Supanz Sabine, Likar Rudolf, Liebmann Peter M, Wintersteiger Reinhold, Sittl Reinhard, Sadjak Anton
Institute of Pathophysiology, Med. University of Graz, Graz, Austria.
Arzneimittelforschung. 2004;54(5):259-64. doi: 10.1055/s-0031-1296968.
In order to assess possible renal mechanisms causing the as yet unexplained side-effects of peripheral edema, weight gain and swollen limbs seen during the chronic administration of opioids in patients, a rat study was designed, mimicking a constant infusion (24 h) of morphine (CAS 57-27-2) using subcutaneous drug delivery device systems. Subcutaneous (s.c.) morphine infusions (0, 10, 30 mg/kg body weight/24 h) have been administered using implantable mini-osmotic pumps with a delivery rate of 10 microl/h. In addition, s.c. implantable inulin/PAH clearance depot systems were used in order to measure renal functions such as glomerular filtration rate (GFR = inulin clearance), renal plasma flow (RPF = PAH clearance), creatinine clearance and urea clearance in the conscious rat. Compared to controls, morphine caused an increase in PAH clearance, creatinine clearance (both dose dependent), urea clearance (higher dose), body weight, and urine potassium concentration (both groups). Urine minute volume was reduced in the 10 mg morphine group, a dose dependent highly significant decrease of urine sodium in the 30 mg morphine group compared to controls and a significant decrease compared to the 10 mg group could be found. Serum sodium was highly significant and food uptake was significantly increased in the 30 mg group compared to controls. The histological examination of kidneys revealed no differences among the various groups. These data indicate a role of the kidney in the induction of peripheral edema during permanent morphine administration.
为了评估在患者长期使用阿片类药物期间出现的外周水肿、体重增加和肢体肿胀等尚未得到解释的副作用可能涉及的肾脏机制，设计了一项大鼠研究，使用皮下给药装置系统模拟吗啡（CAS 57-27-2）的持续输注（24小时）。采用植入式微型渗透泵以10微升/小时的给药速率进行皮下（s.c.）吗啡输注（0、10、30毫克/千克体重/24小时）。此外，使用皮下植入式菊粉/对氨基马尿酸清除率储库系统来测量清醒大鼠的肾功能，如肾小球滤过率（GFR = 菊粉清除率）、肾血浆流量（RPF = 对氨基马尿酸清除率）、肌酐清除率和尿素清除率。与对照组相比，吗啡导致对氨基马尿酸清除率、肌酐清除率（两者均呈剂量依赖性）、尿素清除率（高剂量组）、体重和尿钾浓度（两组）增加。10毫克吗啡组的每分钟尿量减少，30毫克吗啡组的尿钠呈剂量依赖性高度显著降低，与对照组相比有显著差异，与10毫克组相比也有显著降低。与对照组相比，30毫克组的血清钠高度显著升高，食物摄入量显著增加。肾脏的组织学检查显示各组之间无差异。这些数据表明在长期给予吗啡期间，肾脏在外周水肿的诱导中起作用。
