Johnson P L, Bhattacharya S K
Edward Dana Mitchell Surgical Research Laboratory, University of Tennessee Medical Center, Memphis 38163.
J Neurol Sci. 1993 Mar;115(1):76-90. doi: 10.1016/0022-510x(93)90070-f.
Membrane-mediated excessive intracellular calcium accumulation (EICA) is a fundamental pathogenetic event associated with chronic muscle degeneration in patients with Duchenne muscular dystrophy (DMD), and in animals with hereditary muscular dystrophy (HMD). Because of potential Ca(2+)-channel blocking properties, we investigated the relative efficacies of chronic diltiazem (DTZM) (50 mg/kg/d), nifedipine (NFDN) (6 mg/kg/d), and verapamil (VPML) (25 mg/kg/d) therapies in reducing EICA and improving dystrophic pathobiology beginning in 30-day-old male BIO-14.6 strain dystrophic hamsters (DH). Each agent, and sterile distilled water as vehicle control, was given in a single daily oral dose for 180 days to four groups each of DH and BIO-F1B strain normal hamsters (NH). Plasma [Ca] and [Mg]; plasma aldolase (ALD), creatine kinase (CK), and lactate dehydrogenase (LDH) activities; relative cardiac hypertrophy and relative soleus hypertrophy; tissue [Ca] and [Mg] of the heart and rectus femoris muscle, histology of rectus femoris, and overall mortality rate were quantitated. Muscle Mg was not modified in DH, or by any of these agents. NFDN produced significant edema in the soleus and myocardium. During the 6-month therapeutic trial, 45% DH and 18% NH died on VPML, 27% DH and 9% NH on NFDN, and 20% DH controls on distilled water, but none on DTZM; suggesting that DTZM treated DH lived longer than DH controls. Relative efficacy in regulating EICA in both the cardiac and skeletal muscles; plasma ALD, CK, and LDH; and improving associated dystrophic pathobiology was found to be DTZM >>> NFDN > VPML. DTZM appears to be the most effective and safest agent in mitigating EICA in cardiac and skeletal muscles, efflux of intracellular enzymes, histopathology of dystrophic muscle with sporadic necrosis, and chronic muscle degeneration in DH with HMD. DTZM therapy also halted the high morbidity and mortality associated with the dystrophic pathobiology inherent in DH.
膜介导的细胞内钙过度积累（EICA）是与杜兴氏肌营养不良症（DMD）患者以及遗传性肌营养不良症（HMD）动物的慢性肌肉退化相关的基本致病事件。鉴于其潜在的钙通道阻断特性，我们研究了慢性地尔硫䓬（DTZM）（50毫克/千克/天）、硝苯地平（NFDN）（6毫克/千克/天）和维拉帕米（VPML）（25毫克/千克/天）疗法在减少EICA以及改善30日龄雄性BIO-14.6品系营养不良仓鼠（DH）的营养不良病理生物学方面的相对疗效。将每种药物以及作为载体对照的无菌蒸馏水，以每日单次口服剂量给予四组DH和BIO-F1B品系正常仓鼠（NH），持续180天。对血浆[Ca]和[Mg]、血浆醛缩酶（ALD）、肌酸激酶（CK）和乳酸脱氢酶（LDH）活性、相对心脏肥大和相对比目鱼肌肥大、心脏和股直肌组织的[Ca]和[Mg]、股直肌组织学以及总体死亡率进行了定量分析。DH的肌肉Mg未发生改变，这些药物也未对其产生影响。NFDN在比目鱼肌和心肌中产生了明显的水肿。在为期6个月的治疗试验中，VPML治疗组中45%的DH和18%的NH死亡，NFDN治疗组中27%的DH和9%的NH死亡，蒸馏水对照组中20%的DH死亡，但DTZM治疗组无一死亡；这表明DTZM治疗的DH存活时间比DH对照组更长。发现在调节心脏和骨骼肌中的EICA、血浆ALD、CK和LDH以及改善相关的营养不良病理生物学方面，相对疗效为DTZM >>> NFDN > VPML。DTZM似乎是减轻心脏和骨骼肌中的EICA、细胞内酶外流、伴有散在坏死的营养不良肌肉组织病理学以及HMD的DH慢性肌肉退化的最有效和最安全的药物。DTZM疗法还阻止了与DH固有的营养不良病理生物学相关的高发病率和高死亡率。
