A randomized controlled trial comparing non-steroidal anti-inflammatory and fusion protein inhibitors singly and in combination on the histopathology of bovine respiratory syncytial virus infection

Bovine respiratory syncytial virus (RSV) has substantial morbidity in young calves, and closely parallels human RSV in infants. We performed a randomized controlled trial in five to six-week-old Holstein calves (Bos taurus). comparing fusion protein inhibitor (FPI) and non-steroidal anti-inflammatory drug (NSAID) singly and in combination at three and five days after experimental BRSV infection. Thirty-six calves received one of six treatments; Ibuprofen started on day 3, Ibuprofen started on day 5, FPI started on day 5, FPI and Ibuprofen started on day 3, FPI and Ibuprofen started on day 5, or placebo. We have previously reported significant clinical benefits when combined FPI and NSAID treatment was started at three and five days after bovine RSV infection. Necropsy was performed on Day 10 following infection and hematoxylin and eosin staining was performed on sections from each lobe. Histology was described using a four-point scale. We performed canonical discrimination analysis (CDA) to determine the structural level where differences between treatments occurred and mixed effects regression to estimate effect sizes. Separation from placebo was maximal for dual therapy at the levels of the alveolus, septum, and bronchus in CDA. We found that the clinical benefits of combined FPI and NSAID treatment of BRSV extend at least partially from histopathological changes in the lung when treatment was started three days after infection. We found decreased lung injury when ibuprofen was started as monotherapy on day 3, but not day 5 following infection. Combined therapy with both an FPI and ibuprofen was always better than ibuprofen alone. We did not prove that the clinical benefits seen starting FPI and ibuprofen five days after infection can be solely explained by histopathological differences as identified on H&E staining.

Peculiarity of clinical course of postpericardiotomy syndrome in different methods of surgery and postoperative antithrombotic therapy

Aim To compare features of the disease course and the effectiveness of nonsteroidal anti-inflammatory drug (NSAID) treatment of postpericardiotomy syndrome (PPS) in patients after coronary bypass (CB) surgery who were treated with antiplatelet drugs and in patients after surgical correction of heart valve disease (CHVD) who received the anticoagulant warfarin for prevention of thrombotic complications. Material and methods This study included 89 patients of whom 53 patients had underwent CB and 36 patients had underwent CHVD. At 15 [13; 15] days after surgery, the severity of inflammatory response, the state of coagulation hemostasis, and hematocrit were studied. At 5 days after the first test, blood count and measurement of C-reactive protein were repeated. Echocardiography was used to determine the presence and volume of pleural effusion. For prevention of thrombotic complications, antiplatelet drugs were administered after CB and warfarin was administered after CHVD. PPS was detected in 35 (66 %) patients after CB and 18 (50 %) patients after CHVD. The ibuprofen treatment (600 mg twice a day) was administered to all patients with PPS. If positive changes in inflammatory markers were absent during the NSAID treatment, ibuprofen was replaced with prednisolone 0.5 mg/kg body weight with subsequent laboratory and instrumental monitoring. Results Patients after CHVD treated with warfarin had higher values of international normalized ratio (INR) and activated partial thromboplastin time (aPPT) and lower values of prothrombin index (PTI), fibrinogen (p<0.001 for all), hemoglobin (p=0.0016), and hematocrit (p=0,0032) than patients after CB treated with antiplatelet drugs. 21 (40 %) patients with PPS required changing the anti-inflammatory therapy from ibuprofen to prednisolone. These patients displayed hypocoagulation, which was evident as reduced PTI (p=0.0023) and fibrinogen (p=0.0209), increased INR (p=0.0291) and aPPT (p=0.0416), and a higher incidence of pericardial effusion (p=0.0080). The insufficient effectivity of NSAIDs that required administration of prednisolone was more frequently observed in patients after CHVD (61 % vs. 29 %, р=0.037).Conclusion Hypocoagulation observed in patients after CHVD due to the anticoagulant treatment with warfarin was associated with more severe course of PPS and lower effectiveness of the NSAID treatment compared to patients after CB. This results in more frequent replacement of NSAIDs with glucocorticoids in the treatment of patients after CHVD.

Clinical Phenotypes in NSAID-Induced Urticaria/Angioedema

The skin clinical phenotypes of nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity (NH) are very heterogeneous with several syndromes after NSAID intake, which include different symptoms, different organ involvement and different associated concomitant diseases and possibly different underlying pathophysiology and mechanisms. Making a correct diagnosis in NH is an exciting journey for any allergist. Thus, to classify these diseases properly will be pivotal for appropriate diagnostic and management strategy. Treatment modalities are depending on the clinical phenotypes of NH and they will embrace for each patient: the avoidance of culprit NSAID, the finding of well-tolerated NSAID and in certain cases, desensitization procedures when the NSAID treatment was absolutely needed as well as the control of associated diseases such as spontaneous chronic urticarial or allergic respiratory diseases. This review updates the recent evidence of classification, diagnostic strategies, and management of skin NSAID hypersensitivity reactions.

No Additive Clinical or Physiological Effects of Short-term Anti-inflammatory Treatment to Physical Rehabilitation in the Early Phase of Human Achilles Tendinopathy: A Randomized Controlled Trial

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the treatment of Achilles tendinopathy, but whether they have any additive clinical effect on physical rehabilitation in the early phase of tendinopathy remains unknown. Purpose/Hypothesis: To investigate whether an initial short-term NSAID treatment added to a physical rehabilitation program in the early phase of Achilles tendinopathy would have an additive effect. We hypothesized that the combination of NSAID and rehabilitation would be superior to rehabilitation alone. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 69 patients with early phase Achilles tendinopathy (lasting <3 months) were randomly assigned to either a naproxen group (7 days of treatment; 500 mg twice daily; n = 34) or a placebo group (7 days of placebo treatment; n = 35). Both groups received an identical 12-week physical rehabilitation program. The clinical outcome of the study was evaluated using the Victorian Institute of Sports Assessment–Achilles (VISA-A) questionnaire and a numerical rating scale (NRS), and the physiological outcome was evaluated using ultrasonography, magnetic resonance imaging (MRI), and ultra-short time to echo T2* mapping MRI (UTE T2* MRI). Follow-up was performed at 1 week, 3 months, and 1 year. Time effects are presented as mean difference ± SEM. Results: No significant differences were found between the 2 treatment groups for any of the outcome measures at any time point ( P > .05). For the VISA-A score, a significant time effect was observed between baseline and 3-month follow-up (14.9 ± 2.3; P < .0001), and at 1-year follow-up, additional improvements were observed (6.1 ± 2.3; P < .01). Furthermore, the change in VISA-A score between baseline and 3-month follow-up was greater in patients with very short symptom duration (<1 month) at baseline compared with patients who had longer symptom duration (>2 months) (interaction between groups, 11.7 ± 4.2; P < .01). Despite clinical improvements, total weekly physical activity remained lower compared with preinjury levels at 3 months (–2.7 ± 0.5 h/wk; P < .0001) and 1 year (–3.0 ± 0.5 h/wk; P < .0001). At baseline, ultrasonography showed increased thickness (0.12 ± 0.03 cm; P < .0001) and vascularity (0.3 ± 0.1 cm2; P < .005) on the tendinopathic side compared with the contralateral side, but no changes over time were observed for ultrasonography, MRI, or UTE T2* MRI results. Conclusion: Clinical symptoms in early tendinopathy improved with physical rehabilitation, but this improvement was not augmented with the addition of NSAID treatment. Furthermore, this clinical recovery occurred in the absence of any measurable structural alterations. Finally, clinical improvements after a physical rehabilitation program were greater in patients with very short symptom duration compared with patients who had longer symptom duration. Registration: NCT03401177 (ClinicalTrials.gov identifier) and BFH-2016-019 (Danish Data Protection Agency)

Non-steroidal anti-inflammatory drugs dampen the cytokine and antibody response to SARS-CoV-2 infection

Identifying drugs that regulate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its symptoms has been a pressing area of investigation during the coronavirus disease 2019 (COVID-19) pandemic. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently used for the relief of pain and inflammation, could modulate both SARS-CoV-2 infection and the host response to the virus. NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which mediate the production of prostaglandins (PGs). As PGs play diverse biological roles in homeostasis and inflammatory responses, inhibiting PG production with NSAIDs could affect COVID-19 pathogenesis in multiple ways, including: (1) altering susceptibility to infection by modifying expression of angiotensin-converting enzyme 2 (ACE2), the cell entry receptor for SARS-CoV-2; (2) regulating replication of SARS-CoV-2 in host cells; and (3) modulating the immune response to SARS-CoV-2. Here, we investigate these potential roles. We demonstrate that SARS-CoV-2 infection upregulates COX-2 in diverse human cell culture and mouse systems. However, suppression of COX-2 by two commonly used NSAIDs, ibuprofen and meloxicam, had no effect on ACE2 expression, viral entry, or viral replication. In contrast, in a mouse model of SARS-CoV-2 infection, NSAID treatment reduced production of pro-inflammatory cytokines and impaired the humoral immune response to SARS-CoV-2 as demonstrated by reduced neutralizing antibody titers. Our findings indicate that NSAID treatment may influence COVID-19 outcomes by dampening the inflammatory response and production of protective antibodies rather than modifying susceptibility to infection or viral replication. Importance Public health officials have raised concerns about the use of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating symptoms of coronavirus disease 2019 (COVID-19). NSAIDs inhibit the enzymes cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), which are critical for the generation of prostaglandins – lipid molecules with diverse roles in homeostasis and inflammation. Inhibition of prostaglandin production by NSAIDs could therefore have multiple effects on COVID-19 pathogenesis. Here, we demonstrate that NSAID treatment reduced both the antibody and pro-inflammatory cytokine response to SARS-CoV-2 infection. The ability of NSAIDs to modulate the immune response to SARS-CoV-2 infection has important implications for COVID-19 pathogenesis in patients. Whether this occurs in humans and whether it is beneficial or detrimental to the host remains an important area of future investigation. This also raises the possibility that NSAIDs may alter the immune response to SARS-CoV-2 vaccination.

Efficacy and safety of non-steroidal anti-inflammatory drugs for acute attack of gout

Gout is one of the most common forms of inflammatory arthritis. Medical care for gout includes non-steroidal anti-inflammatory drugs (NSAIDs). This paper reviews the efficacy and safety of NSAIDs prescribed for the acute attack of gout, in particular, AMBENIUM® parenteral. It was demonstrated that phenylbutazone is a powerful NSAID that provides significant analgesic and anti-inflammatory effects. Considering a broad spectrum of adverse reactions of NSAIDs, these agents should be prescribed and used under in-depth analysis of patient’s condition, comorbidities and the level of their decompensation, and potential drug interactions. In addition, optimal dosages and duration of NSAID treatment are of particular importance. The authors conclude that AMBENIUM® parenteral is an effective and safe therapeutic modality for gout. Its profile and risk/benefit ratio are regarded as “favorable” compared to other NSAIDs. KEYWORDS: gout, arthritis, pain, non-steroidal anti-inflammatory drugs, parenteral, efficacy, safety. FOR CITATION: Vasilyuk V.B., Syraeva G.I., Faraponova M.V. Efficacy and safety of non-steroidal anti-inflammatory drugs for acute attack of gout. Russian Medical Inquiry. 2021;5(2):96–101. DOI: 10.32364/2587-6821-2021-5-2-96-101.

Analysis of risk factors associated with recurrence of acute pericarditis in patients diagnosed in the emergency room

Background Around 5% of patients consulting to the emergency room (ER) for non-ischemic thoracic pain are diagnosed of acute pericarditis (AP). The good prognosis of this pathology is well known, with a mortality of 1% and a low incidence of serious complications, which has led the research to focus on recurrences. Female sex, corticoid treatment and treatment adherence are related with higher risk of recurrence. Colchicine has been associated with less recurrences. Purpose To analyse the factors associated with recurrence after the diagnosis of AP in the ER of a third-level hospital. Methods Retrospective review of ER consultations oriented as AP, prospectively documented during 10 years (2008–2018). In 2019, a follow up was done in order to identify the recurrences and to search for associated factors (univariate and multivariate analysis). Results 610 patients were diagnosed of AP, 175 (29%) recurrences were documented. Factors associated with an increased risk of recurrence were: previous AP, immunosuppression or history of autoimmune disease, fever or increased acute-phase reactants (CRP; ESR), hospitalization and corticoid treatment. Factors associated with less risk of recurrence were: age, non-steroidal anti-inflammatory drug (NSAID) treatment and idiopatic/viral etiology. No association with sex or colchicine treatment was identified. Multivariate analysis identified 3 factors that were independently associated with the risk of recurrence in a direct way: previous history of AP, [OR (IC95%): 2.09 (1.11–3.92)]; increased CRP [OR (IC95%): 1.09 (1.03–1.15)]; hospitalization [OR (IC95%): 2.65 (1.07–6.58)]. 2 factors were inversely associated with the risk of recurrence: age [OR (IC95%): 0.98 (0.96–0.99)]; NSAID treatment [OR (IC95%): 0.56 (0.32–0.97)]. Conclusions 29% of the patients were readmitted to the ER for an AP recurrence. Previous AP, increased CRP and the need of hospitalization were associated with a higher risk of recurrence. Age and NSAID treatment, on the other hand, were associated with less risk of recurrence. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Ajuts per la Recerca Josep Font

Ibuprofen does not Impair Skeletal Muscle Regeneration Upon Cardiotoxin-Induced Injury

Muscle regeneration is regulated through interaction between muscle and immune cells. Studies showed that treatment with supra-physiological doses of Non-Steroidal Anti-Inflammatory Drug (NSAID) abolished inflammatory signaling and impaired muscle recovery. The present study examines the effects of pharmacologically-relevant NSAID treatment on muscle regeneration. C57BL/6 mice were injected in the tibialis anterior (TA) with either PBS or cardiotoxin (CTX). CTX-injected mice received ibuprofen (CTX-IBU) or were untreated (CTX-PLAC). After 2 days, Il-1β and Il-6 expression was upregulated in the TA of CTX-IBU and CTX-PL vs. PBS. However, Cox-2 expression and macrophage infiltration were higher in CTX-PL vs. PBS, but not in CTX-IBU. At the same time, anabolic markers were higher in CTX-IBU vs. PBS, but not in CTX-PL. Nevertheless, ibuprofen did not affect muscle mass or muscle fiber regeneration. In conclusion, mild ibuprofen doses did not worsen muscle regeneration. There were even signs of a transient improvement in anabolic signaling and attenuation of inflammatory signaling.