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Loxoprofen: A Review in Pain and Inflammation
Abstract
Loxoprofen (Loxonin®, Loxonin® Pap, Loxonin® Tape) is a prodrug-type NSAID that is available in several formulations, including 60 mg tablets, 100 mg hydrogel patches and 50 or 100 mg tape. In active comparator-controlled trials, oral loxoprofen therapy (ranging from 2 days to 6 weeks’ duration depending on the pain type) provided analgesic efficacy that generally did not significantly differ from that of celecoxib for postoperative pain or frozen shoulder, ibuprofen for knee osteoarthritis or naproxen for lumbar pain. In double-blind, double-dummy, multicentre trials, loxoprofen hydrogel patches were noninferior to oral loxoprofen with regard to rates of final overall symptomatic improvement over 1–4 weeks in patients with knee osteoarthritis, myalgia or trauma-induced swelling and pain. Loxoprofen hydrogel patches were also noninferior to other commercially available patches (ketoprofen and indometacin) over 2 or 4 weeks in patients with knee osteoarthritis or myalgia in open-label studies. Oral and topical loxoprofen were generally well tolerated in clinical trials. Thus, loxoprofen is a useful analgesic option for patients with pain and inflammation, with topical loxoprofen potentially reducing the risk of gastrointestinal, cardiovascular and renal complications associated with oral NSAID use.
... Loxoprofen, 2-(4-((2-Oxocyclopentyl)methyl)phenyl) propionic acid, is a non-selective non-steroidal anti-inflammatory drug (NSAID) developed in Japan by Daiichi Sankyo Co. Ltd. in 1986 [1]. Loxoprofen is mainly used to treat pain and inflammation related to musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis [2,3], and post-operative pain [1]. ...
... Loxoprofen, 2-(4-((2-Oxocyclopentyl)methyl)phenyl) propionic acid, is a non-selective non-steroidal anti-inflammatory drug (NSAID) developed in Japan by Daiichi Sankyo Co. Ltd. in 1986 [1]. Loxoprofen is mainly used to treat pain and inflammation related to musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis [2,3], and post-operative pain [1]. Loxoprofen is a prodrug metabolized in the liver by carbonyl reductase enzyme to its active trans-alcohol metabolite (Trans-OH), 2-(4-((trans-2-hydroxycyclopentyl)-methyl)-phenyl) propionic acid ( Figure 1a) [1,4]. ...
... Loxoprofen is mainly used to treat pain and inflammation related to musculoskeletal and joint disorders, such as rheumatoid arthritis, osteoarthritis [2,3], and post-operative pain [1]. Loxoprofen is a prodrug metabolized in the liver by carbonyl reductase enzyme to its active trans-alcohol metabolite (Trans-OH), 2-(4-((trans-2-hydroxycyclopentyl)-methyl)-phenyl) propionic acid ( Figure 1a) [1,4]. The active metabolite exhibits anti-inflammatory activity by inhibiting the cyclooxygenase enzymes, thus impairing the formation of the chemical prostaglandin, which is responsible for pain and inflammation [5,6]. ...
Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.
... After the application of LX-P to the lesion, LX accumulates in local tissues, which can provide strong anti-inflammatory and analgesic effects and rapid relief of pain at the lesion that lasts 24 h. 21 A randomized, controlled, double-blind, double-dummy, multicenter, non-inferiority trial included 169 patients with knee osteoarthritis. 17 Patients were randomly assigned to either LX-P or loxoprofen tablet (LX-T) groups for a 4-week treatment. ...
... To achieve pain relief, oral NSAIDs must achieve systemic efficacy levels, which can also lead to gastrointestinal and cardiovascular complications. 21,22 Topical formulations provide low systemic drug levels, producing peak blood concentrations that are less than 10% of the levels observed after the administration of oral NSAIDs, and produce adverse effects that are usually mild and transient, such as pruritus, which resolve with discontinuation of the ...
Purpose
Chronic inflammatory pain is usually treated with oral non-steroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs can cause some adverse events, and local preparation is an important alternative drug. Currently, small sample clinical studies show that loxoprofen sodium hydrogel patch (LX-P) has good analgesic and anti-inflammatory effects; however, there is a lack of real-world clinical research data.
Patients and Methods
This study included 60 patients with chronic inflammatory pain. They were treated with LX-P without affecting their real-world treatment for two weeks.
Results
After 2 weeks of continuous medication, 93.33% of the patients stated that the treatment was effective. Only 3.33% of the patients had a relapse after 4 weeks. Moreover, the swelling range and degree of swelling decreased markedly and the dysfunction of the pain site was markedly alleviated. The total satisfaction of patients after treatment reached 90.00%.
Conclusion
In this real-world observational study, LX-P showed good efficacy and safety in patients with chronic inflammatory pain.
... Table 1. Structure and characteristics of Loxoprofen [8,9]. ...
... Table 1. Structure and characteristics of Loxoprofen [8,9]. Over the last two decades, industrial-based application of sup has attracted raised attention around the world due to their signi organic solvents, such as non-toxicity, environmental-friendlines ciency [10,11]. ...
Industrial-based application of supercritical CO2 (SCCO2) has emerged as a promising technology in numerous scientific fields due to offering brilliant advantages, such as simplicity of application, eco-friendliness, and high performance. Loxoprofen sodium (chemical formula C15H18O3) is known as an efficient nonsteroidal anti-inflammatory drug (NSAID), which has been long propounded as an effective alleviator for various painful disorders like musculoskeletal conditions. Although experimental research plays an important role in obtaining drug solubility in SCCO2, the emergence of operational disadvantages such as high cost and long-time process duration has motivated the researchers to develop mathematical models based on artificial intelligence (AI) to predict this important parameter. Three distinct models have been used on the data in this work, all of which were based on decision trees: K-nearest neighbors (KNN), NU support vector machine (NU-SVR), and Gaussian process regression (GPR). The data set has two input characteristics, P (pressure) and T (temperature), and a single output, Y = solubility. After implementing and fine-tuning to the hyperparameters of these ensemble models, their performance has been evaluated using a variety of measures. The R-squared scores of all three models are greater than 0.9, however, the RMSE error rates are 1.879 × 10⁻⁴, 7.814 × 10⁻⁵, and 1.664 × 10⁻⁴ for the KNN, NU-SVR, and GPR models, respectively. MAE metrics of 1.116 × 10⁻⁴, 6.197 × 10⁻⁵, and 8.777 × 10⁻⁵errors were also discovered for the KNN, NU-SVR, and GPR models, respectively. A study was also carried out to determine the best quantity of solubility, which can be referred to as the (x1 = 40.0, x2 = 338.0, Y = 1.27 × 10⁻³) vector.
... Loxoprofen, a propionic acid derivative, acts as a cyclooxygenase inhibitor and has been in clinical use since 1986 in the world [1,2]. Loxoprofen is currently the most prescribed non-steroidal anti-inflammatory drug (NSAID) in Japan (30% of~2,000,000 patients using NSAIDs in 2017 [3]). ...
... Here, we describe the case of a 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets (6000 mg) of loxoprofen (usual clinical dose in the range 60-180 mg/day [1,2]). On arrival at Kyoto Medical Center, with empty heat seals for loxoprofen, the patient was suffering disorders of consciousness. ...
Background
Loxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic.
Case presentation
A 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans- alcohol metabolite were 52 and 24 μg/mL, 3.7 and 2.3 μg/mL, 0.81 and 0.54 μg/mL, and 0.015 and 0.011 μg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6–12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans- alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor.
Conclusions
Because the patient’s level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans -alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.
... Loxoprofen is a non-selective cyclooxygenase (COX) inhibitor with anti-inflammatory, analgesic, and antipyretic effects and has fewer adverse events compared with other NSAIDs [24]. However, gastrointestinal, renal, and cardiovascular disorders have been reported in previous studies [25,26]. The associated adverse events are known to be dose-dependent; therefore, patients should take the lowest effective dose for the shortest period [27]. ...
... Morphine exhibits its analgesic effect by mediating opioidergic receptors [30]. By contrast, loxoprofen exhibits its analgesic effect via its antiinflammatory reaction while inhibiting COX-1 and COX-2 enzymes, which are involved in the production of prostaglandins [26]. Therefore, this different mechanism may account for the differences in BVA treatment effects, leading to different research outcomes. ...
This study aimed to investigate the feasibility of a combined treatment of bee venom acupuncture (BVA) and non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of non-specific chronic neck pain (NCNP). Patients with NCNP for ≥3 months were randomly allocated to a BVA, NSAIDs, or combined group (1:1:1), receiving 6 sessions of BVA, loxoprofen (180 mg daily), or a combination, respectively, for 3 weeks. Recruitment, adherence, and completion rates were calculated to assess feasibility. Bothersomeness, pain, disability, quality of life, depressive status, treatment credibility, and adverse events were assessed. In total, 60 participants were enrolled, and 54 completed the trial. Recruitment, adherence, and completion rates were 100%, 95%, and 90%, respectively. Bothersomeness, pain, disability, and depressive symptoms significantly improved in all groups after treatment (p < 0.05). The combined group showed continuous improvement during the follow-up period (p < 0.05). Quality of life was significantly improved (p < 0.05), and treatment credibility was maintained in the BVA and combined groups. No serious adverse events were reported. Combined treatment of BVA and NSAIDs are feasible for the treatment of NCNP, showing high persistence of the effect, credibility, and safety. Additional trials with longer follow-up are needed to confirm this effect.
... This drug is widely used in Japan, Eastern Asia, the Middle East, Latin America, and Africa for the management of pain and inflammation in chronic and transient conditions (e.g., toothache, headache, menstrual cramps, common cold, etc.) (13) . It acts by inhibiting the cyclooxygenase enzymes (COX I and COX-II), which are involved in the biosynthesis of prostaglandins (PGs) (14,15) . Loxoprofen is available as an oral loxoprofen sodium tablet and solution, it is also available as topical preparations such as Loxonin gel (1%), Loxonin spray (1%) which could be applied 3-4 times a day (11,16) . ...
Although topical preparations like creams, ointments, and gels were used for many years to achieve local or sometimes systemic effects, they have many limitations mostly the inability to control the release of medications. In this research, a new emulgel preparation of loxoprofen sodium was formulated as a suitable alternative possessing the properties of both emulsion and gel preparation making it suitable to prolong the release of the hydrophilic drug. For this reason, five different emulgel formulas were prepared using different percentages of liquid paraffin (5%,10%), tween 80 & span 80 emulsifier mixture (2.5%, 5%), and xanthan gum (1%, 2%). The formulations were evaluated for their physicochemical, rheological, and spreading properties, in addition to content uniformity and in-vitro release properties. Furthermore, the optimum selected emulgel formula was subjected to a skin irritation test, stability, and compatibility study besides an in-vitro release comparison with the marketed Loxonin® gel. The result of all formulated emulgels showed excellent homogeneity, consistency with no phase separation and accepted pH (6.12±0.76 to 6.51±0.92), and content uniformity (99.02±0.45 to 99.48±1.49). Moreover, all the formulas showed a thixotropic shear-thinning behavior with the optimum formula F3 exhibiting the highest spreadability value of (8.3±0.1 cm), and the highest extent of drug liberated after 6 hours (94.81±1.30 %). Additionally, the selected loxoprofen emulgel F3 showed no irritation to human skin, and no significant change upon storage at 4±2°C and 25±2°C with acceptable compatibility. Eventually, the selected formula displayed a slower rate of loxoprofen release than the marketed gel, a result that proves the effectiveness of the newly formulated loxoprofen emulgel for a prolonged release giving better patient compliance.
... NSAID inhibits the acetylation of cyclooxygenase to release inflammatory mediators and achieves the purpose of alleviating pain. Loxoprofen (Lox) is a powerful NSAID drug for the treatment of RA [6,7], and the Food and Drug Administration (FDA) has already approved it for use as a topical gel preparation. In addition, tofacitinib (Tof) is a targeted Janus kinase inhibitor [8,9], and oral Tof is a new approach for the treatment of moderate to severe RA in adults who have not responded well to or are intolerant to DMARDs. ...
Rheumatoid arthritis (RA) is an autoimmune disease of synovial inflammation that affects populations worldwide. Transdermal drug delivery systems for treating RA have increased but remain challenging. We fabricated a dissolving microneedle (MN) system with photothermal (PT) polydopamine (PDA) to co-load the non-steroidal anti-inflammatory drug loxoprofen (Lox) and the Janus kinase inhibitor tofacitinib (Tof), with the aim of co-delivering Lox and Tof directly to the articular cavity, aided by the combination of MN and PT. In vitro and in vivo permeation studies showed that the PT MN significantly promoted drug permeation and retention in the skin. An in vivo visualization of the drug distribution in the articular cavity showed that the PT MN significantly promoted drug retention in the articular cavity. Importantly, compared to the intra-articular injection of Lox and Tof, the application of the PT MN to a carrageenan/kaolin-induced arthritis rat model exhibited superior performance in reducing joint swelling, muscle atrophy, and cartilage destruction. Furthermore, the PT MN downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α, IL-1β, iNOS, JAK2, JAK3, and STAT3. The results show that the PT MN transdermal co-delivery of Lox and Tof is a new synergetic therapy with high compliance and good therapeutic efficacy for RA.
... Inflammation is basically a response of the cell defense system against tissue injuries or any external stimuli [2]. The onset of inflammation is associated with pain [3]. In the early ages of human development, plants had been used in the management of inflammation and its associated pain [4]. ...
In the current study, a series of new (2S,3S)-2-(4-isopropylbenzyl)-2-methyl-4-nitro-3-phenylbutanals (FM1-6) with their corresponding carboxylic acid analogues (FM7-12) has been synthesized. Initially, the aldehydic derivatives were isolated in the diastereomeric form, and the structures were confirmed with NMR, MS and elemental analysis. Based on the encouraging results in in vitro COX 1/2, 5-LOX and antioxidant assays, we oxidized the compounds and obtained the pure single (major) diastereomer for activities. Among all the compounds, FM4, FM10 and FM12 were the leading compounds based on their potent IC50 values. The IC50 values of compounds FM4, FM10 and FM12 were 0.74, 0.69 and 0.18 µM, respectively, in COX-2 assay. Similarly, the IC50 values of these three compounds were also dominant in COX-1 assay. In 5-LOX assay, the majority of our compounds were potent inhibitors of the enzyme. Based on the potency and safety profiles, FM10 and FM12 were subjected to the in vivo experiments. The compounds FM10 and FM12 were observed with encouraging results in in vivo analgesic and anti-inflammatory models. The molecular docking studies of the selected compounds show binding interactions in the minimized pocked of the target proteins. It is obvious from the overall results that FM10 and FM12 are potent analgesic and anti-inflammatory agents.
... 7,8 There have also been related studies in clinical medicine in recent years. 2,9,10 Ketoprofen and its related preparations are widely used in the treatment of inflammation (arthritis, scissor synovitis, ankylosing spondylitis, etc.), 11,12 trauma 13,14 and postoperative pain. 7,15 However, as a kind of NSAIDs, its side effects, such as gastrointestinal toxicity, 16,17 are unavoidable, which potentially limits the clinical application of NSAIDs. ...
Purpose
Ketoprofen (KETO) is a traditional non-steroidal anti-inflammatory drug (NSAIDs) with good analgesic and antipyretic effects. However, as NASIDs, the toxicity of KETO towards gastrointestinal (GI) system might limit its clinical use. S-propargyl-cysteine (SPRC) is an excellent endogenous H2S donor showed wide application in the field of anti-inflammation, anti-oxidative stress, or even the protection of cardiovascular system through the elevation of endogenous H2S concentration. As recently studies reported, co-administration of H2S donor might potentially mitigate the GI toxicity and relevant side effects induced by series of NSAIDs.
Methods
In this study, we established a SPRC and KETO co-encapsulated poly (lactic-co-glycolic acid) microsphere (SK@MS), and its particle size, morphology, storage stability and in vitro release profile were firstly investigated. The elevation of endogenous H2S level of SK@MS was then calculated, and the pharmacodynamic study (anti-inflammation and analgesic effects) of SK@MS, SPRC, and KETO towards adjuvant induced arthritis (AIA) in rats were also studied. Finally, to test the potential side effect, the heart, liver, spleen, lung, kidney, stomach, small intestine, and large intestine were resected from rats and examined by H&E staining.
Results
A monodispersed SK@MS could be observed under the SEM, and particle size was calculated around 25.12 μm. The loading efficiency (LE) for SPRC and KETO were 6.67% and 2.64%, respectively, while the encapsulation efficiency (EE) for SPRC and KETO were 37.20% and 68.28%, respectively. SK@MS showed a sustained release of SPRC and KETO in vitro, which was up-to 15 days. SK@MS could achieve a long-term elevation of the H2S concentration in vivo, while SPRC showed an instant H2S elevation and metabolize within 6 h. Interestingly, the KETO did not show any influence on the H2S concentration in vivo. After establishment of AIA model, neither SPRC nor KETO showed scarcely anti-inflammation and anti-nociception effect, while conversely, SK@MS showed an obvious mitigation towards paw edema and pain in AIA rats, which indicated an improved anti-inflammation and anti-nociception effect when co-delivery of SRC and KETO. Besides, low stimulation towards major organs in rats observed in any experimental group.
Conclusion
A monodispersed was successfully prepared in this study, and SK@MS showed a sustained SPRC and KETO release in vitro and H2S release in vivo. In the pharmacodynamics study, SK@MS not only exhibited an excellent anti-inflammation and analgesic effects in AIA rats but also showed low stimulation towards rats.
... LXP is swiftly metabolized in the liver by carbonyl reductase enzyme into its active trans-alcohol form, a potent and nonselective inhibitor of both isoforms of COX enzyme (i.e. COX-1 and COX-2) CONTACT (Renton, 2011;Sarah & Garnock-Jones, 2016;Huda & Nidhal, 2019). ...
The majority of newly developed drugs need to be incorporated with delivery systems to maximize their effect and minimize side effects. Nanoemulsions (NEs) are one type of delivery system that helps to improve the solubility and dissolution of drugs, attempting to enhance their bioavailability and onset of action. The objective of this investigation was to develop an omega-3 oil-based NE loaded with loxoprofen (LXP) to enhance its dissolution, in vitro release, and mucosal penetration and decrease its mucosal ulcerative effects when applied in an oral treatment. LXP-loaded NEs were formulated with varying levels of omega-3 oil (10–30%), surfactant polyoxyethylene-C21-ethers (laureth-21) (40–60%), and co-surfactant polyethylene glycol-40 hydrogenated castor oil (HCO-40) (30–50%) using an extreme vertices mixture design. The developed NEs were characterized for globule size and drug loading capacity. The optimal formulation was tested for in vitro drug release, ex vivo permeation, and ulcer index value. The developed NE acquired a globule size ranging 71–195 nm and drug loading capacity of 43–87%. Considering the results of the in vitro release study, the optimized NE formulation achieved 2.45-fold and 2-fold increases in drug permeation across tested mucosa compared to a marketed tablet and drug aqueous dispersion, respectively. Moreover, the optimum NE exhibited the best ulcer index in comparison to drug aqueous suspension and different formulations when tested in rats. Overall, this research highlights the capacity of NEs to deliver LXP with enhanced solubility, drug release, and permeation while effectively protecting the application site from side effects of the model drug.
... We obtained results that are inconsistent with those observed in human skin regarding LSH and TH. LSH is a nonsteroidal anti-inflammatory drug that can be absorbed by human skin [32]. However, we did not detect it in the blood of zebrafish after exposure and transdermal administrations, even with a high dose. ...
In recent decades, zebrafish (Danio rerio) has become a widely used vertebrate animal model for studying development and human diseases. However, studies on skin medication using zebrafish are rare. Here, we developed a novel protocol for percutaneous absorption of molecules via the zebrafish tail skin, by applying a liquid solution directly, or using a filter paper imbibed with a chemical solution (coating). Human skin is capable of absorbing felbinac and loxoprofen sodium hydrate (LSH), but not glycyrrhetinic acid (GA) and terbinafine hydrochloride (TH). To evaluate the possibility and the quality of transdermal absorption in zebrafish, we transdermally administered these four drugs to zebrafish. Pharmacokinetics showed that felbinac was present in the blood of zebrafish subjected to all administration methods. Felbinac blood concentrations peaked at 2 h and disappeared 7 h after administration. GA was not detected following transdermal administrations, but was following exposure. LSH was not found in the circulatory system after transdermal administration, but TH was. A dose-response correlation was observed for felbinac blood concentration. These findings suggest that zebrafish are capable of absorbing drug molecules through their skin. However, the present data cannot demonstrate that zebrafish is a practical model to predict human skin absorption. Further systemic studies are needed to observe the correlations in percutaneous absorption between humans and zebrafish.
... Clinical studies showed that the efficacy of loxoprofen patch was not inferior to that of oral tablets in the therapy of knee osteoarthritis . In the carrageenan-induced rat toe swelling model, the anti-inflammatory effect of LOX gel patch was significantly higher than that of indomethacin and biphenyl acetate patch (Greig and Garnock-Jones, 2016). Therefore, topical LOX formulation has good clinical application value. ...
Topical administration is a promising clinical strategy to avoid serious gastrointestinal adverse reactions of loxoprofen sodium (LOX), a new non-steroidal anti-inflammatory drug. Small molecule organic acids had been reported with the ability of promoting transdermal rate of several drugs. In this article, the effect of small molecule organic acids on the transdermal delivery of LOX was studied, and the possible mechanism was also explored by Fourier infrared spectroscopy, differential scanning calorimetry, tape stripping, etc. The results showed that lactic acid and fumaric acid could significantly increase the penetration rate of LOX and reduce time lag even without the help of acidic environment. The preliminary mechanism investigation inferred that fumaric acid could increase LOX’s distribution in stratum corneum and might change its complexation state, but had little effect on the drug structure and skin’s lipids and proteins configuration. The topical LOX gel using fumaric acid as penetration enhancer had higher transdermal rate, significant anti-inflammatory effect and no obvious skin irritation. This study proved the promising application of small molecule organic acids in transdermal enhancing and provided a potential strategy for transdermal delivery of LOX combined with fumaric acid.
... Therefore, XO causes gout [3]. In the treatment of this disease, many drugs are used, such as probenecid [4], benzbromarone [4,5], colchicine [6], loxoprofen sodium [7], and allopurinol [5] (Fig. 1). Allopurinol and other gout drugs are XO inhibitors [5]. ...
In this study, novel 1,2,3-triazole compounds containing carbasugar frameworks (5 and 6) were synthesized by the copper-catalyzed azide-alkyne cycloaddition reactions and their in vitro inhibition effects on the enzyme xanthine oxidase were investigated. All of the synthesized compounds were characterized by spectroscopic methods. According to the enzyme inhibition results, compounds 5 (IC50 = 0.586 ± 0.017 μM) and 6 (IC50 = 0.751 ± 0.021 μM) showed stronger inhibition effects than allopurinol (IC50 = 1.143 ± 0.019 μM), which is a standard drug used for inhibition of xanthine oxidase. The binding modes of the 1,2,3-triazole compounds (5 and 6) with the active site of xanthine oxidase were explained based on molecular docking studies. The molecular docking studies showed that the aromatic structure, π-π interactions and hydrophobic interactions play a major role in xanthine oxidase inhibition for compounds 5 and 6.
... Interestingly, there were some other compounds within this cluster, which neither containing this structural fragment nor have active responses in these assays, but are in fact hepatotoxic. For example, loxoprofen (compound 2831), which only has inactive results in the assays in cluster 1, can induce hepatotoxicity in humans (Greig and Garnock-Jones, 2016). According to the information on LiverTox V R , the mechanism of loxoprofen produce hepatic injury is considered an idiosyncratic reaction likely involving an immunologic reaction There are 2 other structural fragments that were identified from clusters 3 and 17, respectively. ...
Hepatotoxicity is a leading cause of attrition in the drug development process. Traditional preclinical and clinical studies to evaluate hepatotoxicity liabilities are expensive and time-consuming. With the advent of critical advancements in High Throughput Screening (HTS), there has been a rapid accumulation of in vitro toxicity data available to inform the risk assessment of new pharmaceuticals and chemicals. To this end, we curated and merged all available in vivo hepatotoxicity data obtained from the literature and public resources, which yielded a comprehensive database of 4,089 compounds that includes hepatotoxicity classifications. After dividing the original database of chemicals into modeling and test sets, PubChem assay data were automatically extracted using an in-house data mining tool and clustered based on relationships between structural fragments and cellular responses in in vitro assays. The resultant PubChem assay clusters were further investigated. During cross-validation procedure, the biological data obtained from several assay clusters exhibited high predictivity of hepatotoxicity and these assays were selected to evaluate the test set compounds. The read-across results indicated that if a new compound contained identified specific chemical fragments (i.e. Molecular Initiate Event) and showed active responses in the relevant selected PubChem assays, there was potential for the chemical to be hepatotoxic in vivo. Furthermore, several mechanisms that might contribute to toxicity were derived from the modeling results including alterations in nuclear receptor signaling and inhibition of DNA repair. This modeling strategy can be further applied to the investigation of other complex chemical toxicity phenomena (e.g. developmental and reproductive toxicities) as well as drug efficacy.
... In 2011, a higher adult dose of acetaminophen (up to the same maximum daily dose of 4,000 mg as that used overseas) was approved in Japan, thereby allowing more effective pain relief, and an increase in the number of patients who were prescribed this medication was expected [3]. To reduce adverse drug reactions (ADRs) such as cardiac and gastrointestinal disorders of conventional NSAIDs, prodrugs of NSAIDs such as loxoprofen, which have a short elimination half-life and no direct effects on the gastrointestinal tract, and cyclooxygenase 2 (COX-2) inhibitors such as celecoxib were developed [4,5]. Both NSAIDs and COX-2 selective NSAIDs are now widely used in daily practice in Japan. ...
Background: Information on prescriptions of oral analgesics for the treatment of pain is beneficial. However, there have been few reports on the prescription status of oral analgesics from a nation-wide, large-scale prescription database in Japan.
Research design and methods: The authors analyzed the prescription data of 2,042,302 patients prescribed oral analgesics in 2017. The numbers/proportions of patients prescribed oral analgesics, adherence with approved doses, co-prescription patterns, dose changes, drug adherence, and treatment-discontinuation rates were evaluated.
Results: Loxoprofen was prescribed to 32.5% of the patients, followed by celecoxib, prescribed to 16.0% of patients. Acetaminophen and pregabalin were prescribed to 10.5% and 9.4% of patients, respectively. Many analgesics were prescribed at lower doses than the approved doses. The most frequently used concomitant medication was pregabalin. For duloxetine and pregabalin, high proportions of patients were prescribed these drugs for > 90 days.
Conclusions: Loxoprofen was the most prescribed of the non-steroidal anti-inflammatory drugs in Japan. The information obtained provides an overview of prescribed oral analgesics in Japan and could be useful for potential research into prescribed oral analgesics in the future.
... Irreversible profound symptomatic bradycardia has never been reported as a side effect of loxoprofen; however, palpitations may occur with oral loxoprofen. 11 The cardiac electrophysiological properties of tizanidine and loxoprofen have yet to be clarified. Thus, it should be considered that the combined use of tizanidine and loxoprofen increases the risk of tizanidine-associated irreversible profound symptomatic bradycardia. ...
A 37-year-old man suffered irreversible profound symptomatic bradycardia requiring a pacemaker 3 days after beginning tizanidine/loxoprofen combination therapy for neck pain. This combination therapy is prescribed frequently for joint pain; however, combining loxoprofen with tizanidine could increase the risk of symptomatic bradycardia that is both permanent and severe. Similar cases have not been reported. This case suggests that tizanidine should be used cautiously when combined with loxoprofen, and drug interaction screening should be performed.
... US and EU guidelines for osteoarthritis management, however, recommend the use of topical rather than oral NSAIDs, especially in the elderly [98]. Accordingly, a review by Greig on the prodrug type loxoprofen concluded that although the incidence of adverse effects did not differ between topical and oral therapy, the risk-tobenefit ratio is in favor of topical administration in long-term treatment [99]. ...
Treatment of pain has always been a major goal in the clinic, as it is related to several pathological conditions of inflammatory origin and surgical procedures, which are associated with inflammatory mediators. Understanding the molecular mechanisms underlying the association between inflammatory mediators and pain perception, from peripheral to central sensitization, can provide the basis for the development of new pharmacological treatments. Despite safety concerns, till date, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to be efficacious, safe, and well tolerated by patients. Thus, choosing the appropriate administration route, developing new formulations and lowering the efficacious dose represent, currently, effective means of treating inflammation and relieving the pain, without inducing significant side effects.
Objectives: We investigated the compression mechanisms for loxoprofen sodium (LXP), which is known to occur as a dihydrate, and identified parameters that influence the tablet hardness of LXP tablets prepared by the wet granulation method. Method: LXP granules were prepared with water or ethanol as the solvent, dried under various conditions and sieved for particle size control, with 1% Mg-st added before tablet compression. Results: The findings indicated that both the granulation solvent and drying temperature significantly impacted the tablet hardness. Granules prepared with ethanol exhibited higher hardness as compared with those prepared with water. The tablet hardness varied with varying drying temperatures. Discussion: Principal component analysis (PCA) identified positive correlations between the tablet hardness and the surface free energy (SFE), polar component (γ(p)), and cohesion, and a negative correlation with the dispersive component (γ(d)). Granules prepared with ethanol exhibited a higher γ(p), likely due to the differing solubility in ethanol and water, leading to enhanced interparticle binding. This study confirmed that use of the eutectic mixture of LXP and Mg-st exerted no significant influence. Crystal structure analysis indicated that the hydration states varied according to the drying temperature, suggesting the higher γ(p) in anhydrous forms, due to the lower hydrophobicity, contributed to increased tablet hardness. Conclusion: This research offers insights for optimizing the formulation conditions to improve the LXP tablet hardness. Appropriate selection of the solvent and drying temperature mitigates tablet hardness issues, while assessment of SFE can help in the selection of suitable additives.
The present study aimed to compare the efficacy and safety of loxoprofen sodium cataplasm (LSC) with those of flurbiprofen cataplasm (FPC) in osteoarthritis (OA) treatment. In this multicenter, randomized controlled trial, subjects meeting the inclusion and exclusion criteria were randomly assigned to the two treatment groups. According to the manufacturer's instructions, the first group received LSC once daily, with the application of one patch per area for 2 weeks, whereas the second group received FPC twice daily, with the application of one patch per area for 2 weeks. The treatment response was evaluated based on the Visual Analog Scale (VAS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) global score, Lysholm score and adverse events for 296 patients enrolled across three subcenters, with 192 patients in the LSC group and 104 patients in the FPC group. The treatment effectiveness rates, based on the VAS, WOMAC global and Lysholm scores, were 74.46, 61.41 and 85.25%, respectively, for the LSC group and 43.14, 31.37 and 66.67%, respectively, for the FPC group. Regardless of the effectiveness criterion used, the LSC group exhibited a superior treatment effectiveness rate compared with the FPC group. After 2 weeks of treatment, OA symptoms improved in both groups, with the LSC group exhibiting lower VAS (P<0.05) and WOMAC global scores (comprising pain, stiffness and physical function scores) compared with the FPC group (P<0.05), while the Lysholm score was higher in the LSC group compared with the FPC group (P<0.05). The FPC group experienced more general adverse events (P>0.05) and dressing shedding (P<0.05) compared with the LSC group, whereas the LSC group had more specific adverse events (such as skin itching, fever and allergy) compared with the FPC group (P>0.05). The results suggested that compared with FPC, LSC exhibited higher short-term efficacy and a consistent safety profile. The present study was registered at Chinese Clinical Trial Register (chictr.org.cn; ChiCTR2300072504; date of registration, June 15, 2023).
Acute Q fever, caused by Coxiella burnetii, is a zoonotic infection presenting with non-specific symptoms such as high fever, severe headache and myalgia, making it challenging to diagnose. Traditional diagnostic methods often fall short due to their time-consuming nature and limited sensitivity. A 26-year-old male presented with severe headache, persistent high fever and nausea following a hiking trip. Initial tests, including serology and PCR, were inconclusive. Targeted next-generation sequencing (tNGS) identified C. burnetii within 24 h, leading to a prompt diagnosis of acute Q fever. This rapid identification facilitated the initiation of appropriate antibiotic therapy, resulting in significant clinical improvement. This case underscores the diagnostic utility of tNGS in rapidly identifying rare pathogens and highlights its potential to influence clinical decision-making and improve patient outcomes. This case highlights the effectiveness of tNGS in diagnosing acute Q fever, particularly in regions where the disease is uncommon. The use of tNGS facilitated rapid identification and treatment, underscoring its potential as a valuable diagnostic tool in clinical practice.
Polymer-drug conjugate is widely used for drug delivery. Herein, we report an injectable hydrogel for local delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) using chitosan (CS) as a carrier polymer. Loxoprofen...
Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.
The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.
The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.
The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.
This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.
The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.
Aim: The present study deals with development and validation of accurate, sensitive and cost-effective RP-HPLC method for Loxoprofen sodium. Method: PRIMESIL C18 column (id 4.6 x 250 mm length) was used as stationary phase and a mobile phase used was mixture of methanol and 0.05% OPA buffer in ratios of 75:25 v/v. The 20µl samples were injected at a flow rate of 1 ml/min. The detector used is G-13148 (DAD) detector, with a wavelength observed of 225nm at ambient column temperature. Further, the method developed was validated as per ICH guidelines. Results: The method's linearity was studied at concentrations between 5 and 25µg/ml, wherein the results were found to be linear with correlation coefficient (r2) values of 0.999. The limits of detection and quantitation for developed method were observed to be 0.09175 and 0.278032 µg/ml respectively. The intraday and interday precision results were analysed and found to be within 2%. The percentage assay of the marketed product was found to be 101.85±0.090%. The percentage recovery of the drug was ranged between 97.7 1% to 101.09%. during accuracy study.
Loxoprofen sodium is a chiral drug with two chiral centers. In our previous work, we found that the elimination of its four isomers showed stereospecificity in rats, while how the stereospecific behavior occurred in vivo was unclear. To clarify this issue, each single isomer of loxoprofen sodium was prepared by a chiral semi‐preparative high‐performance liquid chromatography (HPLC) and then administered to rats. By analysis of each isomer in rat plasma utilizing an analytical chiral HPLC, it was discovered that the chiral inversion occurred only to its (2 R )‐isomers, one from (1′ S ,2 R )‐ to (1′ S ,2 S )‐isomer and the other from (1′ R ,2 R )‐ to (1′ R ,2 S )‐isomer. The reduction of α‐substituted cyclopentanone occurred only to its (1′ R )‐isomers, with (1′ R ,2 R )‐isomer reduced to (2′ S ,1′ R ,2 R )‐ trans ‐alcohol and (1′ R ,2 S )‐ to (2′ S ,1′ R ,2 S )‐ trans ‐alcohol. Interestingly, both the inversion and the reduction reaction occurred to its (1′ R ,2 R )‐isomer due to the special stereo‐structure with both (2 R )‐ and (1′ R )‐configuration, and conversely, neither of them occurred to its (1′ S ,2 S )‐isomer, which caused the significantly different elimination rate in vivo. These new findings were meaningful for evaluation of the safety and efficacy of chiral drugs.
Loxoprofen sodium (LOX) is a propionic acid derivative non-steroidal anti-inflammatory drug (NSAID), existing in the form of four stereoisomers. The main metabolites of LOX in vivo were trans- and cis-alcohol, each consisting of four stereoisomers. The objectives of the present study were to examine the selective pharmacokinetic behavior of LOX stereoisomers and stereoselective formation of its alcohol metabolites in rats based on a chiral liquid chromatographytandem mass spectrometry (LC-MS/MS) method by using an FLM Chiral NQ-RH column, which was reported for the first time. The significant difference in pharmacokinetic parameters of four stereoisomers indicated that stereoselective behavior has occurred in rats after oral administration of LOX. (1′S,2S)-LOX showed the highest concentration among the four stereoisomers in both plasma and urine samples. Trans- and cis-alcohol metabolites of LOX were also detected in plasma and urine, and trans-alcohol was found to be primary and the stereoisomeric fractions (SFs) of its four stereoisomers at different times were calculated. Examination of the stereoisomeric composition indicated a stereo preference for (2S)-configuration with respect to trans-alcohol formation. The overall results of the present study revealed the enantioselective pharmacokinetic properties of LOX stereoisomers in rats, which provided a means to advance understanding of the complex pharmacokinetic of LOX.
This is a reprint of articles from the Special Issue published online in the open access journal Molecules (ISSN 1420-3049) (available at: www.mdpi.com/journal/molecules/special issues/marine NP
diseases).
Background
Although acetaminophen is recommended for the treatment of mild-to-moderate cancer pain, acetaminophen-induced hepatic disorders pose an important clinical challenge. Concomitant prescription of immune checkpoint inhibitors (ICIs) may further increase the risk of hepatic disorders in patients taking acetaminophen; however, there are few clinical studies that confirm this.AimTo evaluate the risk of hepatic disorders in patients taking concomitant acetaminophen and ICIs using a disproportionality analysis from the Japanese Adverse Drug Event Report database.Method
Acetaminophen users aged ≥ 20 years were included; factors that can affect the risk of acetaminophen-induced hepatic disorders were collated. Similar data on the widely used analgesic, loxoprofen, were used for comparison.ResultsAmong 233,594 patients surveyed, 10,403 were prescribed acetaminophen, and among them, 1,245 patients developed hepatic disorders. The disproportionality of hepatic disorders was observed in acetaminophen users regardless of concomitant ICI use (without ICI: reporting odds ratio [ROR], 1.18; 95% confidence intervals [CI], 1.10–1.26; with ICI: ROR 1.87, 95%CI 1.59–2.20); it was even higher in concomitant acetaminophen and ICI users (ROR 1.94, 95%CI 1.65–2.29). However, increased disproportionality of hepatic disorders was not observed in patients taking concomitant loxoprofen and ICI. Multivariable logistic regression showed that the risk of hepatic disorders in acetaminophen users was associated with concomitant use of ICI (ROR, 1.91; 95% CI, 1.49–2.45); (P < 0.01).Conclusion
Our findings suggest that the risk of hepatic disorders is greater with concomitant acetaminophen and ICI treatment than with acetaminophen alone.
Six novel copper(II) complexes with the non–steroidal anti–inflammatory drugs ibuprofen, loxoprofen, fenoprofen and clonixin as ligands were synthesized and characterized by diverse techniques including single–crystal X–ray crystallography. The in vitro scavenging activity of the complexes against 1,1–diphenyl–picrylhydrazyl and 2,2′–azinobis(3–ethylbenzothiazoline–6–sulfonic acid) free radicals and the ability to reduce H2O2 were studied in the context of the antioxidant activity studies. The complexes may interact with calf–thymus DNA via intercalation as revealed by the techniques employed. The affinity of the complexes for bovine and human serum albumins was evaluated by fluorescence emission spectroscopy and the corresponding binding constants were determined. Molecular docking simulations on the crystal structure of CT DNA, human and bovine serum albumins were also employed in order to study in silico the ability of the studied compounds to bind to these target biomacromolecules, in terms of impairment of DNA and transportation through serum albumins, and to explain the observed in vitro activity and establish a possible mechanism of action.
Natural product is a well-known source of bioactive compounds. Herein, a steroidal compound stigmasta-7,22-diene-3-one (stigmastadienone) has been isolated from Isodon rugosus. The potency of isolated compound has been tested for several in-vitro targets. The acetyl and butyrylcholinesterase assays were performed using Ellman's procedure. For the in-vitro antidiabetic potential, α-glucosidase inhibitory assay was performed. Similarly, the cyclo and lipoxygenase pathways were studied to find its potential role in the management of inflammation and analgesia. The 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and hydrogen peroxide (H2O2) assays were performed for the antioxidant potentials. Docking studies were performed against acetylcholinesterase, cyclooxygenase and lipoxygenase targets. In anticholinesterase assays, stigmastadienone exhibited half-maximal inhibitory concentration (IC50) values of 13.52 and 11.53 μg/ml for acetyl and butyrylcholinesterase respectively. The observed IC50 values for that of galantamine were 6.07 and 4.42 μg/ml for acety and butyrylcholinesterase respectively. In inhibiting α-glucosidase enzyme, the compound showed mediocre IC50 of 109.40 μg/ml compared to the standard acarbose (7.60 μg/ml). The stigmastadienone proved to be an excellent inhibitor of cyclooxygenase 2 (COX-2) and 5-lipoxygenase (5-LOX) attaining IC50 values of 4.72 and 3.36 μg/ml respectively. The standard drugs IC50 values for COX-2 (celecoxib) and 5-LOX (montelukast) were 3.81 and 2.74 μg/ml respectively. The enzymatic activities of stigmastadienone were also supplemented with antioxidant results, specifically it was more dominant against DPPH and ABTS free radicals. Docking studies showed that only the carbonyl oxygen is able to form hydrogen bond interaction with the residues. In conclusions, the stigmastadienone has been isolated from Isodon rugosus for the first time. Moreover, the compound has been evaluated for several biochemical pathways which suggest its pharmacological role on the explored targets.
Background
As an anti-inflammatory prodrug, loxoprofen is metabolized into trans-loprofenol to treat diseases related to pain and inflammation. Although loxoprofen has fewer adverse effects than other NSAIDs, the safety of its usage during pregnancy remains unclear and needs to be considered. Fortunately, the toxicokinetics and tissue distribution study of trans-loxoprofen-alcohol in pregnant rats can resolve the problem.
Objective
The purpose of this study is to establish a simple, sensitive and effective LC-MS/MS analysis method for determination the concentration of trans-loxoprofen alcohol in plasma and tissues.
Methods
The analytic samples were precipitated by methanol in one step and separated using a reverse-phase Poroshell 120 EC-C18 column (4.6 mm×50mm; 2.7μm). And the gradient mobile phase at a flow rate of 0.6 mL/min was composed of acetonitrile and 0.1% formic acid in water. The quantitative detection was achieved by multiple-reaction monitoring mode with positive electrospray ionization source, transitional ion pairs of m/z 265.9>184.8 for trans-loxoprofen-alcohol, and 268.8>187.9 for rac-trans-loxoprofen-D3 alcohol (Internal standard).
Results
A good linearity of calibration curves for plasma and tissues were observed in the concentration range from 5.0 to 5000ng/mL, and the lower limit of quantification was detected at 5.0ng/mL. The intra-day and inter-day precision in plasma and tissues were within 8.94% and 7.26%, respectively. The mean extraction recovery and matrix effects in plasma and tissues were in the range of 89.08~109.27% and 89.00~106.80%, respectively. Precision of stability in plasma and tissues were within 8.91% and 7.08%, respectively.
Conclusion
Complying with the requirements of bioanalytical guidelines by validation, this method was successfully adopted to the toxicokinetics and tissue distribution study after intravenously administrated trans-loxoprofen-alcohol into pregnant SD rats.
Continued interest in bioactive alkaloids led to the isolation of four undescribed alkaloids along with 74 known ones from the aerial parts of Tabernaemontana bufalina Lour. The structures of the yet undescribed alkaloids were elucidated based on NMR, IR, UV, MS and CD spectroscopic data and X-ray crystal diffraction and, according to the plant source, named as taberhaines A-D (1-4). The known compounds comprised of 66 monoterpenoid indole, three carboline and five isoquinoline alkaloids. Among them, the known apparicine inhibited significantly the activity of xanthine oxidase, which plays an important role for gout, with an IC50 value of 0.65 μM, compared to the standard drug allopurinol (IC50 = 0.60 μM).
Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for the treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic metabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active, and cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated metabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is primarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism by CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX, since CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics (PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been fully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with dexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A, respectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in mice, and demonstrated that their PK parameters significantly changed in the presence of DEX or KTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active metabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed by CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we conclude that concomitant use of LOX with CYP3A modulators may lead to drug–drug interactions and result in minor to severe toxicity even though there is no direct change in the metabolic pathway that forms the LOX active metabolite.
Loxoprofen is a prodrug that exerts strong analgesic and anti‐inflammatory effects through its active trans‐alcohol metabolite, which is produced in the liver by carbonyl reductase. Previous metabolic studies have evaluated loxoprofen, but its sulfate and taurine conjugates have not yet been studied. We characterized the metabolomic profile of loxoprofen in rat plasma, urine, and feces using high‐resolution mass spectrometry. We identified 17 metabolites of loxoprofen in the three different biological matrices, 13 of which were detected in plasma and feces and 16 in urine. Amongst these metabolites, two novel taurine conjugates (M12 and M13) and two novel acyl glucuronides (M14, M15) were identified for the first time in rats. In addition, we detected three novel sulfate conjugates (M9, M10, and M11) of loxoprofen. Further study of these metabolites of loxoprofen is essential in order to assess their potency and toxicity.
Post-traumatic injury pain is commonly treated with oral nonsteroidal anti-inflammatory drugs (NSAIDs). However, oral NSAIDs causes several adverse events, with topical formulations arising as an important alternative. Therefore, we aimed to evaluate the efficacy and safety of loxoprofen patch in the treatment of patients with post-traumatic pain. This phase III, randomized, double-blind, non-inferiority study enrolled Brazilian patients aged 18-65 years diagnosed with lower and upper limbs post-traumatic injury who were experiencing moderate or severe pain. Patients were assigned to active loxoprofen patch (LX-P) or to loxoprofen tablet (LX-T) and pain intensity was measured based on a Visual Analog Scale (VAS) score variation after seven days of treatment. Data on clinical symptoms, rescue medication use, and adverse events were also collected. VAS score variation was compared using a 10% non-inferiority margin. Two hundred and forty-two patients were randomly assigned to the LX-P (n=123) or to LX-T (n=119). The results showed a reduction in pain after seven days of treatment: -49.96 (n=118; SE 1.7) in the LX-P and -47.71 (n=117; SE 1.6) in the LX-T groups (difference of -2.25; 95% CI: -5.97 - 1.47; p=0.23). On the safety analysis, LX-T group presented twice as many patients with treatment-emergent adverse events as the LX-P group (30.8% and 14.2%, respectively). A sensitivity analysis demonstrated that rescue medication use has not affected the primary endpoint. This study showed that LX-P has a comparable efficacy to LX-T, but with a better safety profile, being a therapeutic option for the treatment of post-traumatic injury pain.
Recycling countercurrent chromatography was successfully applied to resolution of 2‐(4‐bromomethylphenyl)propionic acid, a key synthetic intermediate for synthesis of nonsteroidal anti‐inflammatory drug loxoprofen, using hydroxypropyl‐β‐cyclodextrin as chiral selector. The two‐phase solvent system composed of n‐hexane/n‐butyl acetate/0.1 mol L⁻¹ citrate buffer solution with pH = 2.4 (8:2:10, v/v/v) was selected. Influence factors for the enantioseparation were optimized, including type of substituted β‐cyclodextrin, concentration of hydroxypropyl‐β‐cyclodextrin, separation temperature and pH of aqueous phase. Under optimized separation conditions, 50 mg of 2‐(4‐bromomethylphenyl)propionic acid was enantioseparated using preparative recycling countercurrent chromatography. Technical details for recycling elution mode were discussed. The purities of both the S and R enantiomers were over 99.0% as determined by high‐performance liquid chromatography. The enantiomeric excess of the S and R enantiomers reached 98.0%. The recovery of the enantiomers from eluted fractions was 40.8–65.6%, yielding 16.4 mg of the S enantiomer and 10.2 mg of the R enantiomer. At the same time, we attempted to enantioseparate the anti‐inflammatory drug loxoprofen by countercurrent chromatography and high‐performance liquid chromatography using a chiral mobile phase additive. However, no successful enantioseparation was achieved so far.
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Topical non-steroidal anti-inflammatory drugs (NSAIDs) are recommended in international and national guidelines as an early treatment option for the symptomatic management of knee and hand osteoarthritis (OA), and may be used ahead of oral NSAIDs due to their superior safety profile. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends topical NSAIDs for knee OA in addition to the pharmacological background of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) and rescue analgesia with paracetamol and non-pharmacological treatment, if the patient is still symptomatic. Topical NSAIDs have a moderate effect on pain relief, with efficacy similar to that of oral NSAIDs, with the advantage of a better risk:benefit ratio. In real-life studies, topical and oral NSAIDs demonstrate an equivalent effect on knee pain over 1 year of treatment, with fewer adverse events due to lower systemic absorption of topical NSAIDs compared with oral NSAIDs. As a result, topical NSAIDs may be the preferred treatment option, especially in OA patients aged ≥75 years, and those with co-morbidities or at an increased risk of cardiovascular, gastrointestinal, or renal side effects. Furthermore, using topical NSAIDs in inflammatory rheumatic diseases leads to a 40% reduction in the need for concomitant oral NSAIDs. When selecting a topical NSAID, absorption and bioavailability are important because of heterogeneity among topical drug formulations. Molecules like etofenamate have a bioavailability of >20% and evidence for accumulation in synovial tissues, with efficacy demonstrated as improvement in pain and function in real-life studies of OA patients. Diclofenac also shows good efficacy alongside evidence that diclofenac accumulates in the synovium.
The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) published a treatment algorithm for the management of knee osteoarthritis (OA) in 2014, which provides practical guidance for the prioritization of interventions. Further analysis of real world data for OA provides additional evidence in support of pharmacological interventions, in terms of management of OA pain and function, avoidance of adverse events, disease-modifying effects and long-term outcomes, e.g. delay of total joint replacement surgery, and pharmacoeconomic factors such as reduction in healthcare resource utilization. This paper provides an updated assessment of the literature for selected interventions in OA, focusing on real-life data, with the aim of providing easy-to-follow advice on how to establish a treatment flow in patients with knee OA in primary care clinical practice, in support of the clinicians’ individualized assessment of the patient. In step 1, background maintenance therapy with symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) is recommended, for which high-quality evidence is provided only for the prescription formulations of crystalline glucosamine sulfate and chondroitin sulfate. Paracetamol may be added for rescue analgesia only, due to limited efficacy and increasing safety signals. Topical non-steroidal anti-inflammatory drugs (NSAIDs) may provide additional symptomatic treatment with the same degree of efficacy as oral NSAIDs without the systemic safety concerns. Oral NSAIDs maintain a central role in step 2 advanced management of persistent symptoms. However, oral NSAIDs are highly heterogeneous in terms of gastrointestinal and cardiovascular safety profile, and patient stratification with careful treatment selection is advocated to maximize the risk:benefit ratio. Intra-articular hyaluronic acid as a next step provides sustained clinical benefit with effects lasting up to 6 months after a short-course of weekly injections. As a last step before surgery, the slow titration of sustained-release tramadol, a weak opioid, affords sustained analgesia with improved tolerability.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug–drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available.
There are several guidelines addressing the issues around the use of NSAIDs. However, none has specifically addressed the upper versus lower gastrointestinal (GI) risk of COX-2 selective and non-selective compounds nor the interaction at both the GI and cardiovascular (CV) level of either class of drugs with low-dose aspirin. This Consensus paper aims to develop statements and guidance devoted to these specific issues through a review of current evidence by a multidisciplinary group of experts.
A modified Delphi consensus process was adopted to determine the level of agreement with each statement and to determine the level of agreement with the strength of evidence to be assigned to the statement.
For patients with both low GI and CV risks, any non-selective NSAID (ns-NSAID) alone may be acceptable. For those with low GI and high CV risk, naproxen may be preferred because of its potential lower CV risk compared with other ns-NSAIDs or COX-2 selective inhibitors, but celecoxib at the lowest approved dose (200 mg once daily) may be acceptable. In patients with high GI risk, if CV risk is low, a COX-2 selective inhibitor alone or ns-NSAID with a proton pump inhibitor appears to offer similar protection from upper GI events. However, only celecoxib will reduce mucosal harm throughout the entire GI tract. When both GI and CV risks are high, the optimal strategy is to avoid NSAID therapy, if at all possible.
Time is now ripe for offering patients with osteoarthritis the safest and most cost-effective therapeutic option, thus preventing serious adverse events which could have important quality of life and resource use implications.
Purpose:
This study evaluated the bioequivalence of two types of topical loxoprofen patches, LX-A and LX-P, in healthy Chinese volunteers through a dermatopharmacokinetic approach.
Method:
Based on a pilot study, this study was designed as an open-label, self-controlled trial in 20 males. Subjects received application of two 3.2 x 3.2 cm2 pieces of LX-A and LX-P patches on their backs at randomly assigned positions simultaneously. Stratum corneum (SC) samples were taken with adhesive stripping tapes prior to patch application and at 20 hours and 24 hours postdose following removal of each loxoprofen patch, respectively. Bioassay was performed with a validated high performance liquid chromatography-tandem mass spectrometry method. Bioequivalence was evaluated through a power model on the total amount of loxoprofen at each post-application point and on the percentage change of SC loxoprofen content between the two time-points.
Results:
Mean (± standard deviation) total amount of SC-sampled loxoprofen was similar between LX-A and LX-P at 20 hours (38,722 ± 7,171 ng vs. 39,309 ± 9,688 ng) and 24 hours (36,638 ± 8,149 ng vs. 37,426 ± 9,029 ng) post-administration. The corresponding point estimate (90% confidence interval, 90%CI) of LX-P to LX-A was 1.00 (0.92, 1.09) and 1.02 (0.93, 1.12), respectively. In addition, the 24 hour/20 hour ratio for SC content of loxoprofen was statistically comparable between LX-A and LX-P, with both the point estimate and the 90% CI falling into the range of (0.80, 1.25).
Conclusion:
Our study indicated that LX-P and LX-A are two bioequivalent topical formulations of loxoprofen.
This study is aimed at comparing the efficacy and safety of loxoprofen sodium hydrogel patch (LX-P) with loxoprofen sodium tablet (LX-T) in patients with knee osteoarthritis (OA). One hundred sixty-nine patients were enrolled in a randomized, controlled, double-blind, double-dummy, multicenter, non-inferiority trial of LX-P. Patients were randomly assigned to either LX-P or LX-T groups for a 4-week treatment. The primary efficacy endpoint was the proportion of patients with an overall improvement of ≥50 %, and the secondary efficacy endpoint was the proportion of patients with an improvement of ≥25 % from baseline in each of the seven main symptoms. The non-inferiority trial was based on a power of 80 % and significance level of 2.5 % with a non-inferiority margin of -10 %. In both intention-to-treat (ITT) and per-protocol (PP) analyses, LX-P was as effective as LX-T in regard to the primary endpoint. In the ITT analysis, the difference between the two groups was 12.6 % [95 % confidence interval, -1.7 to 26.9 %]. No significant differences were found between the two groups in any of the secondary efficacy outcomes. A lower incidence of adverse events was observed in LX-P group; however, the difference was not statistically significant. No serious adverse events were reported in the LX-P group, whereas one case was reported in LX-T group. Based on the present study, topical loxoprofen patch was non-inferior to oral loxoprofen in patients with knee osteoarthritis.
Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy.
Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations.
The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR.
Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.
Although nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed globally, their chronic use increases the risk of upper gastrointestinal (GI) damage. Cyclooxygenase-2–selective NSAIDs are considered to reduce this risk. Current guidelines in Japan recommend loxoprofen sodium (loxoprofen), a pro-drug in the propionic acid class of nonselective NSAIDs, as first-line therapy in rheumatoid arthritis.
To confirm the superiority of celecoxib, a cyclooxygenase-2-selective NSAID, to loxoprofen in the incidence of gastroduodenal (GD) endoscopic ulcers.
A randomised, multicentre, placebo-controlled, double-blind, phase IV clinical trial in healthy Japanese volunteers [mean age 57.5 (range: 40–74) years; >70% female], stratified by Helicobacter pylori status at screening (∼40% positive) and randomised 2:2:1 to receive celecoxib 100 mg b.d., loxoprofen 60 mg t.d.s. or placebo. Primary end point was incidence of any GD endoscopic ulcers after 2 weeks of treatment.
Of 190 randomised subjects, 189 received at least one dose of celecoxib (n = 76), loxoprofen (n = 76), or placebo (n = 37). Incidence of GD ulcers was 1.4%, 27.6% and 2.7% in the celecoxib, loxoprofen and placebo groups respectively (P < 0.0001 in favour of the celecoxib group); incidence of adverse events (AEs) was 34.2%, 51.3% and 21.6% in the celecoxib, loxoprofen and placebo groups respectively. No serious or severe AEs were reported.
Celecoxib 100 mg b.d. was superior to loxoprofen 60 mg t.d.s. regarding the incidence of gastro-duodenal endoscopic ulcers over 2 weeks. Celecoxib was well tolerated and no major safety concerns were observed. ClinicalTrials.gov NCT00994461.
Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease.
/Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications.
All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered.
The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.
Background:
Selective cyclooxygenase-2 (COX-2) inhibitors, conventional non-selective nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen have been adopted for the relief of mild to moderate acute and chronic pain. However, it remains unclarified whether the therapeutic differences in pain sensation exist among these agents. The aim of this study was to compare the efficacy of different types of analgesic agents for postoperative acute pain management.
Methods:
A single-center, randomized, controlled study was performed in consecutive patients who underwent the second-look procedure with removal of internal fixation after anterior cruciate ligament reconstruction or arthroscopic meniscal repair/meniscectomy. Celecoxib (400 mg for the first dose and then 200 mg), loxoprofen (60 mg), or acetaminophen (600 mg) was orally administered from postoperative 3 h. The pain intensity on a 100-mm VAS scale and subjective assessment of therapeutic pain-relief were compared among these three treatment groups until postoperative 2 days. The acquired data were analyzed according to the per-protocol analysis principle.
Results:
A total of 432 patients were screened, and 160 were enrolled. The VAS score tended to decrease over time in all groups. There was a significant improvement in the pain score both at rest and on movement, and subjective impression in the celecoxib-treated group compared with acetaminophen at postoperative 2 days. On the other hand, loxoprofen resulted in the benefit only in the pain score at rest in comparison with acetaminophen. Any comparisons between celecoxib and loxoprofen showed insignificant differences throughout observations. No adverse effects were confirmed in each group.
Conclusions:
These obtained findings in our dose setting conditions suggest that celecoxib and loxoprofen treatments were superior to acetaminophen in pain-relief, though the superiority of loxoprofen over acetaminophen was modest. Overall, selective COX-2 inhibitors including conventional NSAIDs seem to have a possible advantage in acute pain management of relatively less invasive surgery.
Objective: To evaluate the efficacy and safety of loxoprofen sodium in treatment of patients with osteoarthritis (OA). Methods: The study was conducted in 40 patients of OA by a random, open and controlled method. All of them were in line with the criteria of American College of Rheumatology. They were divided to receive oral loxoprofen 60 mg tid or sustained release ibuprofen 300 mg bid for 4 weeks. Results: After 4 weeks treatment, all parameters including active pain of knee, time for walking 15 meters, ability of daily life and patientself-evaluation in patients with OA were significantly improved by both agents (ibuprofen and loxoprofen sodium), but there was no significant difference between the 2 medicine groups. Conclusion: Loxoprofen is as effective as ibuprofen in treatment of patients with OA, and has milder side effects.
Gastroenterologists care for users of nonsteroidal anti-inflammatory drugs (NSAIDs) when the vast population exposed to the medication class experiences a relatively uncommon serious gastrointestinal (GI) side effect. As serious adverse cardiovascular (CV) effects of these drugs have also been recognized, there remains continued confusion about the best treatment for patients who benefit from NSAID therapy and are at risk for GI and CV adverse events. Recognition of those patients at risk and strategies to reduce the adverse side effects of NSAIDs continues to provide an opportunity to improve patient outcomes. This review discusses the injury induced by these agents throughout the GI tract as well as strategies to prevent acute injury and reduce the development of serious adverse events. NSAID medication selection as well as GI cotherapy should balance individual patients' GI and CV risks.
The aim of this study was to compare celecoxib with loxoprofen for protection of small intestine.
RCT studies report that COX-2 selective inhibitor celecoxib induces fewer small intestinal injuries than nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a prodrug nonselective NSAID developed to protect upper gastrointestinal tract.
A total of 150 healthy volunteers (40 to 70 y) were enrolled. After medical checkup including laboratory data, subjects were randomly assigned to celecoxib (200 mg daily) or loxoprofen (180 mg daily) plus lansoprazole (15 mg daily). All drugs were prepared using inactive capsules. After randomization, all subjects were first examined by baseline capsule endoscopy (CE). After 14 days, subjects underwent posttreatment CE. We compared baseline and posttreatment CE findings of the 2 groups. All CE data were evaluated blindly by 3 reviewers. Pretreatment and posttreatment laboratory variables were also compared.
A total of 74 subjects (49±6 y, F/M: 36/38) were enrolled in celecoxib group and 76 subjects (49±7 y, F/M: 39/37)in loxoprofen group. Five in celecoxib group and 4 in loxoprofen group were excluded from CE analysis mainly due to incomplete CE. The percentage of subjects with at least 1 posttreatment mucosal break was lower in celecoxib group (10%) than in loxoprofen group (49%) (P<0.0001). A total of 0.3±1.0 posttreatment small intestinal mucosal breaks were detected in the celecoxib group, and 6.8±21.5 in the loxoprofen group (P<0.0001). Posttreatment hemoglobin concentration in loxoprofen group (5.1% reduction) was lower compared with celecoxib group (2.1% reduction) (P=0.006).
In terms of protection of small intestine from NSAIDs toxicity, celecoxib monotherapy was superior to loxoprofen+lansoprazole combination therapy (UMIN: 000007936).
Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used to treat inflammation, pain, and fever, but no criterion standard exists for the management of postoperative pain following spinal surgery. In the present study, we compared the analgesic efficacy of loxoprofen sodium (loxoprofen) and celecoxib for the management of postoperative pain following spinal surgery.
One-hundred forty-one patients (mean age 62.2 years) were randomly assigned to two groups before spinal surgery: a loxoprofen group (n = 73, 180 mg/day) and a celecoxib group (n = 68, 200 mg/day). The drugs were administered from 1 day until 7 days after surgery. A numeric rating scale (NRS) was used to evaluate pain at nine predefined times every day and the findings were compared between the two groups. Laboratory data and adverse events were also recorded.
There was no significant difference in the maximum and mean NRS scores on each day between loxoprofen and celecoxib, suggesting a comparable analgesic effect for these two NSAIDs. Greater improvement in the NRS score between preadministration (baseline) and 30 min or 2 h after administration was obtained for loxoprofen. This tendency was shown for both slight (NRS score <5 at baseline) and severe pain (NRS score ≥5 at baseline). Loxoprofen was discontinued in one patient on day 4 because of renal dysfunction. Celecoxib was discontinued in one patient on day 2 at the patient's request.
Both loxoprofen sodium and celecoxib were well tolerated for the relief of acute postoperative pain after spinal surgery. A single administration of loxoprofen showed superior and rapid effectiveness compared with celecoxib for both slight and severe postoperative pain.
In this open multicentre trial, loxoprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID) 180 mg/day (60mg three times daily) was administered to 4024 elderly (mean age 72.5 years) patients with lumbar pain associated with a range of rheumatic disorders, for a period of up to 8 weeks. Efficacy was evaluated by objective and subjective methods. At week 4, loxoprofen showed subjective improvements of 83%, 30% and 24% in patients with mild to moderate, moderate to severe, and severe lumbar pain, respectively. Objective and subjective improvements were significant after only 1 week’s therapy in patients with mild to moderate pain and after 4 weeks over all intensities of pain.
The incidence of adverse events over this large study population was extremely low, affecting only 2.2% of patients, and were mostly mild in nature and affecting the digestive tract. Loxoprofen is thus a well-tolerated NSAID in the treatment of lumbar pain in elderly patients.
Aim:
Non-steroidal anti-inflammatory drugs have the potential to injure the mucosa of the upper digestive tract and small bowel, whereas celecoxib (a selective cyclooxygenase-2 inhibitor) has less influence on the entire digestive tract mucosa. The present study was conducted to compare the extents of small bowel mucosal injury induced by celecoxib and loxoprofen (the most frequently used non-steroidal anti-inflammatory drugs in Japan).
Methods:
Ten healthy adult males were given celecoxib (200 mg/day, Group C) and loxoprofen (180 mg/day, Group L) in a cross-over design for 14 days, and the influence of each drug on small bowel mucosa was evaluated by comparing pre- and post-treatment capsule endoscopy findings. We measured the percentage of patients with small bowel mucosal injury following administration of these drugs as primary endpoint. Additionally, mean number of small bowel mucosal injuries per subject was analyzed as secondary endpoint.
Results:
The percentage of subjects experiencing small bowel mucosal injury as primary endpoint was 10% in Group C and 70% in Group L after treatment. This magnitude of the difference of between Group C and Group L was statistically significant (P = 0.031). The number of small bowel mucosal injuries as secondary endpoint differed significantly between the two groups, and the influence of celecoxib on small bowel injury was less than that of loxoprofen.
Conclusion:
These results indicate that celecoxib has less influence on small bowel mucosa than loxoprofen and can be used safely.
To update the American College of Rheumatology (ACR) 2000 recommendations for hip and knee osteoarthritis (OA) and develop new recommendations for hand OA.
A list of pharmacologic and nonpharmacologic modalities commonly used to manage knee, hip, and hand OA as well as clinical scenarios representing patients with symptomatic hand, hip, and knee OA were generated. Systematic evidence-based literature reviews were conducted by a working group at the Institute of Population Health, University of Ottawa, and updated by ACR staff to include additions to bibliographic databases through December 31, 2010. The Grading of Recommendations Assessment, Development and Evaluation approach, a formal process to rate scientific evidence and to develop recommendations that are as evidence based as possible, was used by a Technical Expert Panel comprised of various stakeholders to formulate the recommendations for the use of nonpharmacologic and pharmacologic modalities for OA of the hand, hip, and knee.
Both “strong” and “conditional” recommendations were made for OA management. Modalities conditionally recommended for the management of hand OA include instruction in joint protection techniques, provision of assistive devices, use of thermal modalities and trapeziometacarpal joint splints, and use of oral and topical nonsteroidal antiinflammatory drugs (NSAIDs), tramadol, and topical capsaicin. Nonpharmacologic modalities strongly recommended for the management of knee OA were aerobic, aquatic, and/or resistance exercises as well as weight loss for overweight patients. Nonpharmacologic modalities conditionally recommended for knee OA included medial wedge insoles for valgus knee OA, subtalar strapped lateral insoles for varus knee OA, medially directed patellar taping, manual therapy, walking aids, thermal agents, tai chi, self management programs, and psychosocial interventions. Pharmacologic modalities conditionally recommended for the initial management of patients with knee OA included acetaminophen, oral and topical NSAIDs, tramadol, and intraarticular corticosteroid injections; intraarticular hyaluronate injections, duloxetine, and opioids were conditionally recommended in patients who had an inadequate response to initial therapy. Opioid analgesics were strongly recommended in patients who were either not willing to undergo or had contraindications for total joint arthroplasty after having failed medical therapy. Recommendations for hip OA were similar to those for the management of knee OA.
These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines, informed by available evidence, balancing the benefits and harms of both nonpharmacologic and pharmacologic modalities, and incorporating their preferences and values. It is hoped that these recommendations will be utilized by health care providers involved in the management of patients with OA.
Gastrointestinal (GI) disorders are common adverse reactions of nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a representative NSAID widely used in East Asia. A selective cyclooxygenase-2 inhibitor, celecoxib, was introduced in Japan in 2007. In this study, we aimed to compare the efficacy and safety of celecoxib with those of loxoprofen in Japanese patients.
We analyzed the data from 12 clinical studies conducted in Japan. These data of Japanese patients were compared with those of the patients in the West that had been published after 2000.
The efficacy of celecoxib as an analgesic was comparable to that of loxoprofen, whereas serious GI events, including symptomatic ulcers, were significantly less frequent with celecoxib than with loxoprofen in Japanese patients with rheumatoid arthritis (RA) and osteoarthritis (OA) (p = 0.039). These results were consistent with the findings of the studies conducted in the West. The incidence of serious cardiovascular events was 0.1% in 2,398 subjects on celecoxib, which was not statistically different from the incidence in subjects on loxoprofen (0.3%; p = 0.3404) and those on placebo (0.2%); this result was also consistent with the data of the studies conducted in the West.
The analgesic activity of celecoxib, which was used for the treatment of RA, OA, and low back pain, was comparable to that of loxoprofen, and celecoxib was safer in terms of GI injury often caused by other nonselective NSAIDs.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin are widely used clinically but increase the risk of gastrointestinal (GI) complications.
To examine the current prescription of NSAIDs and comedication to prevent GI complications from NSAIDs within East Asia by means of a questionnaire survey.
Representative members of the Committee of the International Gastrointestinal Consensus Symposium provided a questionnaire to physicians in 6 East Asian countries.
A total of 1,568 physicians participated in this survey. Most physicians prescribed nonselective NSAIDs, cyclooxygenase-2 inhibitors (COXIBs) or aspirin for more than 5 patients per week in all countries, with the exception of the prescription of COXIBs in Japan. Of the nonselective NSAIDs, the drug most frequently prescribed as a first choice was loxoprofen (34%), which was mainly prescribed in Japan, followed by diclofenac (30%). The frequency of prescription of comedication with nonselective NSAIDs was higher compared with that for selective COXIBs or aspirin. Physicians in the northern region (China, Japan and Korea) preferred mucoprotective drugs for comedication with NSAIDs or aspirin, while those in southern region (Indonesia, Philippines and Thailand) frequently used proton-pump inhibitors.
Among East Asian countries, there are both similarities and differences in the prescription of NSAIDs and of comedication to prevent GI complications.
Non-steroidal anti-inflammatory drugs (NSAID) are, and have been, frequently used for alleviation of pain in patients; however, they are known to cause gastric mucosal injury in experimental animals and in humans. A decrease in the gastric mucosal blood flow also plays an important role in the aetiology of acute gastric mucosal injury, as we previously reported. This study investigated the effect of a newly synthesized NSAID, loxoprofen sodium (sodium 2[p-2 oxocyclopentylmethyl) phenyl]propionate dihydrate, on gastric mucosal haemodynamics using a reflectance spectrophotometry system. Both single and cross-over methods were used in five volunteer subjects. Loxoprofen sodium 60 mg (one tablet) or indomethacin 25 mg (one tablet), was diluted in 10 mL water at 25 degrees C and sprayed on the gastric mucosa via a polyethylene tube inserted into the biopsy channel of an endoscope. After drug administration, reflectance spectra were taken every 5 min for 30 min. The indices of mucosal haemoglobin content (IHb) and oxygen saturation of haemoglobin (ISO2) were determined by the method previously reported by the authors. Indomethacin administration produced a significant decrease in both IHb and ISO2 values, indication ischaemia. Loxoprofen sodium, however, showed no significant differences in either of the parameters. Haemorrhagic erosions were evident after indomethacin administration, but none were found after loxoprofen sodium administration. The conclusion reached on the basis of this evidence is that one-time topical application of loxoprofen sodium is safer than indomethacin.
We investigated the mechanism of inhibition of loxoprofen sodium, a non-steroidal anti-inflammatory drug (NSAID), and its active metabolite (loxoprofen-SRS) on cyclooxygenase (COX). In in vitro assays, loxoprofen sodium appeared inactive against recombinant human COX-1 and COX-2, whereas loxoprofen-SRS inhibited both. In the investigation of kinetic behavior, loxoprofen-SRS showed time-dependent inhibition for both isozymes. Human whole blood assay also showed that loxoprofen-SRS possesses the profile of a non-selective inhibitor for COX. In a rat air pouch model, oral administration of loxoprofen sodium lowered prostaglandin (PG) E2 in both fluid exudates of the inflammatory pouch and stomach tissue with ED50 values of 2.0 and 2.1 mg/kg, respectively. Additionally, platelet thromboxane B2 production was also inhibited by loxoprofen sodium (ED50 of 0.34 mg/kg). In a rat carrageenan-induced paw edema model, loxoprofen sodium dose-dependently reduced the paw edema, accompanied by a decrease in PGE2 content in inflamed paw exudates. These findings suggest that the COX inhibitory activity of loxoprofen sodium is attributable to its active metabolite, loxoprofen-SRS, and that loxoprofen-SRS shows non-selective inhibition for COX.
Current evidence indicates that selective COX-2 inhibitors have important adverse cardiovascular effects that include increased risk for myocardial infarction, stroke, heart failure, and hypertension. The risk for these adverse effects is likely greatest in patients with a prior history of or at high risk for cardiovascular disease. In these patients, use of COX-2 inhibitors for pain relief should be limited to patients for whom there are no appropriate alternatives, and then, only in the lowest dose and for the shortest duration necessary. More long-term data are needed to fully evaluate the extent to which these important adverse cardiovascular effects may be offset by other beneficial effects of these medications. More data are also needed on the cardiovascular safety of conventional NSAIDs. Until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods of time should only be considered in consultation with a physician. The debate about the increased risk of cardiovascular events attributed to the selective COX-2 inhibitors and the nonselective NSAIDs is part of a broader national debate about drug safety. Optimal safety evaluation of drugs requires timely and complete submission of scientific data from the manufacturers, as well as increased funding and authority granted to the FDA by Congress.
Loxoprofen sodium tablets: Chinese prescribing information
- Daiichi Sankyo Co Ltd
Loxonin® (loxoprofen sodium) tablets 60 mg, fine granules 10 %: Japanese interview form on drugs
- Daiichi Sankyo Co Ltd
Effectiveness and safety of hydrogel patches containing loxoprofen sodium in patients with myalgia: a randomized, controlled, double-blind, double-parallel, multicenter phase 3 trial
- D B Zhao
- Y Q Shi
- Z G Li
Loxonin® Pap 100 mg, Tape 50 mg and 100 mg (loxoprofen sodium hydrate patches): Japanese interview form on drugs
- Daiichi Sankyo Co Ltd
Loxoprofen patches: Chinese prescribing information
- Daiichi Sankyo Co Ltd
Loxonin® Pap 100 mg, Tape 50 mg and 100 mg, Gel 1 %: Japanese summarized product information
- Daiichi Sankyo Co Ltd
Double-blind, multicenter trial to evaluate safety and efficacy of hydrogel patch containing loxoprofen-sodium in treating swelling and pain caused by trauma
- H Zhang
- J Lin
- T Sun
Absorption, distribution, metabolism and excretion after dermal application of hydrogel patch containing loxoprofen sodium in rats
- T Matsuzawa
- H Sairo
- A Kurihara
Evaluation of administration frequency of LX-A in patients with osteoarthritis of the knee: randomized, open label study compared between once-daily administration and twice-daily administration
- S Sugawara
- A Tateishi
- M Tanaka
Loxoprofen sodium (CS-600), a new non-steroidal anti-inflammatory drug
- K Tanaka
- A Terada
- Y Iizuka
The effects of Loxonin
- S Sugawara
- Y Kuroki
- M Tanaka
Anti-inflammatory and analgesic effects of hydrogel patches containing loxoprofen sodium
- T Hamamoto
- S Takeuchi
- M Sasakura
Comparative study of the clinical efficacy of the selective cyclooxygenase-2 inhibitor celecoxib compared with loxoprofen in patients with frozen shoulder
- S Ohta
- O Komai
- H Hanakawa
Pharmacokinetic study of the hydrogel patch containing loxoprofen sodium (LX-A) following 5 days applications repeated once or twice a day
- S Sugawara
- S Hasegawa
- H Naganuma
The effects of Loxonin
- S Sugawara
- Y Iwasaki
- T Aoki
Clinical efficacy of the hydrogel patch containing loxoprofen sodium (LX-A) on myalgia: a randomized, open label clinical study compared with indometacin patch (phase III therapeutic confirmatory study)
- S Sugawara
- F Nobuoka
- D Ogawa
Drug use result survey of Loxonin
- H Mizutani
- F Miyano
- A Uozu
Chinese Orthopaedic Association. Diagnosis and treatment of osteoarthritis
Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the
- E M Antman
- J S Bennett
- A Daugherty
- EM Antman