만복용하는약물들이장내세균에는어떠한영향을주는지에대한연구는많이이뤄지지않고있다. 이에본연구에서는흔하게사용되며장기간복용하는약이항균활성시험으로위장관련박테리아에영향을미치는지 미생물학회지제 51 권제 1 호

5 약물과영양제가장내세균에미치는영향 65 Table 2. Drug susceptibility of beneficial enteric bacteria to various medicines and nutritional supplements Medicin Beneficial enteric bacteria Harmful enteric bacteria L. r a L. c b B. l c B. i d B.a e E. c f E. a g S. f h S. t i E. f j S. a k CAE # + - * DEX IBU CHA TOF BIS RAN CIM LEV MOC GIN FAM TIR FUR ATE ISD HYD WAR OLM FLA ASP GBI FFA OM SIM GLI MET LES ACA ALL MIC V.C &V..B ASA V.C V.C.P AAG YEA * Not detected. # Abbreviations of medicine generic name and used concentrations are shown in Table 1. a L. ruminis KCTC3601, b L. casei KCTC2180, c B. longum KCTC3128, d B. infantis KCTC3127, e B. adolescentis KCTC3352, f E. coli ATCC25922, g E. aerogenes ATCC39751, h S. flexneri ATCC9199, i S. Typhimurium ATCC13311, j E. faecalis ATCC29212, k S. aureus ATCC6538p. Korean Journal of Microbiology, Vol. 51, No. 1

inhibition (mm) Beneficial enteric bacteria Harmful enteric bacteria Medicine L. r a L. c b B. l c B. i d B. a e E. c f E. a g S. f h S.

C 8 - - - - 20 27 15 22-14 V.C.P - - - - - 20 30 10 18 8 24 CAE 9 - - - - 16 12 9 14 10 - DEX 26 30 12 13 12 8-8 8-20 ACA - - - - - 12 8 10

- - - MIC - 20 - - - - - - - 8 8 * Not detected. a L. ruminis KCTC3601, b L. casei KCTC2180, c B. longum KCTC3128, d B.

Typhimurium ATCC13311, j E. faecalis ATCC29212, k S. aureus ATCC6538p.

aureus ATCC 6538p A : CAE, B : DEX, C : ASP, D : IBU L.casei KCTC 2180 A : CAE, B : IBU, C : ASP, D : DEX L.

6 66 Park et al. Table 3. Growth inhibition of beneficial and harmful enteric bacteria by various medicines and nutritional supplements Diameter of zone of inhibition (mm) Beneficial enteric bacteria Harmful enteric bacteria Medicine L. r a L. c b B. l c B. i d B. a e E. c f E. a g S. f h S. t i E. f j S. a k V.C &V.B # * 10 ASA AAG V.C V.C.P CAE DEX ACA IBU FFA MET BIS YEA MIC * Not detected. a L. ruminis KCTC3601, b L. casei KCTC2180, c B. longum KCTC3128, d B. infantis KCTC3127, e B. adolescents KCTC3352, f E. coli ATCC25922, g E. aerogenes ATCC39751, h S. flexneri ATCC9199, i S. Typhimurium ATCC13311, j E. faecalis ATCC29212, k S. aureus ATCC6538p. # Abbreviations of medicine generic name and used concentrations are shown in Table 1. S. aureus ATCC 6538p A : CAE, B : DEX, C : ASP, D : IBU L.casei KCTC 2180 A : CAE, B : IBU, C : ASP, D : DEX L.ruminis KCTC 3601 A : ASP, B : CAE, C : DEX, D : IBU E.aerogenes ATCC A : V.C.P, B : V.C, V.B, C : V. C, D : ASA S. aureus ATCC 6538p A : V.C.P, B : V.C, V.B, C : V.C, D : ASA B. infantis KCTC 3127 A : VAC, B : MGC, C : AAG, D : ASA E : CMV, F : COQ 10, G : OM3 Fig. 1. In vitro anti-enterobacterial activities of Central nervous system drugs and Vitamins & Minerals drugs. These figures are representative results among several separate experiments. 미생물학회지제 51 권제 1 호

약물과영양제가장내세균에미치는영향 67 감사의말 본연구는 2014년도삼육대학교교내연구비로수행되었으며이에감사드립니다. References Fig. 2. S. Typhimurium ATCC 13311 was grows around A, zolpidem tartrate disc and B, melatonin disc. 를조사하였다.

7 약물과영양제가장내세균에미치는영향 67 감사의말 본연구는 2014년도삼육대학교교내연구비로수행되었으며이에감사드립니다. References Fig. 2. S. Typhimurium ATCC was grows around A, zolpidem tartrate disc and B, melatonin disc. 를조사하였다. 그결과비타민및미네랄, 중추신경계에작용하는약들이장내세균과유산균에대해항균력을나타냈으며, 그중중추신경계에작용하는약중항현훈제의 dexibuprofen 는장내유익균인 Lactobacillus casei 과 Lactobacillus rhamnosus 와장내유해균인 Staphylococcus aureus에대해항균력이높게작용하였다. 또한심혈관계, 조혈기계에작용하는약중항이뇨제의 fenofibric acid는장내유익균인 Lactobacillus casei 에대해항균력이나타났다. 비타민및미네랄은대부분의장내균에서항균력을보이지만, 특히 Vitamin B-Complex/with C와 vitamin C가유익균인 Bifidobacterium infantis과장내유해균인 Escherichia coli, Enterobacter aerogenes, Shigella flexneri, Salmonella Typhimurium, Staphylococcus aureus에서높게나타났다. 따라서본연구결과장내유해균과유익균에다양하게복용되는약들이대체적으로항균활성을보이는것으로판단된다. Clinical and Laboratory Standards Institute (CLSI) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved standard, 9th ed. CLSI document M07-A79, CLSI, Wayne, PA, USA. Kau, A.L., Ahern, P.P., Griffin, N.W., Goodman, A.L., and Gordon, J.I Human nutrition, the gut microbiome and the immune system. Nature 474, Kim, J.M Inflammatory bowel diseases and enteric microbiota. Korean J. Gastroenterol. 55, Lee, H.N., Kang, W.S., Song, H.Y., and Chung, J.W A case of bilateral sensorineural hearing lossafter salicylate intoxication. Korean J. Otorhinolaryngol-Head Neck Surg. 53, Marchese-Ragona, R., Marioni, G., Marson, P., Martini, A., and Staffieri, A The discovery of salicylate ototoxicity. Audiol. Neurootol. 13, Masadeh, M.M., Mhaidat, N.M., Alzoubi, K.H., Al-Azzam, S.I., and Shaweesh, A.I Ciprofloxacin-induced antibacterial activity is reversed by vitamin E and vitamin C. Curr. Microbiol. 64, Nisbet, D.J., Edrington, T.S., McReynolds, J.L., Callaway, T.R., and Byrd, J.A Influence of exogenous melatonin administration on Salmonella enteritidis colonization in molted layers. Poult. Sci. 87, Tapadinhas, M.J., Rivera, I.C., and Bignamini, A.A Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. Pharmatherapeutica 3, Korean Journal of Microbiology, Vol. 51, No. 1

untitled

untitled 理葉 CNFH-88-04 行 87 年 9 1 88 年 6 30 類葉 Staphylococcus aureus Staphylococcus epidermidis Streptococcus mutans Streptococcus sanguis Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Candida