INTERMITTENT VERSUS CONTINUOUS ADMINISTRATION OF 1,25-DIHYDROXYVITAMIN-D(3) IN EXPERIMENTAL RENAL HYPERPARATHYROIDISM
INTERMITTENT VERSUS CONTINUOUS ADMINISTRATION OF 1,25-DIHYDROXYVITAMIN-D(3) IN EXPERIMENTAL RENAL HYPERPARATHYROIDISM
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DOI：
10.1038/ki.1993.377
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发表时间：
1993-12-01
影响因子：
19.6
通讯作者：
RITZ, E
中科院分区：
文献类型：
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作者：
REICHEL, H;SZABO, A;RITZ, E
关于间歇性与持续给药125 (OH)2D3治疗继发性甲状旁腺功能亢进的疗效，已有相互矛盾的结果报道。为了解决这个问题，我们研究了假手术对照大鼠和次全（5/6）肾切除术（Nx）的甲状旁腺功能亢进大鼠。Nx动物（每组20 ~ 22只）接受三种处理方案：(i)溶剂处理（Nx-溶剂）；（ii）分别于第0天和第4天ig注射35 pmol 1,25(OH)2D3 (Nx-bolus)；（iii）通过渗透微型泵（Nx-infusion）连续输注70 pmol 125 (OH)2D3 6天。所有测量均在治疗开始6天后进行。与假手术对照组相比，nx溶剂中pre-pro-PTH/ β -actin mRNA比值高2.04倍。125 (OH)2D的两种给药方式都导致PTH mRNA浓度相对于nx溶剂的抑制。而注射组pth - pre-pro / β -actin mRNA比值显著低于注射组（注射组比假手术对照组高1.26，注射组比假手术对照组高1.65）（P < 0.05）。nx溶剂组血清氨基末端甲状旁腺素（N-PTH）浓度（52 +/- 4 pg/ml）高于假手术对照组（32 +/- 3 pg/ml, P < 0.01）。Nx-bolus组N-PTH浓度（38 +/- 4 pg/ml）显著低于nx -溶剂组（P < 0.01）和nx -输液组（46 +/- 4 pg/ml, P < 0.05）。nx溶剂组甲状旁腺重量（马克杯/克体重量）（1.30 +/- 0.08 pg/ml）高于假手术对照组（0.79 +/- 0.04 pg/ml, P < 0.02）。同样，Nx-bolus组甲状旁腺重量（0.99 +/- 0.014 pg/ml，与nx -溶剂组相比P < 0.05）低于Nx-infusion组（1.16 +/- 0.06 pg/ml）。大剂量和输注治疗的不同效果不能用血清钙或磷酸盐的变化来解释。对1,25(OH)2D3浓度时间曲线的分析显示，注射处理的动物（8小时后170至200 pg/ml）的峰值浓度高于输注处理的动物（48小时后125至130 pg/ml）。然而，1,25(OH)2D3血清浓度的时间平均平均增加在输注处理的动物中（42.3 pg/ml/24小时）高于注射处理的动物（26.0 pg/ml/24小时）。我们得出结论，在实验性尿毒症中，与连续输注相同总剂量的125 (OH)2D3相比，间歇给药能更有效地抑制甲状旁腺功能的刺激。我们的结果与1,25(OH)2D3浓度时间曲线，即1,25(OH)2D3峰值浓度，是甲状旁腺对1,25(OH)2D3反应的重要决定因素的概念是一致的。
Conflicting results have been reported regarding the efficacy of intermittent versus continuous administration of 1,25(OH)2D3 in renal secondary hyperparathyroidism. To address this issue we examined sham-operated control rats and hyperparathyroid rats with subtotal (5/6) nephrectomy (Nx). The Nx animals (20 to 22 animals per group) were subjected to three treatment protocols: (i) solvent treatment (Nx-solvent); (ii) two i.p. injections of 35 pmol 1,25(OH)2D3 on days 0 and 4 (Nx-bolus); and (iii) continuous infusion of 70 pmol 1,25(OH)2D3 over six days via osmotic minipump (Nx-infusion). All measurements were performed six days after start of treatment. As compared to sham-operated controls, the pre-pro-PTH/beta-actin mRNA ratio was 2.04-fold higher in Nx-solvent. Both modes of administration of 1,25(OH)2D, resulted in inhibition of PTH mRNA concentrations relative to Nx-solvent. The pre-pro-PTH/beta-actin mRNA ratio was, however, significantly lower (P < 0.05) in Nx-bolus than in Nx-infusion (Nx-bolus 1.26 higher than sham-operated controls; Nx-infusion 1.65 higher than sham-operated controls). Aminoterminal PTH (N-PTH) serum concentrations were higher in Nx-solvent (52 +/- 4 pg/ml) than in sham-operated controls (32 +/- 3 pg/ml, P < 0.01). N-PTH concentrations in Nx-bolus (38 +/- 4 pg/ml) were significantly lower than in Nx-solvent (P < 0.01) and in Nx-infusion (46 +/- 4 pg/ml, P < 0.05). Parathyroid gland weight (mug/g body wt) was higher in Nx-solvent (1.30 +/- 0.08 pg/ml) than in sham-operated controls (0.79 +/- 0.04 pg/ml, P < 0.02). Again, parathyroid weight was lower in Nx-bolus (0.99 +/- 0.014 pg/ml, P < 0.05 vs. Nx-solvent) than in Nx-infusion (1.16 +/- 0.06 pg/ml). Differential effects of bolus versus infusion treatment were not explained by changes in serum calcium or phosphate. Analysis of the 1,25(OH)2D3 concentration time-profile showed higher peak concentrations in bolus-treated animals (170 to 200 pg/ml after 8 hr) than in infusion-treated animals (125 to 130 pg/ml after 48 hr). The time-averaged mean increase in 1,25(OH)2D3 serum concentrations was, however, higher in infusion-treated animals (42.3 pg/ml/24 hr) than in bolus-treated animals (26.0 pg/ml/24 hr). We conclude that the stimulation of parathyroid gland function in experimental uremia is more effectively suppressed when the same total dose of 1,25(OH)2D3 is given by intermittent bolus administration than by continuous infusion. Our results are compatible with the notion that the 1,25(OH)2D3 concentration time-profile, that is, the 1,25(OH)2D3 peak concentration, is an important determinant of the response of parathyroid glands to 1,25(OH)2D3.