Prevention and management of postoperative ocular inflammation with corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) have been evaluated in several randomised controlled trials ...(RCTs). However, neither consensus regarding the efficacies of different regimens nor established guidelines are currently available. This has resulted in different practice patterns throughout the world. A systematic literature review found that for the management of postcataract inflammation nepafenac produced a positive outcome in three of three RCTs (3/3), as did ketorolac (1/1), bromfenac (7/7), loteprednol (3/3) and difluprednate (6/6), but not flurbiprofen (0/1). A single study found that betamethasone produced inconclusive results after retinal detachment (RD) surgery; ketorolac was effective (1/1) after vitrectomy, but triamcinolone was ineffective (0/1) after trabeculectomy. A two-round Delphi survey asked 28 international experts to rate both the inflammatory potential of different eye surgeries and their agreement with different treatment protocols. They rated trabeculectomy, RD surgery and combined phacovitrectomy as more inflammatory than cataract surgery. Vitrectomies for macular hole or epiretinal membrane were not deemed more inflammatory than cataract surgery. For trabeculectomy, they preferred to treat longer than for cataract surgery (NSAID + corticosteroid three times a day for 2 months vs 1 month). For vitrectomy alone, RD surgery and combined phacovitrectomy, the panel preferred the same treatment as for cataract surgery (NSAID + corticosteroid three times a day for 1 month). The discrepancy between preferred treatment and perception of the eye's inflammatory status by the experts for RD and combined vitreoretinal surgeries highlights the need for RCTs to establish treatment guidelines.
To evaluate the efficacy and safety of XG-102 (brimapitide) compared to dexamethasone eye drops in the treatment of postoperative ocular inflammation.
Multicenter, randomized, parallel group, ...double-masked, noninferiority clinical trial.
Patients who underwent anterior and posterior segments combined surgery or glaucoma surgery or complex posterior segment surgery were eligible to participate. Patients were administered a single subconjunctival injection of 250 μL XG-102 90 μg (n = 47) or 900 μg (n = 48) or placebo (n = 50) at the end of ocular surgery. Subconjunctival injection for each group (XG-102 90 μg, XG-102 900 μg, or placebo) was followed by eye drops instilled 4 times per day for 21 days with placebo, placebo, or dexamethasone solution, respectively. The primary outcome measure was anterior chamber cell grades at day 28 comparing XG-102 900 μg with dexamethasone.
The anterior cell grades for both XG-102 groups were noninferior to dexamethasone (−0.054 anterior cell grade 95% confidence interval −0.350–0.242; P < .001 for noninferiority) for XG-102 900 μg and −0.086 anterior cell grade (95% confidence interval −0.214–0.385; P = .003 for noninferiority) for XG-102 90 μg. Rescue medication was introduced for 10 (21%), 7 (15%), and 2 (4%) patients allocated to the XG-102 90 μg, XG-102 900 μg, and dexamethasone groups, respectively. The difference between XG-102 90 μg and dexamethasone was statistically significant (P = .013). The number of patients for whom adverse events were reported and the nature of the events reported was similar between the 3 treatment groups.
A single subconjunctival injection of XG-102 at the end of ocular surgery is noninferior to dexamethasone eye drops in the treatment of postoperative ocular inflammation.
We aimed to investigate the safety, tolerability, and systemic diffusion of a single escalating dose of XG-102 (a 31-D-amino-acid peptide inhibiting JNK pathway activation), administered ...subconjunctivally in the treatment of post-surgery or post-trauma intraocular inflammation.
This is a dose-escalating, tolerance Phase Ib study. Twenty patients with post-surgery or post-traumatic intraocular inflammation were assigned to 1 of the 4 dose escalating (45, 90, 450, or 900 μg XG-102) groups of 5 patients each. Patients were evaluated at 24, 48 h, 8, and 28 days following the administration of XG-102, including laboratory tests, standard eye examinations, vital signs, and occurrence of adverse events. A single plasma quantification of XG-102 was performed 30 min after administration, according to previous pharmacokinetics studies performed on volunteers.
A total of 17 non-serious adverse events, considered unrelated to the study treatment, were reported for 10 patients. The adverse event incidence was not related to the drug dose. All patients experienced a decrease in intraocular inflammation as of 24 h post-administration and this decrease was sustained up to 28 days thereafter. No patient required local injection or systemic administration of corticoids following the administration of XG-102. XG-102 was undetectable in the first 3 dose groups. In the fourth-dose group (900 μg) the XG-102 plasma levels were above the limit of detection for 3 patients and above the limit of quantification for 1 patient.
In this first clinical trial using XG-102, administered as a single subconjunctival injection as adjunct therapy, in patients with recent post-surgery or post-trauma intraocular inflammation is safe and well tolerated. Further studies are required to evaluate its efficacy.
Abstract Purpose To evaluate the efficacy and safety of XG-102 (brimapitide) compared to dexamethasone eye-drops in the treatment of post-operative ocular inflammation. Design Multicenter, ...randomized, parallel group, double-masked, non-inferiority clinical trial Patients Patients who underwent anterior and posterior segments combined surgery, or glaucoma surgery, or complex posterior segment surgery, were eligible to participate. Intervention Patients were administered a single sub-conjunctival injection of 250 μl XG-102 90 μg (N=47) or 900 μg (N=48) or placebo (N=50) at the end of ocular surgery. Sub-conjunctival injection for each group, XG-102 90μg, XG-102 900μg or placebo, is followed by eye drops instilled 4 times/day for 21 days with placebo, placebo or dexamethasone solutions, respectively. Main outcome measure The primary outcome measure was anterior chamber cells grade at day 28 comparing XG-102 900 μg with dexamethasone. Results The anterior cells grade for the XG-102 groups was non-inferior to dexamethasone (-0.054 anterior cell grade, 95% Confidence Interval (CI) -0.350 - 0.242, p for non-inferiority <0.001) for XG-102 900 μg and -0.086 anterior cell grade, 95% CI -0.214 - 0.385, p for non-inferiority=0.003 for XG-102 90 μg. Rescue medication was introduced for 10 (21%), 7 (15%) and 2 (4%) patients allocated to XG-102 90 μg, XG-102 900 μg and dexamethasone respectively. The difference between XG-102 90 μg and dexamethasone was statistically significant (p=0.013). The number of patients for whom adverse events were reported and the nature of the events reported was similar between the three treatment groups. Conclusions A single sub-conjunctival injection of XG-102 (brimapitide) at the end of ocular surgery is non-inferior to dexamethasone eye drops in the treatment of post-operative ocular inflammation.
XG-102, a TAT-coupled dextrogyre peptide inhibiting the c-Jun N-terminal kinase, was shown efficient in the treatment of experimental uveitis. Preclinical studies are now performed to determine ...optimal XG-102 dose and route of administration in endotoxin-induced uveitis (EIU) in rats with the purpose of clinical study design.
EIU was induced in Lewis rats by lipopolysaccharides (LPS) injection. XG-102 was administered at the time of LPS challenge by intravenous (IV; 3.2, 35 or 355 μg/injection), intravitreal (IVT; 0.08, 0.2 or 2.2 μg/eye), or subconjunctival (SCJ; 0.2, 1.8 or 22 μg/eye) routes. Controls received either the vehicle (saline) or dexamethasone phosphate injections. Efficacy was assessed by clinical scoring, infiltrating cells count, and expression of inflammatory mediators inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant-1 (CINC-1). The effect of XG-102 on phosphorylation of c-Jun was evaluated by Western blot.
XG-102 demonstrated a dose-dependent anti-inflammatory effect in EIU after IV and SCJ administrations. Respective doses of 35 and 1.8 μg were efficient as compared with the vehicle-injected controls, but only the highest doses, respectively 355 and 22 μg, were as efficient as dexamethasone phosphate. After IVT injections, the anti-inflammatory effect of XG-102 was clinically evaluated similar to the corticoid's effect with all the tested doses. Regardless of the administration route, the lowest efficient doses of XG-102 significantly decreased the ration of phospho c-Jun/total c-Jun, reduced cells infiltration in the treated eyes, and significantly downregulated iNOS and CINC-1 expression in the retina.
These results confirm that XG-102 peptide has potential for treating intraocular inflammation. SCJ injection appears as a good compromise to provide a therapeutic effect while limiting side effects.
To evaluate the effect of XG-102 (formerly D-JNKI1), a TAT-coupled dextrogyre peptide that selectively inhibits the c-Jun N-terminal kinase, in the treatment of endotoxin-induced uveitis (EIU).
EIU ...was induced in Lewis rats by LPS injection. XG-102 was administered at the time of LPS challenge. The ocular biodistribution of XG-102 was evaluated using immunodetection at 24 hours after either 20 microg/kg IV (IV) or 0.2 microg/injection intravitreous (IVT) administrations in healthy or uveitic eyes. The effect of XG-102 on EIU was evaluated using clinical scoring, infiltration cell quantification, inducible nitric oxide synthase (iNOS) expression and immunohistochemistry, and cytokines and chemokines kinetics at 6, 24, and 48 hours using multiplex analysis on ocular media. Control EIU eyes received vehicle injection IV or IVT. The effect of XG-102 on c-Jun phosphorylation in EIU was evaluated by Western blot in eye tissues.
After IVT injection, XG-102 was internalized in epithelial cells from iris/ciliary body and retina and in glial and microglial cells in both healthy and uveitic eyes. After IV injection, XG-102 was concentrated primarily in inflammatory cells of uveitic eyes. Using both routes of administration, XG-102 significantly inhibited clinical signs of EIU, intraocular cell infiltration, and iNOS expression together with reduced phosphorylation of c-Jun. The anti-inflammatory effect of XG-102 was mediated by iNOS, IFN-gamma, IL-2, and IL-13.
This is the first evidence that interfering with the JNK pathway can reduce intraocular inflammation. Local administration of XG-102, a clinically evaluated peptide, may have potential for treating uveitis.
The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG‐102 in a randomized, double blind, placebo controlled, sequential ascending dose ...parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG‐102 doses (10, 40, and 80 μg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG‐102 relationship. Geometric mean half‐life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG‐102 AUC0–last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized Cmax values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG‐102 single IV doses of 10–80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated.
e00020
Cardiac stem cells in the real world Pouly, Julia, MD; Bruneval, Patrick, MD; Mandet, Chantal ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
03/2008, Letnik:
135, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Objective Cardiac stem cell transplantation as a potential means of regenerating infarcted myocardium is currently receiving a great deal of interest. However, data on these endogenous cardiac ...precursors are primarily derived from animal studies, and their clinical relevance still remains elusive. Methods We prospectively screened 32 endomyocardial biopsies harvested from heart transplant recipients (off rejection episodes) and 18 right appendage biopsies collected during coronary artery bypass surgery, and processed the tissue specimens for the immunohistochemical detection of markers of stemness (c- kit , MDR-1, Isl-1), hematopoietic origin (CD45), mast cells (tryptase), endothelial cells (CD105), and cardiac lineage (Nkx2.5). Confocal microscopy was used for colocalization experiments. Three right appendage biopsies were also cultured for 2 to 3 weeks, at the completion of which c- kit –positive cells were sorted by flow cytometry. Results In endomyocardial biopsies, a median number of 2.7 (1.8–4) c- kit –positive cells/mm2 were found, and this number was even significantly smaller in right appendage biopsies (1 0.5–1.8 c- kit –positive cell/mm2 , P = .01). All of these c- kit –positive cells co-stained for CD45 and were more specifically identified as mast cells by their positive staining for the specific tryptase marker. However, none of the c- kit –positive cells expressed the markers of stemness MDR-1 and Isl-1 or colocalized with CD105. Flow cytometry confirmed the small number of c- kit –positive cells in cultured right atrial appendages. Conclusion These data raise a cautionary note on the therapeutic exploitation of cardiac stem cells in patients with ischemic cardiomyopathy, who may be the elective candidates for regenerative therapy.
Increased oxidative stress is associated with type-2 diabetes and related cardiovascular diseases, but oxidative modification of LDL has been partially characterized. Our aim was to compare the lipid ...and fatty acid composition as well as the redox status of LDL from diabetic patients and healthy subjects. First, to ensure that isolation of LDL by sequential ultracentrifugation did not result in lipid modifications, lipid composition and peroxide content were determined in LDL isolated either by ultracentrifugation or fast-protein liquid chromatography. Both methods resulted in similar concentrations of lipids, fatty acids, hydroxy-octadecadienoic acid (HODE) and malondialdehyde (MDA). Then, LDLs were isolated by ultracentrifugation from eight type-2 diabetic patients and eight control subjects. Compared to control LDL, diabetic LDL contained decreased cholesteryl esters and increased triglyceride concentrations. Ethanolamine plasmalogens decreased by 49%. Proportions of linoleic acid decreased in all lipid classes, while proportions of arachidonic acid increased in cholesteryl esters. Total HODE concentrations increased by 56%, 12- and 15-hydroxy-eicosatetraenoic acid by 161 and 86%, respectively, and MDA levels increased by twofold. α-Tocopherol concentrations, expressed relative to triglycerides, were lower in LDL from patients compared to controls, while γ-tocopherol did not differ. Overall, LDL from type-2 diabetic patients displayed increased oxidative stress. Determination of hydroxylated fatty acids and ethanolamine plasmalogen depletion could be especially relevant in diabetes.
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