Non-steroidal anti-inflammatory drugs (NSAIDs) represent a diverse class of drugs and are among the most commonly used analgesics for arthritic pain worldwide, though long-term use is associated with ...a spectrum of adverse effects. The introduction of cyclooxygenase-2-selective NSAIDs early in the last decade offered an alternative to traditional NSAIDs with similar efficacy and improved gastrointestinal tolerability; however, emerging concerns about cardiovascular safety resulted in the withdrawal of two agents (rofecoxib and valdecoxib) in the mid-2000s and, subsequently, in an overall reduction in NSAID use. It is now understood that all NSAIDs are associated with some varying degree of gastrointestinal and cardiovascular risk. Guidelines still recommend their use, but little is known of how patients use these agents. While strategies and guidelines aimed at reducing NSAID-associated complications exist, there is a need for evidence-based algorithms combining cardiovascular and gastrointestinal factors that can be used to aid treatment decisions at an individual patient level.
A 70-year-old man was admitted to our hospital because of loss of consciousness. He was a chronic user of an NSAID, and also complained of epigastralgia and melena. He was in a pre-shock state and ...upper gastrointestinal bleeding was suspected. After admission he had massive hematemesis and went into shock. Emergency endoscopy revealed a giant ulcer with active bleeding high on the posterior wall of the stomach. The bleeding could not be controlled with endoscopic hemostasis and an emergency laparotomy was performed which confirmed that the gastric ulcer had penetrated the pancreas and the splenic artery, with massive bleeding. A total gastrectomy with distal pancreatectomy was performed and the patient was rescued. Invasion of gastric ulcers into the splenic artery is very rare. Because it soon leads to massive bleeding and a potential fatal outcome, immediate treatment including surgery is important.
Nanotherapeutic-directed approaches to analgesia Mazaleuskaya, Liudmila L.; Muzykantov, Vladimir R.; FitzGerald, Garret A.
Trends in pharmacological sciences (Regular ed.),
07/2021, Volume:
42, Issue:
7
Journal Article
Peer reviewed
Open access
The ongoing opioid crisis highlighted the need for non-steroidal anti-inflammatory drugs (NSAIDs), nonaddictive analgesics against pain, fever, and inflammation. However, NSAIDs may cause ...gastrointestinal and cardiovascular adverse effects. To avoid systemic toxicity and deliver drugs to diseased tissues, nanotechnology methods of NSAID encapsulation have been reported and some have reached clinical development. Currently, 57 micro- and nanodrugs are approved by the US FDA. Already approved nanoanalgesics have revealed superior efficacy or reduced toxicity compared with placebo or lower doses of systemically administered active comparators. In this review, the evidence for approval of the marketed nanodrugs will be discussed, with a focus on therapies for pain and inflammation. Nanomedicine remains an attractive field for the development of targeted analgesics.
Despite the unmet medical need for nonaddictive analgesics, only a small fraction of nanocarrier-based drugs has been approved for pain and inflammation, notably, not a single non-steroidal anti-inflammatory drug (NSAID).Nanotechnology-based analgesic and anti-inflammatory drugs were FDA-approved in small trials and showed superiority in comparison with placebo or an active comparator at less than a clinically effective dose.For analgesics with addictive potential, nanotechnology aims to develop abuse-deterrent formulations (ADFs) of prescription opioids. It remains to be seen if opioids in tamper-resistant nanocarriers will have the same analgesic efficacy but reduced abuse potential than the conventional formulations.Nano-NSAIDs actively targeted to the cells secreting pro-inflammatory mediators, like prostaglandin E2 (PGE2), may present a therapeutic advantage over passively targeted or systemic drugs in chronic pain conditions.
The toxicity for the human body of non-steroidal anti-inflammatory drugs (NSAIDs) overdoses is a consequence of their low water solubility, high doses, and facile accessibility to the population. New ...drug delivery systems (DDS) are necessary to overcome the bioavailability and toxicity related to NSAIDs. In this context, UiO-66(Zr) metal-organic framework (MOF) shows high porosity, stability, and load capacity, thus being a promising DDS. However, the adsorption and release capability for different NSAIDs is scarcely described. In this work, the biocompatible UiO-66(Zr) MOF was used to study the adsorption and release conditions of ibuprofen, naproxen, and diclofenac using a theoretical and experimental approximation. DFT results showed that the MOF-drug interaction was due to an intermolecular hydrogen bond between protons of the groups in the defect sites, (μ3 − OH, and − OH2) and a lone pair of oxygen carboxyl functional group of the NSAIDs. Also, the experimental results suggest that the solvent where the drug is dissolved affects the adsorption process. The adsorption kinetics are similar between the drugs, but the maximum load capacity differs for each drug. The release kinetics assay showed a solvent dependence kinetics whose maximum liberation capacity is affected by the interaction between the drug and the material. Finally, the biological assays show that none of the systems studied are cytotoxic for HMVEC. Additionally, the wound healing assay suggests that the UiO-66(Zr) material has potential application on the wound healing process. However, further studies should be done.
UiO-66(Zr) could be used as DDS of the NSAIDs ibuprofen, naproxen, and diclofenac. Display omitted
Degradation of ibuprofen, one of the most consumed drugs globally, by a mixed bacterial consortium was investigated. A contaminated hospital soil was used to enrich a bacterial consortium possessing ...the ability to degrade 4 mg/L ibuprofen in 6 days, fed on 6 mM acetate as a supplementary carbon source. Maximum ibuprofen degradation achieved was 99.51%, and for optimum ibuprofen degradation modelled statistically, the initial ibuprofen concentration, and temperature were determined to be 0.515 mg/L and 35 °C, respectively. The bacterial community analyses demonstrated an enrichment of Pseudomonas, Achromobacter, Bacillus, and Enterococcus in the presence of ibuprofen, suggesting their probable association with the biodegradation process. The biodegradation pathway developed using open-source metabolite predictors, GLORYx and BioTransformer suggested multiple degradation routes. Hydroxylation and oxidation were found to be the major mechanisms in ibuprofen degradation. Mono-hydroxylated metabolites were identified as well as predicted by the bioinformatics-based packages. Oxidation, dehydrogenation, super-hydroxylation, and hydrolysis were some other identified mechanisms.
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•Enrichment of bacterial consortium for ibuprofen removal.•Effective ibuprofen removal on the addition of acetate through co-metabolism.•Maximum enrichment of Pseudomonas, Bacillus and Enterococcus during degradation.•Hydroxylation and oxidation as the major biodegradation mechanisms.
Preeclampsia (PE) is often associated with multiple organ damage that remains noticeable postnatally. Here, we tested the hypotheses that antenatal therapy with nonsteroidal antiinflammatory drugs ...(NSAIDs) refashions liver damage induced by PE in weaning rats and that the high mobility group box 1 (HMGB1) signaling modulates this interaction. PE was induced by pharmacologic nitric oxide deprivation during the last week of gestation (Nω-nitro-L-arginine methyl ester, L-NAME, 50 mg/kg/day, oral gavage). Compared with control rats, weaning PE rats revealed substantial rises in serum transaminases together with histopathological signs of hepatic cytoplasmic changes, portal inflammation, and central vein dilation. While gestational NSAIDs reversed the elevated transaminases, they had no effects (celecoxib, naproxen) or even worsened (diclofenac) the structural damage. Molecularly, celecoxib was the most effective NSAID in (i) reversing PE-evoked upregulation of hepatic HMGB1 gene expression and concomitant increments and decrements in mitogen-activated protein kinases MAPKERK and MAPKp38 expression, respectively, and (ii) elevating and suppressing serum interleukin-10 and tumor necrosis factor-α, respectively. Alternatively, rises in serum interleukin-1β and shifts in macrophage polarization towards an inflammatory phenotype caused by PE were comparably diminished by all NSAIDs. The data disclose an advantageous therapeutic potential for gestational celecoxib over diclofenac or naproxen in controlling hepatic dysfunction and HMGB1-interrelated inflammatory and oxidative sequels of PE.
•Prenatal NSAIDs reduce PE rises in blood transaminases, but not hepatic damage.•Celecoxib is more potent than diclofenac/naproxen in reversing PE-HMGB1 inflammation.•Celecoxib upregulates hepatic antioxidant machinery.
•Recent advances in anti-inflammatory drug nanocrystal are presented.•The role of nanocrystal approach in improving bioavailability are discussed.•The benefits of its formulation in in vitro and in ...vivo evaluation are highlighted.•Insights of drug nanocrystals targeting to the inflammation site are included.•An overview of preparation and the regulatory perspective is presented.
Anti-inflammatory drugs have been prescribed extensively for a wide range of diseases. Combined with over-the-counter use, approximately 30 billion doses of non-steroidal inflammatory drugs (NSAIDs) are consumed annually in the USA. The global market of glucocorticoids (GCs) is forecast to reach US$ 8.6 billion by 2025. Severe adverse effects have been reported for NSAIDs, GCs, and COX-2 selective NSAIDs (COXIBs). Furthermore, the overwhelming majority of these drug substances are BCS class II, which limits their bioavailability due to poor water solubility. Drug nanocrystals, a carrier-free nanosystem, can increase saturation solubility, dissolution rate, and the mucoadhesiveness of these drugs. The enhancement of these properties was highlighted in our findings. These features improve the efficacy and safety of anti-inflammatory drugs. In this review, we show that drug nanocrystals are an attractive strategy that contributes to an important shift in the development of innovative products for different routes of administration. The possibility of targeting can minimize the adverse effects and improve the efficacy in the management of inflammatory conditions. We comprehensively review the critical quality attributes (CQAs) in the anti-inflammatory drug nanocrystals preparation, which are fundamental to developing a successful marketable product. Despite the advantages, maintaining properties such as average particle size, surface properties, and physicochemical stability of these preparations during shelf life poses challenges to be overcome.
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