Brooks B A, Lant A F, McNabb W R, Noormohamed F H
Br J Clin Pharmacol. 1984 May;17(5):497-512. doi: 10.1111/j.1365-2125.1984.tb02382.x.
The effects of indacrinone (IND) have been investigated in a two part study. First, a total of 36 clearance studies have been performed in 14 healthy volunteers, under conditions of either maximal hydration or hydropenia, to compare the renal sites of action of single oral doses of IND, 20 mg, ethacrynic acid (EA), 100 mg, and hydrochorothiazide (HCTZ), 100 mg. Under conditions of maximal water hydration, IND increased fractional Na+ excretion from a mean of 1.19 +/- 0.05 to 4.93 +/- 0.67% of GFR. This was similar to the response seen with HCTZ, which increased fractional Na+ clearance up to 3.16 +/- 0.17% of GFR; EA increased fractional Na+ excretion up to 14.5 +/- 2.5% of GFR. The mean reduction in fractional free-water clearance (CH2O/GFR X 100%) invoked by IND, (delta = -34.8% of control) was similar to that produced by EA, (delta = -27.2% of control), and by HCTZ, (delta = -26.6% of control). During hydropenia with superimposed mannitol diuresis, both IND and EA caused a fall in fractional free-water reabsorption (TcH2O/GFR X 100%), delta IND = -20.3% of control, delta EA = -70.1% of control. HCTZ produced a significant increase in fractional free-water reabsorption, delta HCTZ = -20.7% of control. In all studies, single doses of IND were both uricosuric and hypouricaemic. Fractional urate excretion increased from a mean 6.7 +/- 0.1 to 15.2 +/- 2.1% of GFR whilst plasma urate concentration fell from a mean of 0.36 +/- 0.03 to 0.34 +/- 0.03 mM (P less than 0.05) within 2-3 h post drug. HCTZ and EA, in single doses, had little effect on urate excretion. In the second part of the study, a total of 16 healthy volunteers received either IND, 10 mg, or HCTZ 50 mg, orally for 8 days, whilst on a diet of controlled electrolyte content. Both drugs were well tolerated by both sets of subjects with no adverse clinical or pathological findings. Both IND and HCTZ caused a significant reduction in weight and standing systolic blood-pressure during the first 48 h of therapy. At the doses administered, IND and HCTZ displayed similar diuretic responses with respect to water, Na+, Cl-, Ca2+ and PO4(3-) excretion. IND produced less kaliuresis than HCTZ during the first treatment day but cumulative K+ loss was similar for both drugs over the eight days of therapy. Fractional urate excretion after IND remained elevated throughout the 8 days of therapy and the subjects remained isouricaemic for 7 days.(ABSTRACT TRUNCATED AT 400 WORDS)
茚达立酮（IND）的作用在一项分为两部分的研究中进行了调查。首先，在14名健康志愿者中进行了总共36项清除率研究，分别在最大水合作用或缺水状态下，比较单次口服20毫克IND、100毫克依他尼酸（EA）和100毫克氢氯噻嗪（HCTZ）的肾脏作用部位。在最大水合作用条件下，IND使钠排泄分数从平均占肾小球滤过率（GFR）的1.19±0.05%增加到4.93±0.67%。这与HCTZ的反应相似，HCTZ使钠清除分数增加到占GFR的3.16±0.17%；EA使钠排泄分数增加到占GFR的14.5±2.5%。IND引起的自由水清除分数（CH2O/GFR×100%）平均降低（δ=-34.8%对照）与EA（δ=-27.2%对照）和HCTZ（δ=-26.6%对照）产生的相似。在缺水并叠加甘露醇利尿的情况下，IND和EA均导致自由水重吸收分数（TcH2O/GFR×100%）下降，δIND=-20.3%对照，δEA=-70.1%对照。HCTZ使自由水重吸收分数显著增加，δHCTZ=-20.7%对照。在所有研究中，单次剂量的IND既增加尿酸排泄又降低血尿酸水平。尿酸排泄分数从平均占GFR的6.7±0.1%增加到15.2±2.1%，而血浆尿酸浓度在给药后2 - 3小时内从平均0.36±0.03毫摩尔降至0.34±0.03毫摩尔（P<0.05）。单次剂量的HCTZ和EA对尿酸排泄影响很小。在研究的第二部分，总共16名健康志愿者口服10毫克IND或50毫克HCTZ，持续8天，同时采用控制电解质含量的饮食。两组受试者对两种药物耐受性良好，无不良临床或病理发现。在治疗的前48小时，IND和HCTZ均导致体重和站立位收缩压显著降低。在所给药剂量下，IND和HCTZ在水、钠、氯、钙和磷酸根（3-）排泄方面表现出相似的利尿反应。在治疗的第一天，IND引起的尿钾排泄比HCTZ少，但在8天的治疗过程中，两种药物的累积钾流失相似。在整个8天的治疗过程中，IND后的尿酸排泄分数一直升高，受试者在7天内保持血尿酸水平不变。（摘要截短至400字）
