Intra-articular Dose Research Articles

Pharmacokinetics of amikacin after intravenous, intra-articular, and combined intravenous and intra-articular administration in healthy neonatal foals.

Pharmacokinetics of amikacin administered IV to neonatal foals are described, but little data are available regarding the plasma concentrations contributed by concurrent intra-articular (IA) administration. Compare the pharmacokinetics of amikacin when the total dose is administered IV compared to being divided between IV and IA routes of administration in neonatal foals and predict the plasma concentrations from various combined IV and IA dosing regimens. Eight healthy neonatal foals. Foals received 3 amikacin treatment protocols: (1) IV-only (25 mg/kg q24h IV), (2) concurrent IV and IA (16.7 mg/kg q24h IV and 8.3 mg/kg q24h into 1 tarsocrural joint), and (3) IA-only (8.3 mg/kg q24h into 1 tarsocrural joint). Protocols were administered for 3 days beginning at 7, 14, and 21 days of age. Plasma concentrations ≥53 μg/mL at 30 minutes were considered therapeutic for isolates with intermediate susceptibility. Foal age was a significant variable. The IV-only protocol met or exceeded the 30-minute plasma concentrations considered therapeutic (mean μg/mL [95% confidence interval, CI]) in 7- to 9-day-old (54.0 [52.2-56.9]), 14- to 16-day-old (58.1 [55.2-61.0]), and 21- to 23-day-old (66.6 [63.7-69.6]) foals. Concurrent IV and IA protocol did not reach the 30-minute concentration considered therapeutic in 7- to 9-day-old foals (46.5 [43.6-49.4]) but did in 14- to 16-day-old (62.9 [60.0-65.8]) and 21-to 23-day-old (62.6 [59.7-65.6]) foals. Concurrent IV and IA administration of amikacin produces 30-minute plasma concentrations considered therapeutic in foals 14 to 23 days old, but concentrations observed in younger foals might be below those considered therapeutic for isolates with intermediate susceptibility to amikacin.

The effect of low dose intra-articular S(+) ketamine on osteoarthritis in rats: an experimental study

BackgroundThis study aimed to investigate the analgesic impact of S(+)-ketamine on pain behavior and synovial inflammation in an osteoarthritis (OA) model. MethodsAnimals were grouped as follows: OA-Saline (n = 24) and OA-Ketamine (n = 24), OA induced via intra-articular sodium monoiodoacetate (MIA); a Non-OA group (n = 24) served as the control. On the 7th day post OA induction, animals received either saline or S(+)-ketamine (0.5 mg.kg−1). Behavioral and histopathological assessments were conducted up to day 28. ResultsS(+)-ketamine reduced allodynia from day 7 to 28 and hyperalgesia from day 10 to 28. It notably alleviated weight distribution deficits from day 10 until the end of the study. Significant walking improvement was observed on day 14 in S(+)-ketamine-treated rats. Starting on day 14, OA groups showed grip force decline, which was countered by S(+)-ketamine on day 21. However, S(+)-ketamine did not diminish synovial inflammation. ConclusionLow Intra-articular (IA) doses of S(+)-ketamine reduced MIA-induced OA pain but did not reverse synovial histopathological changes. IRB approval number23115 012030/2009-05.

Predictive factors for response to viscosupplementation in patients with knee osteoarthritis: an analysis of clinical and imaging factors

IntroductionDespite the widespread use of viscosupplementation in the treatment of knee arthritis, the factors that may influence its effectiveness or failure are still controversial and little explored in the literature. ObjectiveTo identify clinical, radiographic, and magnetic resonance imaging (MRI) predictive factors associated with viscosupplementation failure in the treatment of knee osteoarthritis. DesignIn this prospective study, patients with knee osteoarthritis were evaluated for predictive factors before the intervention, including radiographic images (KL classification and femorotibial angle), magnetic resonance images (MRI) Osteoarthritis Knee Score (MOAKS) and meniscal extrusion), joint effusion, BMI, previous surgery, sex, and age. All patients received a single intra-articular dose of Synolis-VA® 4 ml (80 mg hyaluronic acid + 160 mg sorbitol). The WOMAC, VAS, and SF-12v2 questionnaires were administered at baseline, fifteen days, three months, and six months of clinical follow-up. ResultsThe results showed a significant reduction in WOMAC and VAS scores for all evaluated times after viscosupplementation compared to baseline. Using the OMERACT-OARSI criteria, 53 patients were classified as the "success group" and 55 patients as the "failure group." The KL classification and MOAKS score showed a significant difference between these two groups, p = 0.042 and p = 0.009, respectively. Univariate logistic regression analysis revealed that a KL classification of 3 or 4 and MOAKS score predicted a higher risk of failure. ConclusionPatients with a KL classification of 3 or 4 or a high MOAKS score were more likely to fail viscosupplementation, while the other analyzed factors showed no significant difference.

Effects of Diclofenac Etalhyaluronate (SI-613/ONO-5704) on Cartilage Degeneration in Arthritic Rats and Inflammatory Cytokine-Stimulated Human Chondrocytes.

Cartilage degeneration is a key feature of osteoarthritis (OA) and rheumatoid arthritis and is thought to negatively impact patients' quality of life. Diclofenac etalhyaluronate (DEH, SI-613/ONO-5704) is a hyaluronic acid (HA) derivative chemically bound to diclofenac (DF) that has been reported to improve OA symptoms; however, its effect on cartilage degeneration remains unknown. In the present study, we investigated the chondroprotective effect of DEH in rats with collagen-induced arthritis and interleukin-1β-stimulated human chondrocytes. Rats with collagen-induced arthritis were administered DEH and HA intra-articularly, and DF orally. Knee joint swelling, histological scores of articular cartilage, and inflammatory (Il1b) and catabolic (Mmp3 and Mmp13) gene expression in the synovial tissue and cartilage were evaluated. In vitro direct effects of DEH on matrix metalloproteinase (MMP)-3 and MMP-13 expression were examined in interleukin-1β-stimulated human chondrocytes. In a rat model of collagen-induced arthritis, a single intra-articular dose of DEH inhibited knee joint inflammation and cartilage degeneration. Daily oral administration of DF had similar effects. Conversely, HA administered as a single intra-articular dose had no effect. Only DEH inhibited Mmp3 gene expression in the cartilage, whereas DEH and DF inhibited Mmp3 and Mmp13 mRNA expression in the synovial tissue. In interleukin-1β-stimulated human chondrocytes, DEH and HA inhibited MMP-3 and MMP-13 production, whereas DF had no effect. In this study, we demonstrated the chondroprotective effect of DEH in rats with collagen-induced arthritis and in interleukin-1β-stimulated human chondrocytes. Thus, DEH may suppress cartilage degeneration in patients with musculoskeletal diseases, such as OA.

Intra-articular triamcinolone acetonide injection results in increases in systemic insulin and glucose concentrations in horses without insulin dysregulation.

Corticosteroids are a commonly used, inexpensive intra-articular treatment for osteoarthritis which may increase the risk for laminitis in horses due, in part, to hyperinsulinaemia. Humans with metabolic syndrome experience increases in insulin and glucose concentrations post-injection, but responses in horses are unknown. To determine the effect of a single intra-articular (IA) dose of triamcinolone acetate (TA) on blood insulin and glucose concentrations. Before-after study. Ten horses with normal insulin regulation as assessed by an oral sugar test received 18 mg of TA into one middle carpal joint. Insulin and glucose concentrations were evaluated at baseline and 4, 6, 8, 24, 48, and 72 h following IA corticosteroid injection. Differences from baseline were evaluated using a repeated measures ANOVA with Dunnett's multiple comparison testing or a Friedman test with Dunn's correction (significant at p < 0.05). Mean ± SD blood insulin concentration post IA TA injection was increased at 6 h (15.8 ± 3.1 μIU/mL, p = 0.01), 24 h (23 ± 5.8 μIU/mL, p ≤ 0.001), and 48 h (29 ± 13 μIU/mL, p ≤ 0.01) compared to baseline (10 ± 12.3 μIU/mL), with the peak at 48 h. Median ± 95% CI blood glucose concentration post IA TA injection was increased at 6 h (112.7 ± 20.3 mg/dL, p = 0.006), 8 h (112.9 ± 21.4 mg/dL, p = 0.004), 24 h (122.6 ± 14.6, p ≤ 0.0001), and 48 h (123.5 ± 15.4 mg/dL, p ≤ 0.0001) compared to baseline (89.2 ± 6.6 mg/dL), with the peak at 48 h. Only horses with normal insulin regulation were evaluated. Blood insulin and glucose concentrations modestly increased for 48 h following IA TA.

19 Effects of recombinant equine intra-articular IL-1 on synovial fluid PGE2 and movement asymmetry: A pilot study

Synovitis is a common feature of osteoarthritis (OA). Exogeneous intra-articular inflammatory compounds such as lipopolysaccharide or interleukin 1β (human or equine) produce a convenient, self-limiting, and reversible synovitis in horses, which can be useful to evaluate putative OA interventions. Although biochemical responses to this minimally invasive synovitis model have been described, its effects on functional adaptations in movement remains unclear. The aim of this pilot study was to correlate synovial fluid biochemical responses to intra-articular injection of recombinant equine IL-1b (IL-1) with objective measures of movement asymmetry. Horses (n = 3) randomly received 0, 50 or 75ng reIL-1 in 500μL of sterile saline into the left or right intercarpal joint in a 3-way crossover design, with 50 and 75ng treatments applied to the contralateral carpus and 24 h between treatments. Synovial fluid was collected by aseptic arthrocentesis at 0 (before IL-1 injection), 6, 12 and 24 h after IL-1 injection and analyzed for prostaglandin E2 (PGE2) by ELISA. To quantify movement asymmetry, MinDiff was calculated using withersvertical displacement data (2000 Hz) acquired from an inertial measurement unit (IMU) (Delsys Trigno) during in-hand trot trials at each time point/condition. PGE2 and MinDiff data were analyzed using 2-way repeated measures ANOVA with respect to IL-1 challenge dose and time. Correlations between variables were determined using the Spearman correlation. PGE2 significantly increased at 6 h (314.4 ± 136.4 pg/mL) compared with 0 h (128.0 ± 43.2 pg/mL) following challenge with 75ng IL-1 (P = 0.04). An increase in MinDiff 6 h following 75ng challenge was not significant (P = 0.13). MinDiff and PGE2 peaked simultaneously at 6 h after injection of 75ng IL-1, but the correlation was not significant (P = 0.27). Data from this small pilot study indicate that low intra-articular dose of reIL-1b induces measurable increase in local synovial fluid PGE2, which is a key pro-inflammatory biomarker. Effects on adaptations in gait asymmetry warrant further investigation.

Pharmacokinetics and pharmacodynamics of intra-articular isoflupredone following administration to horses with lipopolysaccharide-induced synovitis

BackgroundIntra-articular corticosteroids, such as isoflupredone acetate, are commonly used in the treatment of joint inflammation, especially in performance horses. Following administration in a non-inflamed joints blood concentrations of isoflupredone were low and detectable for only a short period of time post-administration compared to synovial fluid concentrations. For some drugs, inflammation can affect pharmacokinetics, therefore, the goal of the current study was to describe the pharmacokinetics of isoflupredone acetate following intra-articular administration using a model of acute synovitis. Secondarily, pharmacodynamic effects, including effects on joint circumference, joint flexion, and lameness following intra-articular administration of isoflupredone acetate in the experimental model were described.MethodsSixteen horses received a single intra-articular dose of 8 mg of isoflupredone acetate or saline 12 h post-administration of lipopolysaccharide. Blood and urine samples were collected up to 72 h and synovial fluid for 28 days post-administration, drug concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Joint circumference, maximum angle of pain free joint flexion and lameness were evaluated prior to and post-treatment.ResultsThe maximum isoflupredone plasma concentration was 2.45 ± 0.61 ng/mL at 2.5 ± 0.75 h and concentrations were less than the limit of quantitation by 72 h. Isoflupredone was below detectable concentrations in urine by 72 h post-administration in all horses and no longer detectable in synovial fluid by 96 h post-administration. Joint circumference was significantly decreased in the isoflupredone treatment group compared to the saline group at 24 and 48 h post drug administration. Pain free joint flexion was significantly different between the saline and isoflupredone treatment groups on day 4 post-treatment.ConclusionsSynovial fluid concentrations and maximum plasma concentrations of isoflupredone differed slightly between the current study and a previous one describing administration into a non-inflamed joint, however, the detection time of isoflupredone in blood was comparable. Effects of isoflupredone on joint circumference and degree of pain free joint flexion suggest a short duration of effect with respect to alleviation of lipopolysaccharide induced synovitis, however, results of this study support future studies of the anti-inflammatory effects of intra-articular isoflupredone acetate.

Weakness After an Intraarticular Steroid Injection: A Case Report of Acute Steroid-Induced Myopathy

Introduction: Weakness is a common chief complaint in the emergency department, and the use of glucocorticoids is pervasive in medicine. Muscle weakness, or myopathy, is a well documented side effect of chronic glucocorticoid use. However, acute myopathy, with an onset shortly after initiation of glucocorticoids, is much rarer. Case Report: We present a case of acute steroid-induced myopathy after a single intra-articular dose of triamcinolone in a young, healthy, active male. To our knowledge, this is the first case described in the medical literature of acute steroid-induced myopathy following a single intra-articular injection. Conclusion: In a patient who presents with proximal muscle weakness and has a history of glucocorticoid use, the diagnosis of steroid-induced myopathy should be considered. Acute steroid-induced myopathy should be high on the differential in a patient who presents with typical symptoms and has been prescribed glucocorticoids for less than 14 days or, in rare cases, may have recently received a single dose of glucocorticoids. Treatment is supportive and outpatient management is typically indicated, as respiratory muscle involvement is rare.

Weakness After an Intra-articular Steroid Injection: A Case Report of Acute Steroid-induced Myopathy.

IntroductionWeakness is a common chief complaint in the emergency department, and the use of glucocorticoids is pervasive in medicine. Muscle weakness, or myopathy, is a well documented side effect of chronic glucocorticoid use. However, acute myopathy, with an onset shortly after initiation of glucocorticoids, is much rarer.Case ReportWe present a case of acute steroid-induced myopathy after a single intra-articular dose of triamcinolone in a young, healthy, active male. To our knowledge, this is the first case described in the medical literature of acute steroid-induced myopathy following a single intra-articular injection.ConclusionIn a patient who presents with proximal muscle weakness and has a history of glucocorticoid use, the diagnosis of steroid-induced myopathy should be considered. Acute steroid-induced myopathy should be high on the differential in a patient who presents with typical symptoms and has been prescribed glucocorticoids for less than 14 days or, in rare cases, may have recently received a single dose of glucocorticoids. Treatment is supportive and outpatient management is typically indicated, as respiratory muscle involvement is rare.

Intra-articular administration of vancomycin and tobramycin during primary cementless total knee arthroplasty : determination of intra-articular and serum elution profiles.

Intra-articular administration of antibiotics during primary total knee arthroplasty (TKA) may represent a safe, cost-effective strategy to reduce the risk of acute periprosthetic joint infection (PJI). Vancomycin with an aminoglycoside provides antimicrobial cover for most organisms isolated from acute PJI after TKA. However, the intra-articular doses required to achieve sustained therapeutic intra-articular levels while remaining below toxic serum levels is unknown. The purpose of this study is to determine the intra-articular and serum levels of vancomycin and tobramycin over the first 24 hours postoperatively after intra-articular administration in primary cementless TKA. A prospective cohort study was performed. Patients were excluded if they had poor renal function, known allergic reaction to vancomycin or tobramycin, received intravenous vancomycin, or were scheduled for same-day discharge. All patients received 600 mg tobramycin and 1 g of vancomycin powder suspended in 25 cc of normal saline and injected into the joint after closure of the arthrotomy. Serum from peripheral venous blood and drain fluid samples were collected at one, four, and 24 hours postoperatively. All concentrations are reported in µg per ml. A total of 22 patients were included in final analysis. At one, four, and 24 hours postoperatively, mean (95% confidence interval (CI)) serum concentrations were 2.4 (0.7 to 4.1), 5.0 (3.1 to 6.9), and 4.8 (2.8 to 6.9) for vancomycin and 4.9 (3.4 to 6.3), 7.0 (5.8 to 8.2), and 1.3 (0.8 to 1.8) for tobramycin; intra-articular concentrations were 1,900.6 (1,492.5 to 2,308.8), 717.9 (485.5 to 950.3), and 162.2 (20.5 to 304.0) for vancomycin and 2,105.3 (1,389.9 to 2,820.6), 403.2 (266.6 to 539.7), and 98.8 (0 to 206.5) for tobramycin. Intra-articular administration of 1 g of vancomycin and 600 mg of tobramycin as a solution after closure of the arthrotomy in primary cementless TKA achieves therapeutic intra-articular concentrations over the first 24 hours postoperatively and does not reach sustained toxic levels in peripheral blood. Cite this article: Bone Joint J2021;103-B(11):1702-1708.

Administration of an adeno-associated viral vector expressing interferon-β in patients with inflammatory hand arthritis, results of a phase I/II study

Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA. In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3×1012-1.2×1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations. Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose. Single IA doses of 0.6×1012 or 1.2×1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. NCT02727764.

Treatment response in dogs with naturally occurring grade 3 elbow osteoarthritis following intra-articular injection of 117mSn (tin) colloid

The radionuclide 117mSn (tin-117m) embedded in a homogeneous colloid is a novel radiosynoviorthesis (RSO) device for intra-articular (IA) administration to treat synovial inflammation and mitigate osteoarthritis (OA) in dogs. A study to evaluate tin-117m colloid treatment response in dogs with OA was conducted at two centers, the School of Veterinary Medicine at Louisiana State University, and at a referral practice in Houston, Texas. The tin-117m colloid was administered per-protocol to 14 client-owned dogs with radiographically confirmed, grade 3 OA in one or both elbow joints. Dog owners and attending clinicians assessed the level of pain at baseline (BL) and the post-treatment pain response at 90-day intervals for one year. Owners assessed treatment response according to a pain severity score (PSS) and a pain interference score (PIS) as defined by the Canine Brief Pain Inventory. Clinicians reported a lameness score using a 0-5 scale, from no lameness to continuous non-weight bearing lameness, when observing dogs at a walk and a trot. The rate of treatment success as determined by improved mean PSS and PIS scores reported by dog owners was >70% at all time points. Clinicians reported an improved mean pain score from BL at post-treatment Days 90 (p<0.05), 180, and 270. The dog owner and clinician assessments of treatment success were significantly correlated (p>0.05) at Day 90 and Day 180 time points. Results indicated that a single IA dose of tin-117m colloid provided a significant reduction in pain and lameness and improved functionality for up to a full year, with no adverse treatment related effects, in a high percentage of dogs with advanced, clinical OA of the elbow joint.

Population Pharmacokinetics of Intra-articular and Intravenous Administration of Tranexamic Acid in Patients Undergoing Total Knee Replacement

Tranexamic acid (TXA), an antifibrinolytic drug, is usually administered intravenously; however, intra-articular administration has recently been proven to be as effective as intravenous administration. Limited information regarding the pharmacokinetics (PK) of TXA after intra-articular administration has been reported. The aim of this study was to develop a population PK model of TXA administered as a single intra-articular dose and as two intravenous doses, and to study the sources of interindividual variability (IIV) in the PK processes of TXA. The developed model was used to simulate PK profiles of TXA at different dosage regimens and in patients with renal impairment. Patients who underwent primary unilateral total knee replacement (TKR) received 1g/10 mL (concentration of 100 mg/mL) of TXA applied directly to the surgical field before wound closure, or 2g (two doses of 1g) of intravenous TXA. A population PK model was developed using a nonlinear mixed-effects approach and sources of IIV, such as sex, age, body weight, height, body mass index (BMI), preoperative haemoglobin, preoperative haematocrit, and creatinine clearance. Twenty-four patients were included, 12 in each group. Twenty patients were female, mean age (standard deviation) was 73.7years (5.6). The disposition of TXA was best described as a two-compartment model with clearance dependent on creatinine clearance. Bootstrap results indicated that the model was stable and robust. The estimated bioavailability for intra-articular administration was 81%. Simulations indicated that 100% of patients would have plasma concentrations associated with partial fibrinolysis at 8 h post-administration with the dosages and routes of administration used in the present study. Intra-articular administration would produce complete inhibition of fibrinolysis in only 12% of patients compared with 72.5% with intravenous administration. No adverse events were reported. This population PK model demonstrated that a single dose of high-concentration, low-volume intra-articular TXA can achieve antifibrinolytic plasma concentrations of the drug for 8h, providing both local and systemic effects in patients undergoing TKR. TXA administration to the surgical field could be an alternative to the intravenous; route for patients undergoing TKR; however, clinical studies are needed to assess the toxic local effects of TXA. Spanish Clinical Studies Registry Number: 2017-004059-22. Date of registration: 12 April 2018.

Therapeutic Effects of Intra-articular Botulinum Neurotoxin Versus Physical Therapy in Knee Osteoarthritis.

BackgroundKnee osteoarthritis (KOA) is the most common cause of chronic knee pain, and disability and different modalities have been used to improve pain and function. Botulinum toxin intra-articular injection is proposed to manage resistant joint pains.ObjectivesThis study was carried out to compare therapeutic effects of intra-articular botulinum neurotoxin (BTX) versus physical therapy (PT) in KOA.MethodsIn this single-blind randomized clinical trial, patients with KOA attending to Imam-Reza Hospital, Tehran, Iran, from June 2018 to March 2019 were enrolled. Patients who met the inclusion criteria were randomly divided into BTX receiving a single intra-articular dose of 100 units (250 units from disport brand) and PT groups. The study was described for patients, and informed consent forms were received. For assessment of the pain and related severity, the VAS score and KOOS scales were used. Post-intervention assessment was done 1, 3, and 6 months after the intervention. The level of significance was set at α = 0.05. All data analyses were performed with SPSS version 26 for windows.ResultsIn this study, 50 patients were randomly divided into BTX and PT groups. All patients completed the study, and there was no loss to follow-up. There was no significant difference between demographic data of the two groups, including age and BMI. The VAS score was similar in the two groups at the beginning. KOOS subscales were not significantly different, but the quality of life was better in the BTX than the PT group (86.2 ± 15 vs. 72.1 ± 11.5, P < 0.001). One month after the intervention, all KOOS subscales were improved in the BTX group in comparison to the PT group (P < 0.001). This difference was statistically significant in the 3rd (P < 0.001 in all comparisons except Sport/Rec subscale in which P = 0.02) and 6th months (P < 0.001) after the intervention, and the improvement in all KOOS subscales and VAS score were higher in the BTX group than the PT group. The trend of KOOS subscales and VAS score was improved over time in the BTX (P < 0.001 in all tests), but the PT group showed no improvement (P > 0.05) except for Sport/Rec and VAS score (P < 0.001).ConclusionsTotally, it is concluded that the use of BTX can reduce pain and improve the function and quality of life in patients with KOA.

Intra-articular Injection of Bevacizumab Enhances Bone Marrow Stimulation–Mediated Cartilage Repair in a Rabbit Osteochondral Defect Model

Background: Bone marrow stimulation (BMS) via microfracture historically has been a first-line treatment for articular cartilage lesions. However, BMS has become less favorable because of resulting fibrocartilage formation. Previous studies have shown that angiogenesis blockade promotes cartilage repair. Bevacizumab is a Food and Drug Administration–approved medication used clinically to prevent angiogenesis. Hypothesis: The intra-articular injection of bevacizumab would prevent angiogenesis after BMS and lead to improved cartilage repair with more hyaline-like cartilage. Study Design: Controlled laboratory study. Methods: The dose of bevacizumab was first optimized in a rabbit osteochondral defect model with BMS. Then, 48 rabbits (n = 8/group/time point) were divided into 3 groups: osteochondral defect (defect), osteochondral defect + BMS (BMS group), and osteochondral defect + BMS + bevacizumab intra-articular injection (bevacizumab group). Rabbits were sacrificed at either 6 or 12 weeks after surgery. Three-dimensional (3D) micro–computed tomography (microCT), macroscope score, modified O’Driscoll histology scores, collagen type 2, Herovici staining, and hematoxylin and eosin staining were performed. Angiogenesis markers were also evaluated. Results: The intra-articular dose of 12.5 mg/0.5 mL bevacizumab was found to be effective without deleteriously affecting the subchondral bone. Intra-articular injection of bevacizumab resulted in significantly improved cartilage repair for the bevacizumab group compared with the BMS or the defect group based on 3D microCT, the macroscope score (both P < .05), the modified O’Driscoll histology score (P = .0034 and P = .019 vs defect and BMS groups, respectively), collagen type 2, Herovici staining, and hematoxylin and eosin staining at 6 weeks. Cartilage in the bevacizumab group had significantly more hyaline cartilage than did that in other groups. At 12 weeks, the cartilage layer regenerated in all groups; however, the bevacizumab group showed more hyaline-like morphology, as demonstrated by microCT, histology scores (P < .001 and .0225 vs defect and BMS groups, respectively), histology, and immunohistochemistry. The bevacizumab injection did not significantly change mRNA expressions of smooth muscle actin, vascular endothelial growth factor, or hypoxia-inducible factor-1 alpha. Conclusion: Intra-articular injection of bevacizumab significantly enhanced the quality and quantity of hyaline-like cartilage after BMS in a rabbit model. Future large-animal and human studies are necessary to evaluate the clinical effect of this therapy, which may lead to improved BMS outcomes and thus the durability of the regenerated cartilage. Clinical Relevance: The use of bevacizumab may be an important clinical adjunct to improve BMS-mediated cartilage repair.

Preclinical evaluation of methotrexate-loaded polyelectrolyte complexes and thermosensitive hydrogels as treatment for rheumatoid arthritis

This work proposes new methotrexate (MTX) loaded drug delivery systems (DDS) to treat rheumatoid arthritis via the intra-articular route: a poloxamer based thermosensitive hydrogel (MTX-HG), oligochitosan and hypromellose phthalate-based polyelectrolyte complexes (MTX-PEC) and their association (MTX-PEC-HG). MTX-PEC showed 470 ± 166 nm particle size, 0.298 ± 0.108 polydispersity index, +26 ± 2 mV and 74.3 ± 5.8% MTX efficiency entrapment and particle formation was confirmed by infrared spectroscopy and thermal analysis. MTX-HG and MTX-PEC-HG gelled at 36.7°C. MTX drug release profile was prolonged for MTX-HG and MTX-PEC-HG, and faster for MTX-PEC and free MTX. The in vivo effect of the MTX-DDSs systems was evaluated in induced arthritis rats as single intra-articular dose. The assessed parameters were the mechanical nociceptive threshold, the plasmatic IL-1β level and histological analysis of the tibiofemoral joint. MTX-HG and MTX-PEC-HG performance were similar to free MTX and worse than oral MTX, used as positive control. All DDSs showed some irritative effect, for which further studies are required. MTX-PEC was the best treatment on recovering cartilage damage and decreasing allodynia. Thus, MTX-PEC demonstrated potential to treat rheumatoid arthritis, with the possibility of decreasing the systemic exposure to the drug.

A phase 2, randomized, double-blind, placebo-controlled study of senolytic molecule UBX0101 in the treatment of painful knee osteoarthritis

Purpose: To assess the efficacy and safety of single-dose, intra-articular (IA) administration of UBX0101 in patients with painful knee osteoarthritis (OA). UBX0101 is a p53/MDM2 interaction inhibitor that can induce apoptosis of senescent synoviocytes. Results from a recent Phase 1 study (NCT03513016) suggested that IA UBX0101 had dose-dependent, clinically meaningful effects on pain and function in patients with knee OA. Methods: This was a Phase 2, randomized, double-blind, placebo-controlled, parallel group study in OA patients randomized 1:1:1:1 to IA UBX0101 0.5 mg, 2.0 mg, 4.0 mg or matched placebo. Key eligibility criteria included knee OA by ACR criteria, Kellgren-Lawrence grade (KLG) 1-4, and mean daily pain between 4 and 9 on a Numeric Rating Scale (NRS, 0-10). Study duration was 24 weeks. Clinical outcomes included WOMAC pain (WOMAC-A) and function (WOMAC-C) sub-scores (each on a 0-4 Likert scale), daily pain NRS, patient global assessment (PGA) and patient global impression of change (PGIC). The primary endpoint was the change from baseline (CFBL) in WOMAC-A at Week 12. Key secondary efficacy endpoints included the CFBL to Week 12 of the WOMAC-C and the weekly mean of the daily pain NRS scores. With 45 patients per group, the study had 90% power and an alpha of 0.10 for a two-sided comparison of UBX0101 versus placebo with an effect size of 0.50 and an assumed standard deviation of 0.75 on the WOMAC-A item score least square (LS) mean change at Week 12. Results: A total of 183 patients were randomized. The study population was balanced regarding patient characteristics and baseline outcome measure values. Mean age was 62.9 years, 64% of the population was female, and 78% was white. Mean WOMAC-A sub-score at baseline ranged between 2.05 and 2.20. Decreases in WOMAC-A from baseline to Week 12 were similar for all treatment groups. The LS means CFBL in WOMAC-A at Week 12 were -0.924, -1.52, -1.019, and -1.017 for UBX0101 0.5 mg, 2.0 mg, 4.0 mg, and placebo, respectively. Secondary endpoints were not met. An historically high placebo response through Week 12 confounded the ability to discern a UBX0101 treatment effect. Possible reasons for this were the IA dosing route, patient and/or investigator expectedness, and gender dimorphism in pain reporting. Single IA doses of UBX0101 up to 4 mg were associated with an acceptable safety profile and were well-tolerated. Most adverse events (AEs) were mild. Seven, non-related, serious AEs occurred during the study; one was a death due to coronary artery disease. Conclusions: This Phase 2 study failed to demonstrate efficacy of single IA doses of UBX0101 in patients with painful knee OA. The encouraging symptomatic improvements observed in the previous Phase 1 study were not confirmed in this well-controlled, adequately powered study.

First-in-human trial results of LNA043, a novel cartilage regenerative treatment for osteoarthritis

Purpose: LNA043 is a modified truncated human angiopoietin-like 3 (ANGPTL3) protein identified in a phenotypic screen for inducers of chondrogenesis and cartilage repair. The primary objective of this trial (NCT02491281) was to assess safety and tolerability of single intraarticular doses of LNA043 into the knee of patients with knee osteoarthritis (OA).

Divergent effects of distinct perivascular cell subsets for intra-articular cell therapy in posttraumatic osteoarthritis.

Intra-articular injection of mesenchymal stem cells has shown benefit for the treatment of osteoarthritis (OA). However, mesenchymal stem/stromal cells at the origin of these clinical results are heterogenous cell populations with limited cellular characterization. Here, two transgenic reporter mice were used to examine the differential effects of two precisely defined perivascular cell populations (Pdgfrα+ and Pdgfrβ+ cells) from white adipose tissue for alleviation of OA. Perivascular mesenchymal cells were isolated from transgenic Pdgfrα-and Pdgfrβ-CreERT2 reporter animals and delivered as a one-time intra-articular dose to C57BL/6J mice after destabilization of the medial meniscus (DMM). Both Pdgfrα+ and Pdgfrβ+ cell preparations improved metrics of cartilage degradation and reduced markers of chondrocyte hypertrophy. While some similarities in cell distribution were identified within the synovial and perivascular spaces, injected Pdgfrα+ cells remained in the superficial layers of articular cartilage, while Pdgfrβ+ cells were more widely dispersed. Pdgfrβ+ cell therapy prevented subchondral sclerosis induced by DMM, while Pdgfrα+ cell therapy had no effect. In summary, while both cell therapies showed beneficial effects in the DMM model, important differences in cell incorporation, persistence, and subchondral sclerosis were identified.

Using intra-articular allogenic lyophilized growth factors in primary knee osteoarthritis: a randomized pilot study.

Objective: Investigating the safety in addition to clinical and structural efficacy of allogenic lyophilized growth factors (L-GFs) in patients with symptomatic primary knee osteoarthritis. Design: A prospective, open-label pilot study. A total of31-patients randomized into non-interventionand intervention groups. Materials & methods: The intervention group received two intra-articular doses at baseline and after 2-months. Post-injection complications were documented, and the efficacy was assessed by Western Ontario and McMaster Universities Osteoarthritis Indexscores and ultrasonography. Results: One dropout from the intervention group. The percentage of improvement of mean Western Ontario and McMaster Universities Osteoarthritis Index-scores and ultrasonography-detected effusion were statistically significant in the intervention group compared with the non-intervention. A brief, mild, post-injection pain was reported by all intervention group. Conclusion: This study provides the safety of intra-articular injection of allogenic L-GFs in knee osteoarthritis. The conclusion of efficacy was limited by small sample size and lack of control injection. Clinical trial registration: NCT04331327 (ClinicalTrials.gov, retrospectively registered).