Intra-Articular Slow-Release Triamcinolone Acetonide from Polyesteramide Microspheres as a Treatment for Osteoarthritis.
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SUBMITTER: Tellegen A
PROVIDER: S-EPMC7999265 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Inflammation of the synovium and joint capsule is a main driver of pain in an osteoarthritic (OA) joint. Triamcinolone acetonide (TAA) is a classical corticosteroid that reduces synovitis and alleviates pain, albeit transiently. Biomaterial-based local TAA release may prolong the suppression of pain without the need for multiple injections. Polylactic-co-glycolic acid (PLGA) formulations of TAA prolong OA pain relief to a limited extent. A novel polyesteramide (PEA) microsphere platform allows for extended release in the OA joint for over 3 months. To evaluate their effect on pain and inflammation, TAA-loaded microspheres were intra-articularly delivered to the knee joint in a rat model of acute arthritis induced by intra-articular injection of streptococcal cell wall peptidoglycan-polysaccharide (PGPS) and subsequent flare-ups by intravenous PGPS injections. PEA-loaded microspheres were benchmarked with TAA-loaded PLGA microspheres and bolus TAA injection. TAA treatments were injected intra-articularly before the first induced flare-up. TAA-loaded PEA and PLGA microspheres reduced joint swelling and signs of pain-like behavior over the entire study period, as assessed by weight bearing and referred mechanical hypersensitivity, whereas bolus suspension was effective for a shorter time period. TAA-loaded PEA microspheres reduced lameness to a greater extent than TAA-loaded PLGA microspheres. In conclusion, a single intra-articular injection of TAA-loaded PEA microspheres reduced joint swelling and induced longer pain relief compared to bolus injection. Hence relief of inflammation and pain by PEA-based delivery of TAA may prove to be effective and durable.
| S-EPMC6407600 | biostudies-literature
Project description:IntroductionSingle 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.MethodsKnees 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.ResultsPlasma 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.ConclusionsThese 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.FundingFlexion Therapeutics, Inc. Plain language summary available for this article.
| S-EPMC6251841 | biostudies-literature
Project description:BackgroundIntra-articular corticosteroids are commonly used for pain relief in patients with knee osteoarthritis. Simultaneous intra-articular corticosteroid (CS) knee injections may be beneficial for the ~80-90% of patients who present with, or develop, bilateral knee osteoarthritis, but concurrent injections may increase systemic CS exposure and data on safety/tolerability are lacking. Triamcinolone acetonide extended release (TA-ER) has shown decreased systemic triamcinolone acetonide exposure compared with traditional triamcinolone acetonide crystalline suspension (TAcs) after a single knee injection in patients with knee osteoarthritis. This phase IIa study was designed to assess the safety and systemic triamcinolone acetonide exposure following injections of TA-ER or TAcs into each knee of patients with bilateral knee osteoarthritis.MethodsPatients (⩾40 years) meeting American College of Rheumatology criteria for knee osteoarthritis in both knees received concurrent single intra-articular injections of TA-ER 32 mg or TAcs 40 mg into each knee (total: 64 mg and 80 mg, respectively) and were followed for 6 weeks. Safety was evaluated based on treatment-emergent adverse events (TEAEs). Blood samples for pharmacokinetic analysis were collected pre-injection, and at the following postinjection time points: 1, 2, 3, 4, 5, 6, 8, 10, 12, and 24 h, and days 8, 15, 29, and 43.ResultsBaseline characteristics were balanced between patients randomly assigned to TA-ER (n = 12) or TAcs (n = 12). Both treatments were well tolerated with comparable TEAE profiles. Peak plasma triamcinolone acetonide concentrations (Cmax) were lower following bilateral TA-ER injections [geometric mean, 2277.7 pg/ml (95% CI, 1602.13-3238.04)] compared with bilateral TAcs injections [7394.7 pg/ml (2201.06-24,843.43)], with median times to Cmax (Tmax) of 4.5 and 6.5 h, respectively.ConclusionsIn patients with bilateral knee osteoarthritis, intra-articular injection of TA-ER into both knees was well tolerated. Consistent with pharmacokinetic profiles observed after a single knee injection, plasma triamcinolone acetonide concentrations were lower after bilateral TA-ER injections compared with the higher and more variable concentrations observed after bilateral TAcs injections.Clinicaltrialsgov identifierNCT03378076.
| S-EPMC6796206 | biostudies-literature
Project description:This report describes a dog diagnosed with insertional biceps tendinopathy that was palliated with intra-articular triamcinolone acetonide injections. The patient was a 6-year-old spayed female Chihuahua dog that had left thoracic limb lameness for 3 months before presentation. On physical examination, moderate pain was elicited by performing the biceps test and isolated full elbow extension on the left thoracic limb. Gait analysis showed asymmetrical peak vertical force and vertical impulse between thoracic limbs. Computed tomography (CT) revealed enthesophyte formation on the ulnar tuberosity of the left elbow joint. Ultrasonography showed a heterogeneous fibre pattern at the biceps tendon insertion site on the left elbow joint. These findings confirmed insertional biceps tendinopathy based on physical examination, CT and ultrasonography results. The dog received an intra-articular triamcinolone acetonide injection with hyaluronic acid in the left elbow joint. Clinical signs improved after the first injection, including a range of motion, pain and gait. A second injection was given in the same manner because of recurring mild lameness 3 months later. No clinical signs were observed during the follow-up period.
| S-EPMC10357282 | biostudies-literature
Project description:Background and purposeCorticosteroids such as triamcinolone acetonide (TAA) are potent drugs administered intra-articularly as an anti-inflammatory therapy to relieve pain associated with osteoarthritis (OA). However, the ability of early TAA intervention to mitigate OA progression and modulate immune cell subsets remains unclear. Here, we sought to understand the effect of early intra-articular injection of TAA on OA progression, local macrophages, and peripheral blood monocytes.Experimental approachDegenerative joint disease was induced by intra-articular injection of collagenase into the knee joint of male C57BL/6 mice. After 1 week, TAA or saline was injected intra-articularly. Blood was taken throughout the study to analyse monocyte subsets. Mice were killed at days 14 and 56 post-induction of collagenase-induced OA (CiOA) to examine synovial macrophages and structural OA features.Key resultsThe percentage of macrophages relative to total live cells present within knee joints was increased in collagenase- compared with saline-injected knees at day 14 and was not altered by TAA treatment. However, at day 56, post-induction of CiOA, TAA-treated knees had increased levels of macrophages compared with the knees of untreated CiOA-mice. The distribution of monocyte subsets present in peripheral blood was not altered by TAA treatment during the development of CiOA. Osteophyte maturation was increased in TAA-injected knees at day 56.Conclusion and implicationsIntra-articular injection of TAA increases long-term synovial macrophage numbers and osteophytosis. Our findings suggest that TAA accentuates the progression of osteoarthritis-associated features when applied to an acutely inflamed knee.
| S-EPMC9305889 | biostudies-literature
Project description:BACKGROUND:Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs. METHODS:In this Phase-3, multicenter, double-blinded, 24-week study, adults ?40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ?5 and ?9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit. RESULTS:The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: -3.12 versus -2.14; p < 0.0001) indicating ?50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ? 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments. CONCLUSIONS:FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point). LEVEL OF EVIDENCE:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
| S-EPMC5916484 | biostudies-literature
Project description:IntroductionOsteoarthritis (OA) is common and its prevalence is increased in military service members. In a phase 3 randomized controlled trial (NCT02357459), a single intra-articular injection of an extended-release formulation of triamcinolone acetonide (TA-ER) in participants with unilateral or bilateral knee OA demonstrated substantial improvement in pain and symptoms. Bilateral knee pain has emerged as a confounding factor in clinical trials when evaluating the effect of a single intra-articular injection. Furthermore, unilateral disease is frequently first to emerge in active military personnel secondary to prior traumatic joint injury. In this post hoc analysis, we assessed efficacy and safety of TA-ER in a subgroup of participants with unilateral knee OA.MethodsParticipants ≥ 40 years of age with symptomatic knee OA were randomized to a single intra-articular injection of TA-ER 32 mg, TA crystalline suspension (TAcs) 40 mg, or saline-placebo. Average daily pain (ADP)-intensity and rescue medication use were collected at each of weeks 1-24 postinjection; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), WOMAC-B (stiffness), WOMAC-C (function), and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QoL) were collected at weeks 4, 8, 12, 16, 20, and 24 postinjection. Adverse events (AEs) were assessed throughout the study. Participants with unilateral knee OA were selected for this analysis.ResultsOf 170 participants with unilateral OA (TA-ER, N = 51; saline-placebo, N = 60; TAcs, N = 59), 42% were male and 89% were white. TA-ER significantly (p < 0.05) improved ADP-intensity vs. saline-placebo (weeks 1-24) and TAcs (weeks 4-21). TA-ER significantly (p < 0.05) improved WOMAC-A vs. saline-placebo (all time points) and TAcs (weeks 4, 8, 12, 24). Consistent outcomes were observed for rescue medication, WOMAC-B, WOMAC-C, and KOOS-QoL. AEs were similar in frequency/type across treatments.ConclusionTA-ER provided 5-6 months' pain relief that consistently exceeded saline-placebo and TAcs, suggesting that TA-ER injected intra-articularly into the affected knee may be an effective non-opioid treatment option. Although the participants included in this analysis did not fully represent the diverse demographics of active service members, the substantial unmet medical need in the military population suggests that TA-ER may be an important treatment option; additional studies of TA-ER in active military patients are needed.Trial registrationClinicalTrials.gov NCT02357459.FundingFlexion Therapeutics, Inc. Plain language summary available for this article.
| S-EPMC6824457 | biostudies-literature
Project description:ObjectiveApproximately 30% of patients with type 2 diabetes mellitus have knee osteoarthritis. IA corticosteroids used to manage osteoarthritis pain can elevate blood glucose in these patients. We compared blood glucose levels following intra-articular injection of triamcinolone acetonide extended-release (TA-ER), an extended-release, microsphere-based triamcinolone acetonide formulation, vs standard triamcinolone acetonide crystalline suspension (TAcs) in patients with knee osteoarthritis and comorbid type 2 diabetes.MethodsIn this double-blind, randomized, parallel-group, phase 2 study (NCT02762370), 33 patients with knee osteoarthritis (American College of Rheumatology criteria) and type 2 diabetes mellitus (HbA1c 6.5-9.0% [48-75 mmol/mol]; 1-2 oral hypoglycaemic agents) were treated with intra-articular TA-ER (32 mg n = 18) or TAcs 40 mg (n = 15). Continuous glucose monitoring-measured glucose (CGMG) was assessed from 1 week pre-injection through 2 weeks postinjection. Endpoints included change in average daily CGMG from baseline (days -3 to -1) to days 1-3 postinjection (CGMGdays1-3) (primary) and percent time average hourly CGMG levels remained in prespecified glycaemic ranges.ResultsThe change CGMGdays1-3 was significantly lower following TA-ER vs TAcs (14.7 vs 33.9 mg/dl, least-squares-mean-difference [95% CI]: -19.2 [-38.0, -0.4]; P = 0.0452). The percentage of time over days 1-3 that CGMG was in the target glycaemic range (70-180 mg/dl) was numerically greater for TA-ER (63.3%) vs TAcs (49.7%), and that CGMG was >180 mg/dl was lower for TA-ER (34.5%) vs TAcs (49.9%). Non-glycaemic adverse events were mild and comparable between groups.ConclusionTA-ER may enable intra-articular corticosteroid treatment with minimal blood glucose disruption in patients with knee osteoarthritis and type 2 diabetes mellitus.Trial registrationClinicalTrials.gov, https://clinicaltrials.gov, NCT02762370.
| S-EPMC6256333 | biostudies-literature
Project description:IN THE CRYSTAL STRUCTURE OF THE TITLE COMPOUND [SYSTEMATIC NAME: 2-(4b-fluoro-5-hy-droxy-4a,6a,8,8-tetra-methyl-2-oxo-2,4a,4b,5,6,6a,9a,10,10a,10b,11,12-dodeca-hydro-7,9-dioxa-penta-leno[2,1-a]phenanthren-6b-yl)-2-oxoethyl acetate], C(26)H(33)FO(7), the mol-ecules are connected by inter-molecular O-H⋯O hydrogen bonds into an infinite supra-molecular chain along the b axis. The mol-ecular framework consists of five condensed rings, including three six-membered rings and two five-membered rings. The cyclo-hexa-2,5-dienone ring is nearly planar [maximum deviation = 0.013 (3) Å], while the cyclo-hexane rings adopt chair conformations. The two five-membered rings, viz. cyclo-pentane and 1,3-dioxolane, display envelope conformations.
| S-EPMC3051574 | biostudies-literature
Project description:Objectives: To describe and compare the use and effectiveness of a single intra-articular injection (IA) of triamcinolone acetonide (TA), hyaluronan (HA), and a combination of both (TA+HA) in police working dogs with natural occurring hip osteoarthritis (OA). Study Design: Prospective, randomized, single-blinded study. Sample Population: Thirty animals with naturally occurring hip OA. Methods: Animals were randomly divided in three groups: GT, treated with 20 mg of TA per hip joint; GH, treated with treated 20 mg of HA per hip joint; and GTH, treated with a combination of 20 mg of TA and 20 mg of HA per hip joint. Response to treatment, measured by the Canine Brief Pain Inventory (divided in Pain Interference Score-PIS and Pain Severity Score-PSS) and the Hudson Visual Analog Scale (HVAS), was evaluated in seven different time points: T0 (before treatment), T1 (after 15 days), T2, T3, T4, T5, and T6 (after 1, 2, 3, 4, and 5 months, respectively). Results were compared using a Kruskal-Wallis test or a Wilcoxon signed ranks test, and p < 0.05 was set. Results: Comparing results of the different time points considered with T0, significant differences were registered in GH at T1 for HVAS (p = 0.03) and PIS (p = 0.04); and in GTH at T1 (p = 0.05 for HVAS and p < 0.05 for PIS), T2 (p < 0.04 for PIS), T3 (p < 0.03 for HVAS and p = 0.05 for PIS), T4 (p < 0.03 for HVAS and p < 0.05), and T5 (p < 0.05 for HVAS). No significant differences were found between groups when comparing scores in each time point. Individual treatment is considered successful with a reduction of ≥1 for PSS or ≥2 for PIS. In GTH, treatment was successful in four animals between T1 and T5 (40%, n = 10) and three at T6-T7 (30%, n = 10) for PSS and three animals of GTH at T1 (30%), two at T2 (20%), three between T3 and T4 (30%), and two between T5 and T7 (20%). Conclusions and Clinical Relevance: This study provides direct information on the use of these treatment modalities in patients with hip OA. Intra-articular injection with TA and HA may be a treatment option for dogs with naturally occurring OA, particularly when simultaneously used, as they provide significant improvements of PIS and HVAS scores. Individual scores improved in some animals with PIS, PSS, and HVAS.
| S-EPMC7690322 | biostudies-literature