Injection-site Reactions to Sustained-release Meloxicam in Sprague–Dawley Rats

An extended-release formulation of the NSAID meloxicam (MSR) is used to provide 72 h of continuous analgesia in many species, including rodents. Although standard formulations of meloxicam are frequently used in rats with no observable injection-site reactions, the potential adverse effects from MSR have not been characterized sufficiently nor has a prospective study of these effects been performed in rats. To address this deficiency, we evaluated injection-site reactions after a single subcutaneous administration of MSR (n = 16) or sterile saline (SC, n = 6) in the flank of age- and sex-matched Sprague–Dawley rats. Mass and erythema scores were measured daily for 2 wk, and injection sites were collected for histopathology after euthanasia. Rats were randomly selected for euthanasia at 7 d (n = 12) or 14 d (n = 10) after injection to capture the subacute and chronic phases of mass and erythematic lesion formation. No rats in the SC group developed lesions, whereas all 16 MSR-treated rats developed masses. The median time to first mass in the MSR treatment group was 3 d (95% CI, 2–3 d), and nearly 8 d for erythema (95% CI, 6.7–9.1 d). The trajectory of mass lesion severity showed rapid progression from score 1 at onset (day 2 or 3) to score 2 for almost all animals by day 5 or 6. Histopathology was characterized by localized inflammation with central necrosis and peripheral fibrosis, with some sections showing developing draining tracts. Given the high prevalence and severity of localized skin reactions, MSR analgesia should be considered carefully for Sprague–Dawley rats.

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Injection Reactions after Administration of Sustained-release Meloxicam to BALB/cJ, C57BL/6J, and Crl:CD1(ICR) Mice

Journal of the American Association for Laboratory Animal Science ◽

10.30802/aalas-jaalas-20-000042 ◽

2021 ◽

Author(s):

Stephanie R Fuetsch ◽

Leslie A Stewart ◽

Denise M Imai ◽

Laurel A Beckett ◽

Yueju Li ◽

...

Keyword(s):

Sustained Release ◽

Injection Site ◽

Treated Group ◽

Saline Control ◽

Point System ◽

Release Formulation ◽

Skin Reactions ◽

Sustained Release Formulation ◽

Injection Site Reactions ◽

Severity Scores

The sustained-release formulation of meloxicam (MSR) is a compounded NSAID that may provide pain relief for as longas 72 h after administration. MSR injection-site skin reactions have occurred in several species but have not previously been observed in mice. We investigated the development and progression of localized skin reactions after a single injection of MSR in Crl:CD1(ICR), C57BL/6J, and BALB/cJ mice. Each mouse received a subcutaneous injection of MSR (n = 60), standardformulation meloxicam (MEL; n = 24) or saline (control; SC; n = 24) and was scored daily according to a 5-point system for erythema and mass characteristics. Mice were euthanized at either 7 or 14 d after injection and underwent postmortem analysis.MSR-treated mice had more erythematous and mass reactions than did MEL and SC mice. Mass lesions developed in 49 MSRmice (82%; 95% CI, 70% to 90%), 5 MEL animals (21%; 95% CI, 7% to 42%), and 1 SC mouse. MSR-treated BALB/cJ developed erythematous lesions less frequently than similarly treated Crl:CD1(ICR) or C57BL/6J. Lesions often were ventrolateral to the injection site. The median times to the appearance of mass and erythematous lesions were 2 d and 3 d, respectively. Histologically, the erythematous and mass reactions correlated with necrotizing to pyogranulomatous injection-site panniculitis.Inflammation severity scores at 7 and 14 d after injection were greater in the MSR-treated group than the other 2 groups. No strain- or sex-associated differences emerged except that inflammation severity scores at day 14 were higher in Crl:CD1(ICR) females than males. The character of the inflammatory response in MSR-treated mice did not differ between 7 and 14 d after injection, indicating that MSR-induced inflammation is slow to resolve. The ventral migration and delayed onset of MSR injection-site reactions could result in their being attributed to another cause or not being identified. Researchers and clinicians should be aware of the potential for slowly resolving injection-site reactions with MSR.

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Recurrent injection‐site reactions after incorrect subcutaneous administration of a COVID‐19 vaccine

Journal of the European Academy of Dermatology and Venereology ◽

10.1111/jdv.17341 ◽

2021 ◽

Author(s):

M Gyldenløve ◽

L Skov ◽

CB Hansen ◽

P Garred

Keyword(s):

Injection Site ◽

Subcutaneous Administration ◽

Injection Site Reactions

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Repeated dose subcutaneous administration of 1E10 vaccine in Sprague–Dawley rats

Toxicology Letters ◽

10.1016/j.toxlet.2007.05.580 ◽

2007 ◽

Vol 172 ◽

pp. S230-S231

Author(s):

Yana González ◽

Ana Bada ◽

Bárbara González ◽

Osvaldo Hernández ◽

Juana Hernández ◽

...

Keyword(s):

Subcutaneous Administration ◽

Repeated Dose ◽

Sprague Dawley ◽

Sprague Dawley Rats

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Extended-release formulation of morphine for subcutaneous administration

Cancer Chemotherapy and Pharmacology ◽

10.1007/bf00686214 ◽

1993 ◽

Vol 33 (3) ◽

pp. 187-190 ◽

Cited By ~ 30

Author(s):

Taehee Kim ◽

Joon Kim ◽

Sinil Kim

Keyword(s):

Extended Release ◽

Subcutaneous Administration ◽

Release Formulation ◽

Extended Release Formulation

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Subacute Intramuscular Toxicity of the Acetylcholinesterase Reactivating Agent HI-6 in Rats and Dogs

Journal of the American College of Toxicology ◽

10.3109/10915819309140638 ◽

1993 ◽

Vol 12 (2) ◽

pp. 185-193 ◽

Cited By ~ 2

Author(s):

Barry S. Levine ◽

Michael J. Tomlinson

Keyword(s):

Injection Site ◽

Creatine Kinase Activity ◽

High Dose ◽

Sprague Dawley ◽

Hi 6 ◽

Sprague Dawley Rats ◽

High Doses ◽

Hematology Parameters ◽

Dose Levels ◽

Dose Injection

Studies herein describe the toxicity of HI-6 in Sprague-Dawley rats and Beagle dogs following i.m. injection for 14 days. Dose levels were 0, 50, 150, and 450 mg/kg/day for 10 rats/sex/dose and 0, 35, 70, and 140 mg/kg/day for 4 dogs/sex/dose. Three rats at the high dose, 2 males and 1 female, died prior to scheduled sacrifice. Reduced weight gain, decreased activity, tremors, hunched posture, and poor grooming were seen in high dose survivors. Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities at the mid and high doses suggested hepatotoxicity, although liver weights and histology were normal. Hematology parameters were unaffected except for slight, dose-related increases of platelets in both sexes. Injection site inflammation was seen; however, serum creatine kinase activity was not altered. In dogs, slight weight loss, vomiting, salivation, and diarrhea occurred at the high dose, but no deaths were observed at any of the doses. As with rats, dose-related increases in ALT and AST activities occurred at the mid and high doses, and were, in this case, accompanied at the high dose by hepatomegaly and hepatocellular vacuolization. Cardiotoxicity was evidenced by increased relative heart weights and subtle ECG changes, the latter of which occurred almost exclusively at the highest dose. Injection site inflammation, which was accompanied by dose-related elevations in serum CK-MM2 activity, was also observed.

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Resolvin D1 Reduces the Immunoinflammatory Response of the Rat Eye following Uveitis

Mediators of Inflammation ◽

10.1155/2012/318621 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 27

Author(s):

Rossi Settimio ◽

Di Filippo Clara ◽

Ferraraccio Franca ◽

Simonelli Francesca ◽

D'Amico Michele

Keyword(s):

T Lymphocytes ◽

Clinical Score ◽

Myeloperoxidase Activity ◽

Sprague Dawley ◽

Resolvin D1 ◽

Sterile Saline ◽

Sprague Dawley Rats ◽

Pmn Leukocytes ◽

Significant Release ◽

Inflammatory Profile

This study investigated whether the administration of resolvin D1 to rats with endotoxininduced uveitis (EIU) ameliorates the immuno-inflammatory profile of the eye. 24 h after the administration of 200 μg LPS into the footpad of Sprague-Dawley rats, severe changes of the structure of the eye occurred concomitantly with a severe inflammatory and immune response. These latter included strong infiltration of PMN leukocytes CD11b+T-lymphocytes CD4+and CD8+within the eye and a significant release of the cytokines/chemokines TNF-alpha, CXCL8, and RANTES too. Bolus of resolvin D1 (RvD1; 10–100–1000 ng/kg in 200 μL of sterile saline via the tail vein) significantly and dose-dependently (i) reduced the development of the ocular derangement caused by LPS; (ii) reduced the clinical score attributed to EIU; (iii) reduced the protein concentration and myeloperoxidase activity (MPO) in aqueous humor (AqH); and (iv) reduced neutrophils, T-lymphocytes, and cytokines within the eye.

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An extended-release formulation of methotrexate for subcutaneous administration

Cancer Chemotherapy and Pharmacology ◽

10.1007/s002800050057 ◽

1994 ◽

Vol 33 (4) ◽

pp. 303-306 ◽

Cited By ~ 1

Author(s):

Andrea Bonetti ◽

Etienne Chatelut ◽

Sinil Kim

Keyword(s):

Extended Release ◽

Subcutaneous Administration ◽

Release Formulation ◽

Extended Release Formulation

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Disruption of mineralocorticoid receptor function increases corticosterone responding to a mild, but not moderate, psychological stressor

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00521.2004 ◽

2005 ◽

Vol 288 (6) ◽

pp. E1082-E1088 ◽

Cited By ~ 35

Author(s):

Thaddeus W. W. Pace ◽

Robert L. Spencer

Keyword(s):

Hpa Axis ◽

Negative Feedback ◽

Glucocorticoid Receptors ◽

Feedback Regulation ◽

Sprague Dawley ◽

Negative Feedback Regulation ◽

Novel Environment ◽

Sterile Saline ◽

Sprague Dawley Rats ◽

Psychological Stressor

Glucocorticoid negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis is mediated by corticosteroid receptors. It is widely thought that during stress, glucocorticoid receptors (GR) are essential for this negative feedback. In contrast, mineralocorticoid receptors (MR) are associated with HPA axis regulation in basal, nonstress conditions. Notions about the relative roles of MR and GR for HPA axis regulation during stressor challenge may not be complete. Recent work in our laboratory suggests that previous estimates of MR occupancy at resting plasma levels of corticosterone (CORT) may be overestimated. It is possible that a significant number of MR may be available to mediate negative feedback during stressor challenge. We hypothesized that this may be especially the case during mild stressor challenge when the plasma CORT response is weak. In the present studies, adult male Sprague-Dawley rats were first treated systemically or centrally with the selective MR antagonist RU28318 (50 mg/kg sc or 500 ng·10 μl−1·2 h−1 icv) or vehicle (300 μl propylene glycol sc or 10 μl/2 h sterile saline icv) and then challenged with 60-min novel environment or restraint. In vehicle controls, restraint resulted in a greater plasma CORT response than novel environment. Both systemic and central treatment with RU28318 significantly increased CORT responding to novel environment relative to vehicle controls. However, RU28318 treatment did not increase the CORT response to restraint. These data suggest that MR may be necessary for glucocorticoid regulation of HPA axis activity during mild stressors, but not during stressors that result in a more robust CORT response.

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