궁둥신경 결찰로 유발된 통증에 미치는 minocycline의 작용

구은영(Eun Young Gu),한형수(Hyung Soo Han),박재식(Jae-Sik Park) 대한해부학회 2004 Anatomy & Cell Biology Vol.37 No.4

신경이 손상을 받으면 신경병증 통증이 지속적으로 나타나게 된다고 알려져 있다. 최근의 연구에 의하면 이러한 통증 발생이 미세아교세포(microglia)의 증식과 관련이 있다고 알려져 있다. 한편, 항생제로 사용되고 있는 minocycline은 중추신경손상시 활성화되는 미세아교세포의 증식을 억제하는 물질로 알려져 있고 여러 질병에 실험적으로 사용되어왔다. 하지만 말초신경의 손상에 의한 신경병증 통증에 대한 작용은 잘 알려져 있지 않다. 본 실험에서는 궁둥신경(sciatic nerve)에 손상을 일으킨 후 통각 및 미세아교세포의 증식이 시간이 경과함에 따라 어떻게 변하는지 관찰하여 보았다. 또 minocycline을 투여하여 통각 및 미세아교세포 증식에 미치는 영향을 연구하였다. 실험동물은 수컷 Sprague-Dawley (150~180 g)를 ketamine (60 mg/kg)과 xylazine (7 mg/kg)을 주사하여 마취한 뒤 왼쪽다리 넓적다리의 궁둥신경을 chromic실로 느슨하게 묶어 신경손상을 주었다. 통각을 검사하기 위해 실험동물의 뒷발바닥에 온각, 냉각 그리고 기계적 감각을 가하여 그 반응을 측정하였다. 행동실험은 수술 전, 수술 후 1, 4, 7, 10일에 시행되었으며 행동실험이 끝난 동물에서 L4~6 척수를 분리하여 미세아교세포 활성화 표지인 ED1 항체로 면역조직화학염색법에 이용하였다. Minocycline (50 mg/kg)은 마지막 행동실험이 끝날 때까지 매일 경구 투여하였는데 수술 전에 투여를 시작한 군과 수술 후 1, 3, 그리고 5일이 지나서 투약을 시작하는 군으로 나누어 투여시기에 따른 차이를 비교하였다. 신경성 통각에 대한 실험에서 궁둥신경 수술 후 4일부터 온각, 냉각, 기계적 자극에 대한 역치가 상승하였으며 10일째에 가장 강한 통각을 나타냈다. Minocycline을 수술 전부터 투여한 경우 통각 역치의 변화가 없거나 진통작용이 일어났는데 이런 효과는 약물 투여를 수술 후 1일 또는 3일에 시작하였을 때에는 볼 수 있었으나 5일에 시작한 경우에는 볼 수 없었다. 활성화된 미세아교세포 수의 변화는 통각의 변화와 경시적으로 일치하였다. 또 minocycline 처치는 미세아교세포 활성화를 효과적으로 억제하였다. Nerve injury leads to chronic neuropathic pain syndromes. Activation of microglia has been studied to investigate the role in pain development. Minocycline is known as a potent inhibitor of microglial activation in many types of the brain injury models. But it is not known whether minocycline interferes with pain and microglial activation after the peripheral nerve injury. In this study, we investigated the time course of pain and microglial activation after sciatic nerve injury and also tested the effect of minocycline using sciatic nerve ligation model. All experiments were performed using 150~180 g male Sprague-Dawley rats. The chronic constriction injury (CCI) of the sciatic nerve with four 4.0 chromic gut suture was used to induce neuropathic pain in the left sciatic nerve. The behavioral response of rats to the stimuli (heat, cold & pressure) was assessed by measuring the lifting of the foot and the avoidance of touching the floor at pre-surgical day 1, post-surgical day 1, 4, 7, and 10. The L4~6 spine was fixed and used to detect microglia. Oral minocycline (50 mg/kg) was administered daily to the last day of the experiment. Minocycline was administered to one group of rats from pre-surgical day 1 and minocycline treatment was initiated from post-surgical day 1, 3, and 5 in other groups. Neuropathic pain was evident from day 4 and the peak response was observed at 10 days after CCI. Minocycline significantly attenuated neuropathic pain even when treatment was delayed by 3 days. But, it had no effet when treatment initiated 5 days after injury. Minocycline also attenuated microglial activation. In summary, a correlation was evident between the neuropathic pain and microglial activation in our model and minocycline reduced both development of pain and microglial activation. Thus, minocycline can be a good candidate for the treatment of neuropathic pain. However, the administration should be initiated prior to microglial activation.

P027 Pulsed dye laser treatment combined with oral minocycline for more than 4 weeks reduces recurrence rate of rosacea

( Hye Soo Ko ),( Hee Seong Yoon ),( Si Hyub Lee ),( Seung Dohn Yeom ),( Young Ju Suh ),( Ji Won Byun ),( Gwang Seong Choi ),( Jeonghyun Shin ) 대한피부과학회 2016 대한피부과학회 학술발표대회집 Vol.68 No.2

Background: Minocycline is one of the most commonly used agents for treatment of rosacea. Pulsed dye laser (PDL) has been suggested to be used adjunctively with oral and topical rosacea regimens for more effective symptom resolution. However, it is not known which treatment method can reduce the recurrence of rosacea effectively. Objectives: The primary objective was to identify whether 595nm-PDL treatment reduced recurrent rate among rosacea patients who were treated with oral minocycline. The secondary objective was to evaluate that the factors such as sex, age, rosacea type, topical agents, and the treatment duration with oral minocycline were associated with the hazard of recurrence of rosacea. Methods: 107 Korean patients with rosacea who started treatment with oral minocycline (100mg per day) with or without 595nm-PDL (total 2-4 sessions) between January 2013 and May 2015 were evaluated retrospectively. The follow-up period was 1 year from the end of the treatment. Results: The recurrence-free survival analysis revealed that the group with oral minocycline plus PDL was significantly different compared with the group with oral minocycline alone. Treatment of oral minocycline for 4 or less weeks without PDL remained a statistically significant risk factor compared with treatment of oral minocycline for more than 4 weeks with PDL. Conclusion: Pulsed dye laser can be used in combination with oral minocycline for more than 4 weeks to reduce relapses of rosacea.

Pulsed Dye Laser Treatment Combined with Oral Minocycline Reduces Recurrence Rate of Rosacea

( Hye Soo Ko ),( Young Ju Suh ),( Ji Won Byun ),( Gwang Seong Choi ),( Jeonghyun Shin ) 대한피부과학회 2017 Annals of Dermatology Vol.29 No.5

Background: The recurrence rate of rosacea was not known very well, but has been reported as 60% in 6 months after withdrawal of the drug. It is not known which treatment can reduce relapses of rosacea effectively. Objective: The objective was to identify whether 595 nm-pulsed dye laser (PDL) treatment reduced recurrence rate among rosacea patients who were treated with oral minocycline. Methods: One hundred and seven Korean patients with rosacea who started treatment with oral minocycline (100 mg/d) with or without PDL (2∼4 sessions) were evaluated retrospectively. The recurrence rate was estimated using the Kaplan-Meier method, and difference was evaluated using the log-rank test. Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals (CIs) of risk factors for the recurrence of rosacea. Results: The recurrencefree survival analysis revealed that the group with oral minocycline plus PDL was significantly different compared with the group with oral minocycline alone (p=0.011). Cox proportional hazards model showed that the combined use of PDL with oral minocycline appeared to be a significant protective factor for the hazard of recurrence of rosacea (hazard ratio, 0.492; 95% CI, 0.257∼0.941; p=0.032). Conclusion: PDL can be used added to oral minocycline to reduce relapses among rosacea patients who are undergoing oral minocycline treatment. (Ann Dermatol 29(5) 543∼547, 2017)

Effect of Minocycline on Activation of Glia and Nuclear Factor kappa B in an Animal Nerve Injury Model

Eun Young Gu,Hyung Soo Han,Jae-Sik Park 대한생리학회-대한약리학회 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCI). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

Minocycline-induced Periarticular Black Bones in Inflamed Joints Which Underwent Arthroplastic Reconstruction

Suran Yang,Yuya Takakubo,Shinji Kobayashi,Tamon Asano,Akiko Sasaki,Kan Sasaki,Hiroharu Ohki,Yasunobu Tamaki,Michiaki Takagi 대한정형외과학회 2012 Clinics in Orthopedic Surgery Vol.4 No.3

Background: Minocycline-induced pigmentation of bone (black bone) is well described in tooth-bearing intra-oral bone, but is less known in periarticular bone in patients who have undergone total joint arthroplasty. On a retrospective basis, we investigated the short-term clinico-radiological results of total joint arthroplasties in which the patient developed minocycline-induced periarticular black bone. Methods: We found 5 cases (0.08%), in 4 patients, of periarticular bone pigmentation revealed during total joint arthroplasties (2 hips, 2 knees, and 1 ankle) in our series of total joint surgeries (6,548 cases) over a 10-year time period in our 3 institutes. Their mean age was 56 years at surgery. All patients had received long-term minocycline treatment. Mean dosage and duration of minocycline was 160 mg/day and 2.2 years, respectively. Minocycline had been prescribed for reactive arthritis (one), rheumatoid arthritis (two) and late infection after total joint arthroplasty (two patients). Mean follow-up period was 3.4 years after the surgeries. Results: All cases had black or brown pigmentation in the periarticular bones during the surgery. There was no pigmentation in the cartilage or soft tissues of the joints. The mean Japanese Orthopaedic Association (JOA) score or Japanese Society for Surgery of the Foot (JSSF) scale for rheumatoid arthritis foot and ankle joints at latest follow-up (case 1, 66; case 2, 87; case 3, 77; case 4, 77; case 5, 80) improved compared to those of pre-surgery (case 1, 47; case 2, 45; case 3, 55; case 4, 34; case 5, 55). No implant loosening was noted on radiographic examination during the follow-up period. No abnormal bone formation, bone necrosis, hemosiderin deposition, malignancy or metallic debris was found on histological examination. Conclusions: No clinico-radiological symptoms of total joint arthroplasties showed in the patients with minocycline-induced periariticular black bone in the short-term. Systemic minocycline treatment has the potential to induce significant black pigmentation of many tissues. In particular, minocycline-induced pigmentation of periarticular bone may be accelerated by inflammation due to rheumatic or pyogenic arthritis. Surgeons should recognize the risk of bone pigmentation in inflamed joints due to the systemic treatment of minocycline and explore its influence on periarticular bone and total joint arthroplasty in the long-term.

Effect of Minocycline on Activation of Glia and Nuclear Factor kappa B in an Animal Nerve Injury Model

Gu, Eun-Young,Han, Hyung-Soo,Park, Jae-Sik The Korean Society of Pharmacology 2004 The Korean Journal of Physiology & Pharmacology Vol.8 No.5

Glial cells are activated in neuropathy and play a key role in hyperalgesia and allodynia. This study was performed to determine whether minocycline could attenuate heat hyperalgesia and mechanical allodynia, and how glial cell activation and nuclear factor kappa B (NF-kappaB) were regulated by minocycline in a model of chronic constriction of sciatic nerve (CCl). When minocycline (50 mg/kg, oral) was daily administered from 1 day before to 9 days after ligation, heat hyperalgesia and mechanical allodynia were attenuated. Furthermore, when minocycline treatment was initiated 1 or 3 days after ligation, attenuation of the hypersensitive behavior was still robust. However, the effect of attenuation was less when minocycline was started from day 5. In order to elucidate the mechanism of pain attenuation by minocycline, we examined the changes of glia and NF-kappaB, and found that attenuated hyperalgesia and allodynia by minocycline was accompanied by reduced microglial activation. Furthermore, the number of NF-kappaB immunoreactive cells increased after CCI treatment and this increase was attenuated by minocycline. We also observed translocation of NF-kappaB into the nuclei of activated glial cells. These results suggest that minocycline inhibits activation of glial cells and NF-kappaB, thereby attenuating the development of behavioral hypersensitivity to stimuli.

저산소 상태로 유도된 백서 심근세포 배양에서 Minocycline의 심근보호 효과

양범석,박혜진,김홍태,이종원,이동석,노은석,정혜리,김우택 대한소아과학회 2004 小兒科 Vol.47 No.6

[P463] A case of drug-induced lupus after minocycline administration

( Jae Yun Lim ),( Junghwa Yang ),( Yun Ho Lee ),( Jung Yup Kim ),( Sunmin Yim ),( Ju-yeon Choi ),( Han-saem Kim ),( Jun Hong Min ),( Young Jun Choi ),( Jae-hui Nam ),( Ga-young Lee ),( Won-serk Kim ) 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.1

Minocycline has increasingly been associated with different adverse reactions including drug-induced lupus (DIL). DIL is a less well-defined syndrome. Patients with DIL usually show the clinical features of polyarthralgia, polyarthritis often accompanied by liver abnormalities and positive antinuclear antibody test results. Representative dermatological manifestations are subcutaneous nodules, rash, livedo reticularis, oral ulceration, alopecia. A 20-year-old female presented with multiple erythematous, slightly elevated tender subcutaneous nodules on back, thigh and forearm. The patient had a past history of taking minocycline (Minocin^®, 50 mg/day) steadily for 10 months with acne. Two weeks after taking minocycline (100 mg/day) again due to recurrence of acne, new skin lesions as well as arthralgia were newly developed. Laboratory test for anti-histone antibodies and anti-SSA were positive. Histological findings of the skin lesion revealed mild septal panniculitis with mild lymphoid lobular infiltration. Finally, the patient was diagnosed with DIL. After stopping minocycline and taking hydroxychloroquine sulfate (Oxiklorin^® 200 mg/day) and methylprednisolone (Somelon^® 12 mg/day), arthralgia completely disappeared within 2 weeks. Herein, we report this patient as a rare and educational case of DIL triggered by long-term exposure to minocycline.

Minocycline-Induced Autoimmune Hepatitis: A Rare But Important Cause of Drug-Induced Autoimmune Hepatitis

Elizabeth G. Harmon,Randolph McConnie,Anil Kesavan 대한소아소화기영양학회 2018 Pediatric gastroenterology, hepatology & nutrition Vol.21 No.4

Drug-induced autoimmune hepatitis (DIAIH) is an increasingly recognized form of drug-induced liver injury that leads to a condition similar to idiopathic autoimmune hepatitis. A number of drugs have been associated with DIAIH, minocycline is one of the most well characterized. Minocycline is a semisynthetic tetracycline antibiotic used in the treatment of acne vulgaris. Minocycline-induced autoimmune hepatitis presents with serologic and histologic features similar to idiopathic autoimmune hepatitis. However, the natural history and outcomes of these two conditions differ significantly. The majority of patients with minocycline-induced autoimmune hepatitis experience complete resolution of symptoms after withdrawal of the medication. Some patients may require a short course of steroids and rarely use of an immunomodulator to achieve resolution of disease. Recurrence of symptoms is rare and typically only occurs with reintroduction of minocycline. It is important for primary care providers to consider minocycline-induced autoimmune hepatitis when liver injury develops during minocycline therapy.

Protective Effect of Minocycline Against Cisplatin-induced Ototoxicity

이치규,신장인,조양선 대한이비인후과학회 2011 Clinical and Experimental Otorhinolaryngology Vol.4 No.2

Objectives. Cisplatin, a widely used chemotherapeutic agent, has serious side effects, including nephrotoxicity and ototoxicity. Minocycline is a semisynthetic second-generation tetracycline that exerts anti-inflammatory and neuroprotective effects. The purpose of this study was to elucidate the protective effect of minocycline against cisplatin-induced ototoxicity in the auditory hair cell. Methods. The House Ear Institute-Organ of Corti 1 (HEI-OC1) cell line and guinea pigs were used for in vitro and in vivo experiments. Cells were exposed to cisplatin with or without pre-treatment with minocycline. Cell survival was analyzed using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide). Whole-cell lysates were collected and immunoblotted with antibodies against Bcl-2, p-c-Jun, active caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), and apoptosis-inducing factor (AIF). The guinea pigs received intraperitoneal injections of cisplatin alone or following minocycline pretreatment. The auditory brainstem response was tested and the cochleae were harvested and evaluated using scanning electron microscopy. Results. Survival significantly increased in cells pretreated with minocycline compared with cells exposed to cisplatin alone. Cisplatin treatment increased the expression of active caspase 3, p-c Jun, PARP, and AIF, and pretreatment with minocycline attenuated this response. In animal study, the threshold shift by cisplatin injection in the auditory brainstem response was less pronounced in animals pretreated with minocycline. Scanning electron microscopy revealed more severe damage to the outer hair cells at the basal and middle turns than the apical turn. Conclusion. Minocycline partially protects against cisplatin-induced ototoxicity via both caspase-dependent and independent apoptosis pathways.