Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog.
Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog.
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DOI：
10.1111/j.1525-1403.2012.00479.x
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Miljanich GP
中科院分区：
文献类型：
--
作者：
Yaksh TL;de Kater A;Dean R;Best BM;Miljanich GP
齐考诺肽是一种能够阻断N型钙通道的肽，鞘内给药后具有抗痛觉过敏作用。我们在此描述了犬鞘内推注和输注齐考诺肽的脊髓动力学特征。雄性比格犬（N = 5）准备长期鞘内（IT）腰椎注射和脑脊液（LCSF）采样导管连接到背心安装泵。每只犬接受：i）IT推注齐考诺肽（10 µg + 1 µCi 3 H-菊粉），ii）IT输注齐考诺肽48小时（1 µg/100 µL/hr），iii）IT输注齐考诺肽48小时（5 µg/100 µL/hr），iv）静脉注射齐考诺肽（0.1 mg/kg）。IT推注后，LCSF齐考诺肽和菊粉显示出初始峰值和双相（分布/消除）清除（齐考诺肽T1/2 α /半衰期分别为0.14和1.77 h，菊粉T1/2 α /半衰期分别为0.16和3.88 h）。LCSF：血浆齐考诺肽浓度比在30分钟时为20，000：1，在8小时时为30：1。IT输注1 μg/hr，然后是5 μg/hr，导致LCSF浓度在8小时达到峰值，并分别稳定在343和1380 ng/mL，直至48小时输注结束。终止连续输注后的终末消除T1/2为2.47 hr。输注1 µg/hr和5 µg/hr后齐考诺肽LCSF：脑池CSF：血浆浓度比分别为1：0.017：0.001和1：0.015：0.003。IT输注齐考诺肽1 µg/hr可抑制热皮肤抽搐24小时，并产生中度颤抖、共济失调和觉醒降低。在48小时输注期内，效应持续存在，在随后的5 µg/hr输注期内强度增加，并在药物清除后消失。鞘内推注或输注后，齐考诺肽显示线性动力学，与约2500 Da的亲水分子一致，其从LCSF中清除的速度略快于菊粉。行为效应具有剂量依赖性和可逆性。
Ziconotide is a peptide that blocks N-type calcium channels and is anti-hyperalgesic after intrathecal delivery. We here characterize the spinal kinetics of intrathecal bolus and infused ziconotide in dog. Male beagle dogs (N = 5) were prepared with chronic intrathecal (IT) lumbar injection and cerebrospinal fluid (LCSF) sampling catheters connected to vest-mounted pumps. Each dog received: i) IT bolus ziconotide (10 µg + 1 µCi 3H-inulin), ii) IT infusion for 48 hr of ziconotide (1 µg/100 µL/hr), iii) IT infusion for 48 hr of ziconotide (5 µg/100 µL/hr), and iv) intravenous injection of ziconotide (0.1 mg/kg). After IT bolus, LCSF ziconotide and inulin showed an initial peak and biphasic (distribtution/elimination) clearance (ziconotide T1/2 α / ß = 0.14 and 1.77 hr, and inulin T1/2 α / ß = 0.16 and 3.88 hr, respectively). The LCSF: plasma ziconotide concentration ratio was 20,000: 1 at 30 min, and 30: 1 at 8 hr. IT infusion of 1 and then 5 µg/hr resulted in LCSF concentrations that peaked by 8 hr and remained stable at 343 and 1380 ng/mL, respectively, to the end of the 48-hr infusions. Terminal elimination T1/2 after termination of continuous infusion was 2.47 hr. Ziconotide LCSF: cisternal CSF: plasma concentration ratios after infusion of 1 µg/hr and 5 µg/hr were 1: 0.017: 0.001 and 1: 0.015: 0.003, respectively. IT infusion of ziconotide at 1 µg/hr inhibited thermal skin twitch by 24 hr, and produced modest trembling, ataxia, and decreased arousal. Effects continued through the 48-hr infusion period, increased in magnitude during the subsequent 5 µg/hr infusion periods, and disappeared after drug clearance. After intrathecal bolus or infusion, ziconotide displays linear kinetics that are consistent with a hydrophilic molecule of approximately 2500 Da that is cleared slightly more rapidly than inulin from the LCSF. Behavioral effects were dose dependent and reversible.
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影响因子：
3
作者：
Newcomb, R;Abbruscato, TJ;Miljanich, G
通讯作者：
Miljanich, G
影响因子：
7.4
作者：
Penn, RD;Paice, JA
通讯作者：
Paice, JA
DOI：
10.1053/bean.2002.0255
发表时间：
2002-12-01
期刊：
Best practice & research. Clinical anaesthesiology
影响因子：
--
作者：
Bernards, Christopher M
通讯作者：
Bernards, Christopher M
影响因子：
2.5
作者：
DOUCETTE, R;THERIAULT, E;DIAMOND, J
通讯作者：
DIAMOND, J
影响因子：
3
作者：
McGuire, D;Bowersox, S;Luther, RR
通讯作者：
Luther, RR