주요우울증에 대한 Milnacipran의 효과 및 안정성 : Fluoxetine과의 비교

이민수,함병주,기백석,김정범,연병길,오강섭,오병훈,이철,정한용,지익성,최병무,백인호 大韓神經精神醫學會 2004 신경정신의학 Vol.43 No.4

Objectives : This 6-week, open label randomized, multicenter study was conducted to evaluate the antidepressant effect and safety of milnacipran and fluoxetine in patients with major depression. Methods : The study was done in patients with major depression diagnosed by DSM-IV who score ≥17 in 17 items Hamilton Rating Scale for Depression (17-item HAM-D) and score ≥25 in Montgomery and Asberg Depression Rating Scale (MADRS). A total of 87 patients were randomized to milnacipran group and fluoxetine group. In cases of the patients taking other antidepressants, 6 weeks of each medication was administered after 7 days of drug excretion period. The evaluation was done using 17 item HAM-D, MADRS, Clinical Global Impression Scale (CGI), and COVI scale after baseline, 1 week, 2 weeks, 4 weeks, and 6 weeks. The side effects that had occurred during the period of our study were put in records by developed/disappeared time, severities, incidences, managements and results. Results : A total of 87 patients were enrolled. 70 (mitnacipran group 39 ; fluoxetine group 31) of them were included for the 6 weeks of research and 17 of them dropped out with in the first week, not due to adverse reactions or deficiency of effects. Total 17 item HAM-D scores, total points of MADRS, and CGI showed significant decrease after 1 week in each treatment group and continued decrease after 2 weeks and 4, 6 weeks. But there was no difference between milnacipran group and fluoxetine group in the antidepressant effect. There were no significant changes in vital sign, CBC, chemistry, and EKG in each treatment group. The commonly reported side elfects of minlacipran were nausea (25.0%), headache (10.7%), vomiting (7.1%),constipation (7.1%), dizziness (7.1%) and those of fluoxetne were GI trouble (11.1%), diarrhea (11.1%), insomnia (11.1%),agitation (5.6%), and dizziness (5.6%). Conclusion : Milnacipran was effective for the improvement of depressive symptoms and was well tolerated and safe in patients with depression.

Milnacipran의 섬유근통 증후군치료에 대한 연구 검토

이경은 한국임상약학회 2010 한국임상약학회지 Vol.20 No.3

섬유근통 증후군은 만성 전신 통증을 나타내며 피곤, 두통, 우울증, 수면장애등을 동반하는 질환이다. 주로 30-50대의 여성에게서 많이 나타나며 미국에서 2-4%, 한국에서 2%의 발병률을 보이고 있다. 정확한 원인과 기전이 밝혀져 있지않아서 진단과 치료에 많은 논란과 어려움이 있다. 현재는 증상치료에 목표를 두고 삼환계항우울약을 많이 사용하고 있으나 심각한 부작용의 문제가 있다. 이러한 문제때문에 최근에는 selective serotonin reuptake inhibitor (SSRI) 또는 serotoninnorepinephrine reuptake inhibitor (SNRI)를 빈번히 사용하고 있다. 본 연구는 SNRI의 하나인 milnacipran의섬유근통 증후군 치료에 대한 효능 및 안정성을 알아보기 위해, MEDLINE에 등재된 논문을 기한없이 milnacipran과 fibromyalgia로 검색하여 무작위 배정 및 이중맹검 임상연구자료들을 선별하였다. 선별된 6개의 임상연구 결과, milnacipran를 사용했을때 일관된 효능성과 안정성이 관찰되었고 섬유근통증후군 치료와 그에 수반되는 여러증상에 효과적인것으로 나타났다.

흰 쥐의 신경병증성 통증 모델에서 Gabapentin과 Milnacipran의 병용 효과

이현정 ( Hyoen Jeong Lee ),신상욱 ( Sang Wook Shin ),장희정 ( Hee Jeong Jang ) 대한통증학회 2007 The Korean Journal of Pain Vol.20 No.1

섬유근통 환자에 대한 Milnacipran과 Pregabalin 약물치료에 대한 기능적 자기공명영상에서의 후속 영향 비교

강민재,문치웅,이영호,김성호 대한자기공명의과학회 2014 Investigative Magnetic Resonance Imaging Vol.18 No.4

목적 : 섬유근통 증후군의 치료에 주로 쓰이는 두 계열의 약물인 Milnacipran (이하 MLN)과 Pregabalin (이하 PGB)의환자 투여에 따른 약물 치료 효과를 뇌 활성도 변화의 비교 분석을 통해 비교하였다. 대상 및 방법 : 섬유근통 증후군 환자 20명을 대상으로 진행하였으며 20명의 환자 중 약물 치료 군에 따라 MLN 치료군 10명과 PGB 치료군 7명으로 분류하였다. 모든 환자군은 섬유근통 증후군 이외의 요인을 배제하기 위해 정신건강 의학과적 평가를 통해 선별된 후 섬유근통 진단을 위한 임상적 평가가 진행 되었다. 기능적 자기공명영상의 촬영 시 엄지손가락에 블록형태의 압통 자극을 가해 주었고 영상은 약물 치료 전과 약물 치료 후에 각각 획득하였다. 영상 획득 후 일련의 전처리 과정을거쳐 약물 치료 전후의 자기공명 혈중산소치의존 (Blood Oxygen Level Dependent, 이하 BOLD) 신호 비교를 위한 대응표본 t-검정과 두 표본 t-검정을 실시 하였다. 결과 : 임상적 평가에 있어 약물 치료 전에는 두 그룹간에 유의한 차이가 나지 않았으며 약물 치료 후 전신통증지수(Widespread Pain Index, WPI)와 대상자 스스로 피로도를 평가하는 검사 (Brief Fatigue Inventory, BFI)에서 PGB군에 유의한 수준으로 낮게 나타났다. 기능적 영상 분석에 있어 약물 치료 후의 영상 비교 결과 앞 띠이랑과 대뇌섬을 포함한 영역에서 PGB군이 높은 활성도를 보였다. 또한 약물 치료 전후 효과 비교에서는 MLN군에서 대뇌섬, 시상을 포함한 영역에서치료 후 BOLD 신호가 감소하는 경향을 볼 수 있었지만 PGB군에서는 MLN에 비해 감소된 영역의 수와 크기가 비교적 작게나타났다. 결론 : 전체 결과에서 두 치료군 모두 증상이 호전되는 경향을 나타냈으나 임상적 평가와 기능적 영상 평가에서 서로 다른 경향을 나타내었다. 이는 두 약물 치료 기전과 세부 치료 목적이 다르고, 전체 환자 수의 부족으로 인한 임상적 평가와의 낮은상관관계에 의한 영향으로 보이며 이러한 영향을 최소화 시킨다면 두 약물 간의 정확한 치료 효과 비교를 할 수 있을 것으로예상된다.

Evaluation of the Neurological Safety of Epidural Milnacipran in Rats

( Seung Mo Lim ),( Mee Ran Shin ),( Kyung Ho Kang ),( Hyun Kang ),( Francis Sahngun Nahm ),( Baek Hui Kim ),( Hwa Yong Shin ),( Young Jin Lim ),( Sang Chul Lee ) 대한통증학회 2012 The Korean Journal of Pain Vol.25 No.4

Background: Milnacipran is a balanced serotonin norepinephrine reuptake inhibitor with minimal side effects and broad safety margin. It acts primarily on the descending inhibitory pain pathway in brain and spinal cord. In many animal studies, intrathecal administration of milnacipran is effective in neuropathic pain management. However, there is no study for the neurological safety of milnacipran when it is administered neuraxially. This study examined the neurotoxicity of epidural milnacipran by observing behavioral and sensory-motor changes with histopathological examinations of spinal cords in rats. Methods: Sixty rats were divided into 3 groups, with each group receiving epidural administration of either 0.3 ml (3 mg) of milnacipran (group M, n = 20), 0.3 ml of 40% alcohol (group A, n = 20), or 0.3 ml of normal saline (group S, n = 20). Results: There were no abnormal changes in the behavioral, sensory-motor, or histopathological findings in all rats of groups M and S over a 3-week observation period, whereas all rats in group A had abnormal changes. Conclusions: Based on these findings, the direct epidural administration of milnacipran in rats did not present any evidence of neurotoxicity in behavioral, sensory-motor and histopathological evaluations.

Effect of the Combined Use of Tramadol and Milnacipran on Pain Threshold in an Animal Model of Fibromyalgia

( Seong Ho Kim ),( Jun Hwa Song ),( Hyun Il Mun ),( Keon Uk Park ) 대한내과학회 2009 The Korean Journal of Internal Medicine Vol.24 No.2

Background/Aims: Acidic saline injections produce mechanical hyperresponsiveness in male Sprague-Dawley rats. We investigated the effect of milnacipran in conjunction with tramadol on the pain threshold in an acidic saline animal model of pain. Methods: The left gastrocnemius muscle of 20 male rats was injected with 100 μL of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Rats administered acidic saline injections were separated into four study subgroups. After determining the pre-drug pain threshold, rats were injected intraperitoneally with one of the following regimens; saline, milnacipran alone (60 mg/kg), milnacipran (40 mg/kg) plus tramadol (20 mg/kg), or milnacipran (40 mg/kg) plus tramadol (40 mg/kg). Paw withdrawal in response to pressure was measured at 30 min, 120 min, and 5 days after injection. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) by applying increasing pressure to the right or left hind paw until the rat withdrew the paw. Results: A potent antihyperalgesic effect was observed when tramadol and milnacipran were used in combination (injected paw, p=0.001; contralateral paw, p=0.012). This finding was observed only at 30 min after the combination treatment. Conclusions: We observed potentiation of the antihyperalgesic effect when milnacipran and tramadol were administered in combination in an animal model of fibromyalgia. Further research is required to determine the efficacy of various combination treatments in fibromyalgia in humans. (Korean J Intern Med 2009;24:139-142)

Evaluation of the Neurological Safety of Epidural Milnacipran in Rats

Lim, Seung-Mo,Shin, Mee-Ran,Kang, Kyung-Ho,Kang, Hyun,Nahm, Francis Sahn-Gun,Kim, Baek-Hui,Shin, Hwa-Yong,Lim, Young-Jin,Lee, Sang-Chul The Korean Pain Society 2012 The Korean Journal of Pain Vol.25 No.4

Background: Milnacipran is a balanced serotonin norepinephrine reuptake inhibitor with minimal side effects and broad safety margin. It acts primarily on the descending inhibitory pain pathway in brain and spinal cord. In many animal studies, intrathecal administration of milnacipran is effective in neuropathic pain management. However, there is no study for the neurological safety of milnacipran when it is administered neuraxially. This study examined the neurotoxicity of epidural milnacipran by observing behavioral and sensory-motor changes with histopathological examinations of spinal cords in rats. Methods: Sixty rats were divided into 3 groups, with each group receiving epidural administration of either 0.3 ml (3 mg) of milnacipran (group M, n = 20), 0.3 ml of 40% alcohol (group A, n = 20), or 0.3 ml of normal saline (group S, n = 20). Results: There were no abnormal changes in the behavioral, sensory-motor, or histopathological findings in all rats of groups M and S over a 3-week observation period, whereas all rats in group A had abnormal changes. Conclusions: Based on these findings, the direct epidural administration of milnacipran in rats did not present any evidence of neurotoxicity in behavioral, sensory-motor and histopathological evaluations.

Release modulation of highly water soluble drug using solid dispersion: impact of dispersion and its compressed unit

Punit B. Parejiya,Bhavesh S. Barot,Hetal K. Patel,Dharmik M. Mehta,Pragna K. Shelat,Arunkumar Shukla 한국약제학회 2014 Journal of Pharmaceutical Investigation Vol.44 No.3

In present day, availability of various carriers,innovative techniques of production and plenty of solventssupport the growth of solid dispersion (SD) technology inpharmaceutical industries to overcome many issues. Thepresent study was aimed to develop SD based sustainedrelease system of Milnacipran HCl (MH). The SD containingethyl cellulose, Eudragit RLPO and Eudragit RSPOat drug–polymer ratios of 1:1, 1:2, and 1:3 were developedusing solvent evaporation technique and different waxes atratio of 1:1, 1:1.25, 1:1.5 and 1:1.75 with drug weredeveloped by melting method. The physicochemicalproperties of SD were evaluated using Fourier transforminfrared spectroscopy (FTIR), differential scanning calorimetry(DSC) and X-ray diffraction (XRD). The desiredSD batch was further compressed into tablet unit to achievepredetermined once a day drug release. Tablets preparedwere evaluated for physicochemical parameters, in vitrodrug release, drug release kinetics and scanning electronmicroscopy. Out of selected carriers, bees wax had shownmaximum release retardation. The results of FTIR, DSCand XRD studies exhibited poor interaction amongst MH–bees wax and retention of crystalline state of MH in SDsystem. The presence of Benecel (HPMC K 200 M;75 mg) in tablets comprising SD (1:1.25, MH:bees wax)revealed remarkable drug release extension and it wasconsidered an optimal. The later was submitted to shortterm stability study and its results indicated the stablecharacteristic of system. Drug release from optimizedformulation fitted well into Higuchi model with anomalousdiffusion. The compressed unit of SD system of highlywater soluble drug can be successful single day regimen.