리스페리돈이 타액선 세포에 미치는 영향
The effect of risperidone on salivary gland cells
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
리스페리돈(risperidone)은 세계적으로 가장 널리 처방되고 있는 정신분열증 치료제로서 소아자폐증의 선택약물로 FDA 승인을 받았으며 틱장애, 뚜렛장애의 치료제로도 쓰이고 있다. 치과와 관련된 리스페리돈의 이상반응으로 구강건조가 보고되고 있으며 그 기전은 밝혀지지 않은 상태이다. 본 연구의 목적은 리스페리돈이 타액분비 기전의 중요한 요소인 세포내 칼슘농도에 미치는 영향을 세포수준에서 밝히고자 하는 것이다. 세포내 칼슘농도를 측정하기 위해 Human salivary gland cell line(HSG)에 Fura-2/AM을 세포내로 부하한 뒤 340 및 380 nm의 파장으로 교대로 여기시킬 때 방출되는 형광강도를 500 nm 파장에서의 비율로 측정하였다. 각 실험 후 형광강도의 비율을 실제 세포내 칼슘농도로 보정하기 위한 calibration 실험을 시행하였다. 카바콜, ATP, 히스타민을 처리하여 세포내 칼슘농도의 변화를 측정하고 리스페리돈의 전처리가 이에 미치는 효과를 비교하였으며 다음과 같은 결과를 얻었다. 1. HSG에서 카바콜, ATP, 히스타민 처리로 인해 세포내 칼슘농도가 증가하였으며 리스페리돈을 전처리한 경우 카바콜과 ATP의 작용에는 영향을 주지 않았으나 히스타민의 작용을 억제하였다. 2. HSG의 세포내 칼슘 변화에 미치는 히스타민의 효과는 농도의존적인 양상을 보였으며 50% 유효농도(EC50)는 3.3±0.5 μM이었다. 3. 히스타민에 의한 HSG에서 칼슘 변화에 미치는 리스페리돈의 저해 효과는 농도의존적인 양상을 보였으며 대조군의 효과를 50% 억제하는 농도(IC50)는 104.4±14 nM로 리스페리돈의 적정혈중농도 이하에 해당되었다. 4. 리스페리돈은 히스타민에 의한 소포체에서의 칼슘 유리와 세포 밖 칼슘 유입을 모두 유의성 있게 억제하였다(p<0.05). 항정신병 약물은 장기간 복용하고 적정혈중농도가 계속 유지되기 때문에 이러한 약물이 타액분비감소를 일으킬 경우 다발성우식증 등 심각한 치과적 질환을 야기할 수 있으므로 이에 대한 예방 및 치료방안이 필요하리라 사료된다.
Abstract
Risperidone is a widely prescribed atypical antipsychotic agent. Approved by the FDA as the first drug to treat irritability associated with autism in children, it is also used to treat tic disorder and Tourette’s syndrome. Its adverse reactions related to dentistry include dry mouth, the mechanism of which is yet to be identified. The aim of this study is to identify, at the cellular level, how and to what extent risperidone affects intracellular free calcium concentration ([Ca2+]i), an primary intracellular factor in the regulation of fluid secretion in salivary gland cells. The human salivary gland cell line (HSG) was grown in MEM supplemented with 10% BCS. In order to measure [Ca2+]i, Fura-2/AM was loaded in the HSG, and fluorescence at 340 nm/380 nm excitation was measured in the 500 nm emission ratio. After every experiment, a calibration experiment was conducted in order to readjust the ratio to the actual [Ca2+]i. Changes in [Ca2+]i were measured in the presence of carbachol, ATP and histamine. The researcher then explored how the pretreatment of risperidone affected such changes. Findings of this study include: 1. In HSG, [Ca2+]i increased due to the addition of carbachol, ATP and histamine. The presence of risperidone inhibited the action of histamine on this process, while making little effect on that of carbachol and ATP. 2. A quantification of [Ca2+]i in relation to histamine of different concentrations indicates that the effect of histamine was concentration dependent with an EC50 of 3.3±0.5 μM. 3. The inhibitory effect of risperidone on histamine-induced [Ca2+]i was concentration-dependent with an IC50 of 104.4±14 nM. 4. Risperidone inhibits histamine-induced Ca2+ release from endoplasmic reticulum and influx of extracellular Ca2+ in HSG cells(p<0.05).
참고문헌 (49)
- Aparasu RR, "Patterns and determinants of antipsychotic prescribing in children and adolescents, 2003-2004", Curr Med Res Opin, 23, pp.49~56 (2007)
- "First drug to treat irritability associated with autism", FDA Consum, 41, pp.4~ (2007)
- 조수철, "소아정신약물학", pp.101~276 (2005), 서울대학교출판부
- De Oliveira IR, "Treatment of psychosis: 30 years of progress", J Clin Pharm Ther, 31, pp.523~534 (2006)
- Ipser J, "Systematic review of pharmacotherapy of disruptive behavior disorders in children and adolescents", Psychopharmacology, 191, pp.127~140 (2007)
- Luby J, "Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy", J Child Adolesc Psychopharmacol, 16, pp.575~587 (2006)
- West L, "Risperidone use in the treatment of behavioral symptoms in children with autism", Pediatr Nurs, 32, pp.545~549 (2006)
- Hori T, "Hypersalivation induced by olanzapine with fluvoxamine", Prog Neuropsychopharmacol Biol Psychiatry, 30, pp.758~760 (2006)
- Kontaxakis VP, "Risperidone augmentation of clozapine: a critical review", Eur Arch Psychiatry Clin Neurosci, 256, pp.350~355 (2006)
- Duran JC, "Evaluation of risperidone in the treatment of behavioral and psychological symptoms and sleep disturbances associated with dementia", Int Psychogeriatr, 17, pp.591~604 (2005)
- Boyce HW, "Sialorrhea: a review of a vexing, often unrecognized sign of oropharyngeal and esophageal disease", J Clin Gastroenterol, 39, pp.89~97 (2005)
- Cheng-Shannon J, "Second-generation antipsychotic medications in children and adolescents", J Child Adolesc Psychopharmacol, 14, pp.372~394 (2004)
- Fernandez HH, "Treatment of psychosis in Parkinson’s disease: safety considerations", Drug Saf, 26, pp.643~659 (2003)
- Freudenreich O, "Antipsychotic combination therapy in schizophrenia. A review of efficacy and risks of current combinations", Acta Psychiatr Scand, 106, pp.323~330 (2002)
- Fleischhacker WW, "A qualitative assessment of the neurological safety of antipsychotic drugs; an analysis of a risperidone database", Pharmacopsychiatry, 34, pp.104~110 (2001)
- Buitelaar JK, "A randomized controlled trial of risperidone in the treatment of aggression in hospitalized adolescents with subaverage cognitive abilities", J Clin Psychiatry, 62, pp.239~248 (2001)
- Roerig JL, "A comparison of the effects of olanzapine and risperidone versus placebo on eating behaviors", J Clin Psychopharmacol, 25, pp.413~418 (2005)
- Srisurapanont M, "Quetiapine for schizophrenia", Cochrane Database Syst Rev 2:CD000967 (2004)
- Potkin SG, "The safety and pharmacokinetics of quetiapine when coadminis tered with haloperidol, risperidone, or thioridazine", J Clin Psychopharmacol, 22, pp.121~130 (2002)
- Mullen J, "A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study", Clin Ther, 23, pp.1839~1854 (2001)
- Bhana N, "Olanzapine: an updated review of its use in the management of schizophrenia", Drugs, 61, pp.111~161 (2001)
- Koran LM, "Olanzapine augmentation for treatment-resistant obsessivecompulsive disorder", J Clin Psychiatry, 61, pp.514~517 (2000)
- Guggenheimer J, "Xerostomia: etiology, recognition and treatment", Am Dent Assoc, 134, pp.61~69 (2003)
- Scully C, "Drug effects on salivary glands", dry mouth. Oral dis, 9, pp.165~176 (2003)
- Bergdahl M, "Low unstimulated salivary flow an subjective oral dryness: association with medication, anxiety, depression, and stress", J Dent Res, 79, pp.1652~1658 (2000)
- Gupta A, "Hyposalivation in elderly patients", J Can Dent Assoc, 72, pp.841~846 (2006)
- Cassolato SF, "Xerostomia: clinical aspects and treatment", Gerodontology, 20, pp.64~77 (2003)
- Ambudkar IS, "Regulation of calcium in salivary gland secretion", Crit Rev Oral Biol Med, 11, pp.4~25 (2000)
- 이종흔, "구강생리학 4판", pp.177~210 (1994), 군자출판사
- i in rat parotid acinar cells. Comparison with the muscarinic agonist carbachol, "J Gen Physiol", 1990, 319~346
- 이주석, "흰쥐 악하선 세포에서 gap junction 봉쇄제인 octanol이 타액분비 및 세포내 Ca2+ 농 도 조절에 미치는 영향", 대한소아치과학회지, 26, pp.399~415 (1999)
- Grynkiewicz G, "A new generation of Ca2+ indicators with greatly improved fluorescence properties", J Biol Chem, 260, pp.3440~3450 (1985)
- Uto A, "Reassessment of Fura-2 and the ratio method for determination of intracellular Ca2+ concentrations", Cell Calcium, 12, pp.29~37 (1991)
- Flarakos J, "Quantification of risperidone and 9-hydroxyrisperidone in plasma and saliva from adult and pediatric patients by liquid chromatography-mass spectrometry", J Chromatogr A, 1026, pp.175~183 (2004)
- Medori R, "Plasma antipsychotic concentration and receptor occupancy, with special focus on risperidone long-acting injectable", Eur Neuropsychopharmacol, 16, pp.233~240 (2006)
- Yagiela JA, "Pharmacology and therapeutics for dentistry 5th edition" (2004), Mosby
- 김경환, "이우주의 약리학강의 5판", pp.7~26 (2003), 의학문화사
- Bertram Katzung, "Basic and clinical pharmacology 9th edition" (2004), McGraw-Hill
- Elad S, "Saliva secretion in patients with allergic rhinitis", Int Arch Allergy Immunol, 141, pp.276~280 (2006)
- Richelson E, "Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds", Life Sci, 68, pp.29~39 (2000)
- Tumilasci OR, "Quantitative study of salivary secretion in Parkinson’s disease", Mov Disord, 21, pp.660~667 (2006)
- Edwards LL, "Characterization of swallowing and defecation in Parkinson’s disease", Am F Gastroenterol, 1, pp.15~25 (1994)
- Leopold NA, "Laryngeal deglutition movement in Parkinson’s disease", Neurology, 48, pp.373~376 (1997)
- Pinnington LL, "Non-invasive assessment of swallowing and respiration in Parkinson’s disease", J Neurol, 247, pp.773~777 (2000)
- Bagheri H, "A study of salivary secretion in Parkinson’s disease", Clin Neuropharmacol, 22, pp.213~215 (1999)
- Beteson MC, "Salivary symptoms in Parkinson’s disease", Arch Neurol, 29, pp.274~275 (1973)
- Persson M, "Influence of Parkinson’s disease on oral health", Acta Odontol Scand, 50, pp.37~42 (1992)
- Proulx M, "Salivary production in Parkinson’s disease", Mov Disord, 20, pp.204~207 (2005)
- 김영신, "타액 우식 관련 검사와 치아 우식 경험과의 관계에대한 연구", 대한소아치과학회지, 32(1), pp.67~74 (2005), 대한소아치과학회