Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs.
Local Effects Following Single and Repeat Intra-Articular Injections of Triamcinolone Acetonide Extended-Release: Results from Three Nonclinical Toxicity Studies in Dogs.
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DOI：
10.1007/s40744-018-0125-3
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发表时间：
2018-12
影响因子：
3.8
通讯作者：
Lightfoot-Dunn R
中科院分区：
文献类型：
--
作者：
Bodick N;Williamson T;Strand V;Senter B;Kelley S;Boyce R;Lightfoot-Dunn R
单次关节内（IA）注射基于聚乳酸-羟基乙酸共聚物（PLGA）微球的曲安奈德缓释剂（TA-ER;以前称为FX 006）在膝关节骨关节炎患者中显示出持续的临床相关获益。在三项非临床研究中，在正常犬膝关节中评估了TA-ER的局部作用。在单次注射TA-ER（2.1/6.25/18.75 mg TA）或TA结晶混悬液（TAcs，18.75 mg TA）后，对膝关节进行长达6周或9个月的评价，以及在三次注射（每1或3个月）TA-ER（6.25/18.75 mg TA）或TAcs（18.75 mg）后长达6个月的评价。溶剂稀释剂、空白微球和未处理膝关节用作对照。进行血浆和滑液（SF）TA浓度和滑膜的标准组织病理学评估。通过改良的Mankin评分评估关节软骨形态。血浆和SF浓度表明，与TAC相比，TA-ER的剂量依赖性TA关节驻留时间延长。对关节软骨的影响具有剂量和时间依赖性，与皮质类固醇对正常膝关节的已知影响一致。发生番红O染色的损失，表明软骨基质蛋白聚糖减少，并且在所有研究中以类似的方式恢复TA-ER和TAC。结构性病变不常见，TA-ER和TAC的严重程度基本相当，但TA-ER的发生率略高。在滑膜浅层观察到PLGA的局灶性/多灶性异物反应（FBR），4-6周后达到峰值，6个月时显著恢复或完全消退。这些发现表明，IA注射TA-ER对软骨的影响主要是短暂的，并且与在正常犬膝关节中用TAC观察到的效果相当。在正常关节中的这些轻度作用不同于在疾病模型中用TA-ER和其他皮质类固醇观察到的有益作用。PLGA微球的滑膜FBR是局灶性和一过性的。Wisconon Therapeutics，Inc.本文提供了简明的语言摘要。本文的在线版本（10.1007/s40744-018-0125-3）包含补充材料，可供授权用户使用。
Single intra-articular (IA) injections of poly(lactic-co-glycolic acid) (PLGA) microsphere-based triamcinolone acetonide extended-release (TA–ER; formerly FX006) demonstrated sustained, clinically relevant benefits in patients with knee osteoarthritis. The local effects of TA–ER were assessed in normal canine knees in three nonclinical studies. Knees were evaluated for up to 6 weeks or 9 months after a single injection of TA–ER (2.1/6.25/18.75 mg TA), or TA crystalline suspension (TAcs, 18.75 mg TA), and for up to 6 months after three injections (every 1 or 3 months) of TA–ER (6.25/18.75 mg TA) or TAcs (18.75 mg). Vehicle-diluent, blank microspheres, and untreated knees were used as controls. Plasma and synovial fluid (SF) TA concentrations and standard histopathological assessment of the synovium were conducted. Articular cartilage morphology was assessed via modified Mankin scoring. Plasma and SF concentrations indicated prolonged dose-dependent TA joint residency with TA–ER compared with TAcs. Effects in articular cartilage were dose- and time-dependent and consistent with known effects of corticosteroids in the normal knee. Loss of Safranin O staining occurred, indicative of a reduction in cartilage matrix proteoglycan, and recovered in a similar manner for TA–ER and TAcs across all studies. Structural lesions were infrequent and generally comparable in severity between TA–ER and TAcs but slightly higher in incidence for TA–ER. Focal/multifocal foreign-body responses (FBR) to PLGA were observed in the superficial layer of the synovium, peaking after 4–6 weeks, with significant recovery or complete resolution by month 6. These findings suggest that the effects of IA injections of TA–ER on cartilage are predominantly transient, and comparable to those observed with TAcs in the normal canine knee joint. These mild effects in the normal joint differ from the beneficial effects observed with TA–ER and other corticosteroids in disease models. The synovial FBR to PLGA microspheres was focal and transient. Flexion Therapeutics, Inc. Plain language summary available for this article. The online version of this article (10.1007/s40744-018-0125-3) contains supplementary material, which is available to authorized users.
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影响因子：
1.8
作者：
FOLAND, JW;MCILWRAITH, CW;LAMAR, CH
通讯作者：
LAMAR, CH
影响因子：
2.2
作者：
Frisbie, DD;Kawcak, CE;McIlwraith, CW
通讯作者：
McIlwraith, CW
DOI：
10.2131/jts.28.109
发表时间：
2003-08-01
期刊：
The Journal of toxicological sciences
影响因子：
--
作者：
Boelsterli, Urs A
通讯作者：
Boelsterli, Urs A
骨关节炎的炎症。
影响因子：
5.1
作者：
Goldring MB;Otero M
通讯作者：
Otero M
影响因子：
27.4
作者：
GIBSON, T;BURRY, HC;GLASS, J
通讯作者：
GLASS, J