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Adverse Effects of Nonsteroidal Antiinflammatory Drugs: An Update of Gastrointestinal, Cardiovascular and Renal Complications
Abstract
p>Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor’s files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail.
This article is open to POST-PUBLICATION REVIEW . Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.</p
... Using SAIDs may cause obesity and sodium retention, which result in serious health hazardous, including liver toxicity and gastrointestinal ulcers, the most common NSAID side effects. 1 Clinical investigations have found local adverse effects in 6.3% of participants following local administration of NSAIDs, such as irritation at the application site and itching. Several studies have reported on new drug products that improve the anti-inflammatory performance of drugs and limit their undesirable effects. ...
Introduction:
Ginger extract (GE) has sparked great interest due to its numerous biological benefits. However, it suffers from limited skin permeability, which challenges its transdermal application. The target of the current work was to develop transethosomes as a potential nanovehicle to achieve enhanced transdermal delivery of GE through the skin.
Methods:
GE-loaded transethosomes were prepared by cold injection using different edge activators. The fabricated nanovesicles were evaluated for particle size, ζ-potential, encapsulation efficiency, and in vitro drug release. The selected formulation was then laden into the hydrogel system and evaluated for ex vivo permeability and in vivo anti-inflammatory activity in a carrageenan-induced rat-paw edema model.
Results:
The selected formulation comprised of sodium deoxycholate exhibited particle size of 188.3±7.66 nm, ζ-potential of -38.6±0.08 mV, and encapsulation efficiency of 91.0%±0.24%. The developed transethosomal hydrogel containing hydroxypropyl methylcellulose was homogeneous, pseudoplastic, and demonstrated sustained drug release. Furthermore, it exhibited improved flux (12.61±0.45 μg.cm2/second), apparent skin permeability (2.43±0.008×10-6 cm/second), and skin deposition compared to free GE hydrogel. In vivo testing and histopathological examination revealed that the GE transethosomal hydrogel exhibited significant inhibition of edema swelling compared to free GE hydrogel and ketoprofen gel. The animals that were treated with ginger transethosome hydrogel showed a significant decrement in reactive oxygen species and prostaglandin E2 compared to untreated animals.
Conclusion:
Transethosomes might be a promising new vehicle for GE for effective skin permeation and anti-inflammation. To the best of our knowledge, this work is the first utilization of transethosomes laden into hydrogel as a novel transdermal delivery system of GE.
... The recent development of a portable ultrasonic device provides great convenience for LIPUS application in daily life and experimental researches [32,33]. Moreover, LIPUS would not impact the metabolic homeostasis and aggravate the liver and kidney burden in contrast to chemical treatments [6,34]. Because of its therapeutic potency, targeting ability, non-invasive feature, and convenience, LIPUS is an ideal therapy for inflammation disorders. ...
Low-intensity pulsed ultrasound (LIPUS), as a safe and potent physical therapy, has been widely used. It has been demonstrated that LIPUS could induce multiple biological effects, such as relieving pain, accelerating tissue repair/regeneration, and alleviating inflammation. A number of in vitro studies have indicated that LIPUS could significantly reduce the expression of proinflammatory cytokines. This anti-inflammatory effect has also been verified in many in vivo researches. However, the molecular mechanisms underlying LIPUS against inflammation are far from fully elucidated and may differ among different tissues and cells. Here, we review the applications of LIPUS against inflammation through different signaling pathways including nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol-3-kinase/serine/threonine kinase (PI3K/Akt), and discuss the underlying mechanisms. The positive effects of LIPUS on exosomes against inflammation and related signaling pathways are also discussed. A systematic overview of recent advances will present a deeper understanding of the molecular mechanisms of LIPUS, thus boosting our ability to optimize this promising anti-inflammatory therapy.
... They regulate the activity of cyclooxygenase enzymes COX-1 and COX2 [7][8][9]. However, the long-term use of oral NSAIDs has adverse effects on multiple organs [10][11][12], while topical NSAIDs have limited efficacy due to limited penetration through the skin [13,14]. In addition, physical therapy, while effective, is expensive and requires frequent visits to the medical facility [15]. ...
Background:
The use of long duration sonophoresis (LDS) for musculoskeletal injuries is a new and emerging treatment option for patients undergoing rehabilitation. The treatment is non-invasive, provides multi-hour mechanical stimulus expediating tissue regeneration and deep tissue heat along with local application of therapeutic compound for improved pain relief. The objective of this prospective case study was to evaluate real-world application of diclofenac LDS as an add-on intervention for patients non-responsive to physical therapy alone.
Methods:
Patient who failed to respond to at least 4 weeks of physical therapy were treated with the addition of 2.5% diclofenac LDS daily for 4 weeks. The numerical rating scale, global health improvement score, functional improvement, and treatment satisfaction index were measured to assess pain reduction and quality of life improvement from treatment. Patient outcome data was organized by injury type and patient age groups, and statistically analyzed with ANOVA to assess treatment differences within and between groups. The study was registered on clinicaltrails.gov NCT05254470.
Result:
The study included (n=135) musculoskeletal injury LDS treatments with no adverse events. Patients reported a mean pain reduction from baseline of 4.44 points (p<0.0001) and a 4.85point health improvement score after 4-week of daily sonophoresis treatment. There were no age-related differences in pain reduction, and 97.8% of patients in the study reported functional improvement with the addition of LDS treatment. Significant pain relief was observed in injuries related to tendinopathy, sprain, strain, contusion, bone fracture, and post-surgical recovery.
Conclusion:
The use of LDS significantly reduced pain and improved musculoskeletal function and quality of life for patients. Clinical findings suggest that LDS with 2.5% diclofenac is a viable therapeutic option for practitioners and should be further investigated.
... Ibuprofen, even being one of the most prescribed nonsteroidal anti-inflammatory drugs, must be administered with caution due to negative secondary effects related to dose. 32 In the designed CaSyr-1(ibu), the merging of the COX-2 anti-inflammatory activity of syringic acid and that of ibuprofen is expected to result in a positive decrease of the required dosage of ibuprofen. Moreover, the use of ibuprofen is associated with increasing blood pressure and must be excluded from patients diagnosed with hypertension, ca. ...
A facile, fast and green strategy in ethanol is utilized to prepare a new bioMOF, namely CaSyr-1 , with the particular characteristics of full biocompatibility given by using just calcium and...
Chikungunya virus (CHIKV) infection, a global public health problem, might lead to acute/chronic polyarthritis causing long term morbidity among infected patients. But, except NSAIDs (Non‐steroidal anti‐inflammatory drugs) with gastrointestinal, cardiovascular and immune‐related side‐effects, no FDA‐approved analgesic drug is available till date for treatment of CHIKV‐induced arthritis. Curcumin, a plant product with minimal toxicity has been FDA‐approved as Generally Recognized As Safe drug. This study aimed to determine analgesic and prophylactic effect of curcumin, if any, among CHIKV‐induced arthralgic mice. Arthritic pain was evaluated by von Frey assay, locomotory behavior by open‐field test, feet swelling by calipers. Cartilage integrity and proteoglycan loss was evaluated by Safranin‐O‐staining followed by OARSI (Osteoarthritis Research Society International), SMASH (Standardised Microscopic Arthritis Scoring of Histological sections) score and type II collagen loss by immuno‐histochemistry. Mice were administered High (HD), Mid (MD) and Low (LD) curcumin doses, before (PT:Pre‐treatment), during (CT:Co‐treatment) and after (Post‐T:Post‐treatment) CHIKV‐infection. Curcumin treatment using PTHD (2000mg/kg), CTHD and Post‐TMD (1000mg/kg) significantly alleviated CHIKV‐induced arthritic pain by improving pain‐threshold, locomotory behavior and reducing feet swelling of infected mice. Also, decreased proteoglycan loss and cartilage erosion with lower OARSI, SMASH scores was observed among these three sub‐groups compared to infected ones. Compared to infected ones, 1‐2‐fold increased intensity of type II collagen in knee medial femoral condyle and medial tibial plateau regions of these sub‐groups was observed by immuno‐histochemical staining. Thus, this study highlighted both analgesic (CT, Post‐T), and prophylactic (PT) activity of curcumin in alleviating CHIKV‐induced acute/chronic arthritis within mouse model. This article is protected by copyright. All rights reserved.
Objective:
To investigate the effects of mesotherapy in patients with mild to moderate knee osteoarthritis (KOA).
Methods:
The study included 43 patients (56 knees) who were randomly assigned to either the mesotherapy group (MG, n=28) or the saline group (SG, n=28) and received a total of 4 weekly mesotherapy (MG) or saline injections (SG). Pain, functional status and quality of life were evaluated by a Visual Analogue Scale (VAS), the Western Ontario Universities Osteoarthritis Index (WOMAC) and the Short Form-36 (SF-36) subscales at baseline and at 8 and 16 weeks of follow-up.
Results:
A total of 39 patients (52 knees) completed the study. Eight weeks after treatment, a significant improvement was found in VAS pain scores, WOMAC scores and physical component scores (PCS) of the SF-36 in both groups compared to baseline (p<0.05). The VAS activity pain score, WOMAC-pain, WOMAC-physical function and WOMAC-total scores were found to have decreased significantly in the MG compared to the SG (p<0.001) at both 8 weeks and 16 weeks. The PCS scores significantly improved in the MG compared to the SG at 8- and 16-week follow-ups (p<0.001 and p<0.001, respectively).
Conclusions:
Mesotherapy is a well-tolerated, safe and effective alternative treatment option in patients with mild and moderate KOA.
A rapid rise in industrialization has led to the release of pharmaceutical pollutants into water bodies, rendering water inappropriate for consumption by humans and animals, challenging our efforts to achieve the clean water sustainable development goal. These pharmaceutical pollutants include antibiotics, anticancer drugs, antidepressants, etc., which are highly stable and persistent in water, in addition to being harmful to life. At times, the secondary pollutant that is formed after degradation is more potent than the parent drug. Conventional water purification methods cannot completely remove these pollutants. Hence, efficient and robust methods are required to degrade pharmaceutical waste. Photocatalytic degradation of drugs is deemed an efficient and effective method for environmental remediation, along with recovery of photocatalysts, which are important for recycling and sustainable use. Herein, we present the synthesis of nanoparticles (NPs) and their application for photocatalytic degradation of pharmaceutical waste as a preferred water treatment method. Additionally, green synthesis of photocatalytic nanomaterials offers the benefit of avoiding secondary pollution. The green synthesis of NPs is employed by using plant extracts that offer a number of metabolites as reducing agents or capping agents, as well as the use of microbes as green nanofactories to tackle the issue of water cleanliness with respect to pharmaceutical waste. Despite regulations concerning drug disposal, some underdeveloped countries do not enforce and practice these guidelines in letter and spirit. Hence, the current work presenting a promising water cleanliness method is expected to contribute to the assurance of strict policy compliance and enforcement, resulting in the resolution of the health concerns with respect to hazardous pharmaceutical waste disposal in water bodies.
Objective:
To explore the efficacy and safety of Iguratimod (IGU) intervention in the treatment of Ankylosing Spondylitis (AS).
Methods:
We used computer to search literature databases, collected randomized controlled trials (RCTs) related to IGU treatment of AS, and searched the relevant literature in each database until Sep. 2022. Two researchers independently carried out literature screening, data extraction, and evaluation and analysis of the risk of bias in the included studies, and then used Rev Man5.3 software for meta-analysis. The protocol is CRD42020220798.
Results:
A total of 10 RCTs involves in 622 patients were collected. The statistical analysis showed that IGU can decrease the BASDAI score (SMD -1.62 [-2.20, -1.05], P<0.00001. Quality of evidence: low), the BASFI score (WMD -1.30 [-1.48, -1.12], P<0.00001. Quality of evidence: low) and the VAS (WMD -2.01 [-2.83, -1.19], P<0.00001. Quality of evidence: very low). Meanwhile, the addition of IGU into the conventional therapy would not increase the adverse events (RR 0.65 [0.43, 0.98], P=0.04. Quality of evidence: moderate).
Conclusion:
IGU may be an effective and safe intervention for AS.
Systematic review registration:
https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42020220798.
Background: Acute soft tissue injuries are common and carry significant societal costs. Cyclo-oxygenase 2 (COX-2) inhibitors (coxibs), non-selective nonsteroidal anti-inflammatory drugs (NSAIDs) and other analgesics are used to treat acute soft tissue injuries, with ongoing debate about their analgesic efficacy, effects on tissue healing and adverse effects (AEs). Objectives: To systematically review the evidence comparing oral coxibs with other oral analgesics for acute soft tissue injuries, using the outcomes: pain, swelling, function and AEs. Methods: The following databases were searched: MEDLINE, EMBASE, Cochrane CENTRAL, CINAHL, AMED, PEDro and SPORTDiscus. Further studies were sought through clinical trials registries, dissertations, correspondence with pharmaceutical companies and manual searches of relevant journals. There was no language restriction. Definitions: 'Coxibs' were defined as drugs that inhibit COX-2 >5-fold more than COX-1; 'acute' was defined as injury occurring within 48 hours of enrolment; 'soft tissue injury' was defined as closed injuries to upper or lower limb soft tissues (ligaments, muscles or tendons). Study selection: Randomized controlled trials in humans comparing a coxib to a different class of oral analgesic agent for the treatment of acute soft tissue injuries for <30 days, and in which >= 80% of participants met the definition of acute soft tissue injury, were included. Studies were excluded if >20% of participants enrolled had back pain, cervical spine injury, repetitive strain injuries, delayed-onset muscle soreness, fractures, cartilage injury, penetrating wounds or primary inflammatory conditions (tendonitis, bursitis and arthritis). Nine out of 23 (39.1%) potentially relevant studies met the selection criteria. Data extraction: A standard form was used to extract data. Included studies were screened by the authors for risk of bias using the Cochrane risk of bias tool and evidence was graded for quality using the GRADE tool. Data synthesis: Clinical heterogeneity was minimized by application of strict selection criteria. Statistical heterogeneity was assessed using the I(2) statistic and meta-analysis was undertaken if appropriate. Weighted mean difference (WMD) was used to assess pain, relative risk (RR) to assess AEs, and Peto odds ratio (OR) to assess return to function. Results: The nine RCTs evaluated in the meta-analysis included 3060 patients. Coxibs were found to be equal to NSAIDs (day 7+, n = 1884, 100 mm visual analogue scale [VAS]), WMD = 0.18 mm (95% CI -1.76, 2.13), p = 0.85 and tramadol (day 7+, n = 706, 100 mm VAS), WMD = -6.6 mm (95% CI -9.63, -3.47) [single study, difference clinically insignificant] for treating pain after soft tissue injuries. Coxibs had fewer gastrointestinal AEs than NSAIDs, even with short-term use (RR 0.59 [95% CI 0.41, 0.85], p = 0.004) [low quality evidence]. Swelling was measured in two studies with no difference being found between groups, but the presentation of the data was not sufficient to allow further analysis. Coxibs were found to be unlikely to be different to NSAIDs in helping patients return to function (OR 1.0 [95% CI 0.77, 1.3], p = 0.99); however, a single study suggested they may improve time to return to function (moderate quality evidence) and may have fewer AEs than tramadol (very low quality evidence). The risk of serious AEs with both coxibs and NSAIDs in this setting was low (but incompletely defined). Conclusions: More studies comparing coxibs with NSAIDs and other analgesics in the setting of acute soft tissue injuries are necessary. A different review methodology would be required to answer the question of cardiovascular risk associated with short-term use of coxibs and NSAIDs.
Celecoxib (Celebrex®) was the first cyclo-oxygenase (COX)-2 selective inhibitor (coxib) to be introduced into clinical practice. Coxibs were developed to provide anti-inflammatoryanalgesic activity similar to that of nonselective NSAIDs, but without their upper gastrointestinal (GI) toxicity, which is thought to result largely from COX-1 inhibition. Celecoxib is indicated in the EU for the symptomatic treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis in adults. This article reviews the clinical efficacy and tolerability of celecoxib in these EU-approved indications, as well as overviewing its pharmacological properties.In randomized controlled trials, celecoxib, at the recommended dosages of 200 or 400mgday, was significantly more effective than placebo, at least as effective as or more effective than paracetamol (acetaminophen) and as effective as nonselective NSAIDs and the coxibs etoricoxib and lumiracoxib for the symptomatic treatment of patients with active osteoarthritis, rheumatoid arthritis or ankylosing spondylitis.Celecoxib was generally well tolerated, with mild to moderate upper GI complaints being the most common body system adverse events. In meta-analyses and large safety studies, the incidence of upper GI ulcer complications with recommended dosages of celecoxib was significantly lower than that with nonselective NSAIDs and similar to that with paracetamol and other coxibs. However, concomitant administration of celecoxib with low-dose cardioprotective aspirin often appeared to negate the GI-sparing advantages of celecoxib over NSAIDs.Although one polyp prevention trial noted a dose-related increase in cardiovascular risk with celecoxib 400 and 800mgday, other trials have not found any significant difference in cardiovascular risk between celecoxib and placebo or nonselective NSAIDs. Meta-analyses and database-derived analyses are inconsistent regarding cardiovascular risk. At recommended dosages, the risks of increased thrombotic cardiovascular events, or renovascular, hepatic or hypersensitivity reactions with celecoxib would appear to be small and similar to those with NSAIDs.Celecoxib would appear to be a useful option for therapy in patients at high risk for NSAID-induced GI toxicity, or in those responding suboptimally to or intolerant of NSAIDs. To minimize any risk, particularly the cardiovascular risk, celecoxib, like all coxibs and NSAIDs, should be used at the lowest effective dosage for the shortest possible duration after a careful evaluation of the GI, cardiovascular and renal risks of the individual patient.
Background: Selective cyclo-oxygenase 2 inhibitors (‘coxibs’) have been demonstrated to increase cardiovascular risk, but the cumulative burden of adverse effects in the US population is uncertain.
Objective: To quantify cardiovascular and gastrointestinal (GI) haemorrhage disease burden from coxibs and traditional ‘non-selective’ non-steroidal anti-inflammatory drugs (t-NSAIDs) in the US population.
Design, setting and participants: Adult respondents from the 1999–2003 Medical Expenditure Panel Survey, a representative sample of the US population which first became available in December 2006, were included. Respondents were followed for 2 years. Exposure was defined by two or more prescriptions of rofecoxib, celecoxib or a t-NSAID in the first year.
Main outcome measures: Acute myocardial infarction (AMI), stroke and/or GI haemorrhage in the year following exposure.
Results: Exposure to rofecoxib was associated with an adjusted odds ratio (OR) of 3.30 for AMI (95% CI 1.41, 7.68; p = 0.01) and 4.28 for GI haemorrhage (95% CI 1.33, 13.71; p = 0.02). Celecoxib was not associated with a statistically significant effect on AMI (OR 1.44; 95% CI 0.57, 3.69; p = 0.44), but there was an OR of 2.43 for stroke (95% CI 1.05, 5.58; p = 0.04) and 4.98 for GI haemorrhage (95% CI 2.22, 11.17; p
Atherosclerosis is a process with inflammatory features and selective
cyclooxygenase 2 (COX-2) inhibitors may potentially have antiatherogenic effects
by virtue of inhibiting inflammation. However, by decreasing vasodilatory
and antiaggregatory prostacyclin production, COX-2 antagonists may lead to
increased prothrombotic activity. To define the cardiovascular effects of
COX-2 inhibitors when used for arthritis and musculoskeletal pain in patients
without coronary artery disease, we performed a MEDLINE search to identify
all English-language articles on use of COX-2 inhibitors published between
1998 and February 2001. We also reviewed relevant submissions to the US Food
and Drug Administration by pharmaceutical companies.Our search yielded 2 major randomized trials, the Vioxx Gastrointestinal
Outcomes Research Study (VIGOR; 8076 patients) and the Celecoxib Long-term
Arthritis Safety Study (CLASS; 8059 patients), as well as 2 smaller trials
with approximately 1000 patients each. The results from VIGOR showed that
the relative risk of developing a confirmed adjudicated thrombotic cardiovascular
event (myocardial infarction, unstable angina, cardiac thrombus, resuscitated
cardiac arrest, sudden or unexplained death, ischemic stroke, and transient
ischemic attacks) with rofecoxib treatment compared with naproxen was 2.38
(95% confidence interval, 1.39-4.00; P = .002). There
was no significant difference in cardiovascular event (myocardial infarction,
stroke, and death) rates between celecoxib and nonsteroidal anti-inflammatory
agents in CLASS. The annualized myocardial infarction rates for COX-2 inhibitors
in both VIGOR and CLASS were significantly higher than that in the placebo
group of a recent meta-analysis of 23 407 patients in primary prevention
trials (0.52%): 0.74% with rofecoxib (P = .04 compared
with the placebo group of the meta-analysis) and 0.80% with celecoxib (P = .02 compared with the placebo group of the meta-analysis).The available data raise a cautionary flag about the risk of cardiovascular
events with COX-2 inhibitors. Further prospective trial evaluation may characterize
and determine the magnitude of the risk.