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Objectives: To evaluate the efficacy and safety of non-steroid mineralocorticoid receptor antagonists (ns-MRAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) in patients with diabetic kidney disease (DKD). Methods: Systematic literature searches were performed using PubMed, Embase and Web of Science encompassing inception until January 20, 2024. Randomized control trials (RCTs) comparing ns-MRAs and SGLT2is in DKD were selected. The efficacy outcomes of interest included kidney-specific composite outcome, cardiovascular (CV)-specific composite outcome, end-stage kidney disease (ESKD), and overall mortality. We also investigated safety outcomes, including acute kidney injury (AKI) and hyperkalemia. Results: A total of 10 randomized clinical trials with 35,786 patients applying various treatments were included. SGLT2is (SUCRA 99.84%) have potential superiority in kidney protection. SGLT2is (RR 1.41, 95%CI 1.26 to 1.57) and ns-MRAs (RR 1.17, 95% CI 1.08 to 1.27) were associated with significantly lower kidney-specific composite outcome than the placebo. Regarding the reduction in CV-specific composite outcome and ESKD, SGLT2is (SUCRA 91.61%; 91.38%) have potential superiority in playing cardiorenal protection. Concerning the CV-specific composite outcome (RR 1.27, 95%CI 1.09 to 1.43) and ESKD (RR 1.43, 95%CI 1.20 to 1.72), SGLT2is significantly reduced the risks compared to placebo. Regarding the reduction in overall mortality, SGLT2is (SUCRA 83.03%) have potential superiority in postponing mortality. Concerning the overall mortality, SGLT2is have comparable effects (RR 1.27, 95%CI 1.09 to 1.43) with placebo to reduce the risk of overall mortality compared to placebo. For AKI reduction, ns-MRAs (SUCRA 63.58%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. For hyperkalemia reduction, SGLT2is (SUCRA 93.12%) have potential superiority. SGLT2is have comparable effects (RR 1.24, 95%CI 1.05 to 1.46) with placebo to reduce the risk of AKI. Concerning hyperkalemia reduction, nsMRAs (RR 1.24 95%CI 0.39 to 3.72) and SGLT2is (RR 1.01 95%CI 0.40 to 3.02) did not show significant benefit compared to placebo. Conclusion: Concerning the efficacy and safety outcomes, SGLT2is may be recommended as a treatment regimen for maximizing kidney and cardiovascular protection, with a minimal risk of hyperkalemia in DKD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023458613.

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BACKGROUND: Hepatocellular Carcinoma (HCC) can be classified as one of the most common malignancies worldwide. There is scarcity of the published data on the risk factors for HCC in the Gulf Cooperation Council countries specifically Kuwait. Therefore, this case-control study sought to examine the risk factors associated with HCC in Kuwait. METHODS: Fifty-three histopathologically confirmed HCC cases were recruited from the Kuwait Cancer Control Center Registry. One hundred ninety-six controls (1:4 ratio) were selected from medical and/ or surgical outpatient's clinics at all six public hospitals of Kuwait. A structured questionnaire was used to collect the data both from cases and controls through face-to-face interviews. A multivariable logistic regression model was fitted to the case-control data. Adjusted odds ratios (ORadj) and their 95% confidence intervals (CI) were computed using the parameters' estimates of the final model and used for interpretation of the model. RESULTS: The HCC cases compared with the controls were 41.6 times more likely to have had the history of non-alcoholic fatty liver disease (NAFLD) (ORadj = 41.6; 95% CI: 8.9-193.5; p < 0.001). The cases compared with the controls were more likely to have reported the history of heavy alcohol drinking (ORadj = 14.2; 95% CI: 1.2-173.4; p = 0.038). Furthermore, compared with the controls, the HCC cases tended to frequently consume milk and/or milk substitutes (≥ 3 glass/ week) (ORadj = 7.2; 95% CI: 1.2-43.4). Conversely however, there was a significant protective effect if the participants reportedly have had regularly used olive oil in their routine diet as a source of fat (ORadj = 0.17; 95% CI: 0.04-0.80) or regularly used non-steroid anti-inflammatory drugs (NSAIDs) (ORadj = 0.20; 95% CI: 0.05-0.71). CONCLUSIONS: This study showed that heavy alcohol consumption, NAFLD history, and excessive consumption of milk/ milk substitutes were associated with a significantly increased HCC risk. Conversely however, regular use of olive oil in the diet as a source of fat or regular use of NSAIDs had a significantly protective effect against HCC risk. Adapting healthy dietary habits and preventing/ treating NAFLD may minimize the HCC risk. Future research with a larger sample size may contemplate validating the results of this study and unraveling additional risk factors contributing to HCC risk. The resultant data may help design and implement evidence-based educational programs for the prevention of HCC in this and other similar settings.

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BACKGROUND: Andrographolide (AP), a bioactive anti-inflammatory compound of Sambiloto, inhibits NF-κB, TNF-α, and interleukin IL-6. Nowadays, molecular docking simulation between AP and dexamethasone against NF-κB receptor presented the energy AP higher than dexamethasone. This becomes a potential treatment for psoriasis. OBJECTIVE: This manuscript reported the effectiveness of AP from Sambiloto in treating psoriasis compared to topical steroids. METHODS: This study conducted TLC analysis of AP content and its metabolite impurities, emulgel formulation, molecular docking, in-silico skin toxicity study, and in-vivo anti-psoriatic activity. This was a combination study of an in-silico study and an in-vivo study. This in-silico study was analyzed through multivariate statistical analysis (PCA) to elucidate the data constellation relationship of andrographolide derivatives with several target proteins. The intervention was performed in seven days. The PASI score, molecular parameters (IL-6, IL-17, VEGF, and TNF-a levels), and histopathological findings were assessed. RESULTS: Molecular docking results revealed andrographolide to exhibit a relatively high binding affinity towards IL-6, NF-kB, and TNF-α which is comparable to the corticosteroids, andrographolide also shares similar residue interaction profile with each of the respective protein's native ligand. In the in-vivo study, we found several parameters statistically significantly different regarding the intervention, including final PASI score (p = 0.017), redness (p = 0.017), scale (p = 0.040), thickness (p = 0.023), total histopathology of psoriasis score (p = 0.037), keratin layer score (p = 0.018). CONCLUSION: Emulgel AP 0.1% could lower the anti-inflammatory agent, which is vital to psoriasis progression.

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OBJECTIVE: Subacute thyroiditis(SAT) is an acute inflammatory, self-limited, and destructive disease of the thyroid gland. Although it is a temporary disease, it has permanent consequences. We aim to investigate the influences of the treatment choice on permanent hypothyroidism occurring after SAT and whether there are predictive factors for the development of permanent hypothyroidism. METHODS: We retrospectively investigated 57 SAT patients admitted to our tertiary hospital between 2017 and 2019. After excluding 6 patients, demographic, clinical, laboratory, and imaging findings of 36 patients treated with NSAIDs and 15 patients treated with corticosteroids were compared. The median duration of follow-up was 4 (3.5-5.5) years. RESULTS: Permanent hypothyroidism occurred in 16 patients (31.4%) of 51 patients. It developed at a significantly higher rate in NSAID users (p=0.019). There was no significant difference in the occurrence of transient hypothyroidism and recurrence (p=0.472, p=0.082). The early maximum TSH values were strongly associated with permanent hypothyroidism. The Odds Ratio (OR) value was 2.59 (95% CI = 1.26 - 5.33, p=0.009), Nagelkerke R2 = 0.821. The early maximum TSH level had a predictive value, with an AUC of 0.966 for post-SAT permanent hypothyroidism (p<0.001). The cutoff values for the early maximum TSH were 9.07uIU/ml (81.3% sensitivity, 100% specificity), and 7.05 uIU/ml (87.5% sensitivity, 94.3% specificity). CONCLUSION: Corticosteroid therapy is significantly effective in preventing permanent hypothyroidism from developing after SAT. The early maximum TSH values are an indicator for the prediction of the development of permanent hypothyroidism.

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Post-marketing hepatotoxicity findings are more common or occur much later. NSAIDs (non-steroidal anti-inflammatory drugs) like ibuprofen are consumed in large quantities around the world. NSAIDs have a low incidence of hepatotoxicity but their wide use makes them a major contributor to drug-induced liver injury. Hepatitis is linked to systemic oxidative stress which results in cellular necrosis and fibrosis, as well as tissue lipoprotein peroxidation and glutathione depletion. Given the lack of safe and effective anti-hepatitis drugs in medicine today, natural substances appear to be a promising and safe alternative. Propolis and chitosan are considered natural substances that have a protective effect on the hepatocytes. The purpose of this study was to validate the protective effect of propolis/chitosan nanoparticle extracts on ibuprofen-induced hepatotoxicity. Thirty (30) albino rats were used for the experiment. Animals were exposed to ibuprofen (400 mg/kg body weight/day) for 4 weeks (7 days/week) followed by treatment with propolis (200 mg/kg body weight/day) and chitosan extract (200 mg/kg body weight/day) separately and also in combination for consecutive 4 weeks. This study revealed a significant increase in serum transaminases, alkaline phosphatase, albumin, and total bilirubin in serum, as well as an increase in lipid peroxidation (MDA) and nitric oxide (NO). Furthermore, GSH, GST, and SOD decreased significantly in the group that was exposed to ibuprofen. Furthermore, there was a significant increase in pro-inflammatory parameters such as IL-1ß and NF-ĸB, as well as low levels of anti-inflammatory parameters such as IL-6 and BCl-2. These alterations were improved by propolis and chitosan extracts, which was further confirmed in experimental animals. This study demonstrated that propolis and chitosan nanoparticle extracts have the potential to protect against hepatotoxicity induced by ibuprofen, due to their ability to regulate anti-inflammatory and anti-oxidative defense activities.

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BACKGROUND: Although NSAIDs possess notable therapeutic and pharmaceutical qualities, it's essential to acknowledge that excessive doses can result in toxicity within the human body. Moreover, the importance lies in identifying and measuring their trace amounts. Due to their existence within intricate matrices, the creation of novel electrospun nanofibers as sorbents for electrically-assisted solidphase microextraction (EA-SPME) becomes vital. This innovation caters to the requirement for the effective pre-treatment of NSAID samples, providing a strategic approach to managing the complexities associated with trace quantities found in various matrices. RESULTS: First, polyvinylalcohol/casein/tannic acid/polyaniline/titanium dioxide nanoparticles (PVA/CAS/TA/PANI/TiO2 NPs) electrospun nanofibers were prepared for EA-SPME on pewter rode and then, trace amounts of six NSAIDs (Acetaminophen, Caffeine, Naproxen, Celecoxib, Ibuprofen and mefenamic acid) were adsorbed chemically on these nanofibers. In the next step, the desorption of six NSAIDs was electrochemically done from prepared electrospun nanofibers on a pewter rod which was as working electrode at three electrodes system. Finally, these drugs were quantified from different human plasma samples with HPLC-UV. The synthesis of electrospun nanofibers was confirmed through a series of analytical techniques including field emission-scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy with elemental mapping analysis (EDX-Mapping), X-ray diffraction (XRD), and Fourier transform-infrared (FT-IR). The optimal percentage of additive compounds to PVA/CAS for electrospinning, as well as the factors influencing adsorption and desorption processes, were determined through both of Design Expert software and MATLAB programming language. SIGNIFICANCE: Under optimum conditions, the wide linear range was 27-8000 ng mL-1 with R2≥ 0.9897, low detection limits were ranged from 8 to 27.3 ng mL-1 based on S/N = 3 and significant enrichment factors were acquired. The intra-day and inter-day RSDs% were obtained within the 4.51% - 5.68% and 4.28%-5.45%, respectively. Finally, The effectiveness of the EA-SPME-HPLC-UV method was assessed for determining NSAIDs in plasma samples, demonstrating good recoveries ranging from 90.2% to 105.2%.

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Periorbital emphysema is rare and associated with facial trauma. Its main distinguishing feature is crepitation on palpation of the edema. It resolves spontaneously in a few days, but there are cases of orbital compartment syndrome that can lead to loss of vision. Here we present the case of a 55-year-old male who came to the emergency department for bilateral periorbital edema associated with non-steroidal anti-inflammatory drug (NSAID) usage, for pain following a fall from a ladder. He was treated with antihistamines and corticosteroids, for presumed allergic reaction, but without response, and subsequently developed acute onset dyspnea. Chest x-ray revealed a left pneumothorax in the context of chest trauma. Chest CT scan after drain placement shows extensive subcutaneous emphysema. In the differential diagnosis of periorbital edema, in addition to allergic, inflammatory, and systemic causes, the traumatic ones should not be excluded.

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AIMS: The use of non-steroid anti-inflammatory drugs (NSAIDs) is conventional in management of postoperative pain in cancer patients, and further investigations have reported that some of these drugs correlated with the outcome in cancers. However, the prognostic value of the use of NSAIDs during surgery in non-small cell lung cancer (NSCLC) patients has been less addressed. METHODS: NSCLC patients staged I-III are retrospectively enrolled, and the data of the use of NSAIDs during surgery are collected. Patients are divided into two subgroups according to the use intensity (UI) (low or high) of the NSAIDs, which was calculated by the accumulate dosage of all the NSAIDs divided by the length of hospitalization. The differences of the clinical features among these groups were checked. And the disease-free survival (DFS) and overall survival (OS) differences in these groups were compared by Kaplan-Meier analysis; risk factors for survival were validated by using a Cox proportional hazards model. RESULTS: The UI was significant in predicting the DFS (AUC = 0.65, 95% CI: 0.57-0.73, P = 0.001) and OS (AUC = 0.70, 95% CI: 0.59-0.81, P = 0.001). Clinical features including type of resection (P = 0.001), N stages (P < 0.001), and TNM stages (P = 0.004) were significantly different in UI low (< 74.55 mg/day) or high (≥ 74.55 mg/day) subgroups. Patients in UI-high subgroups displayed significant superior DFS (log rank = 11.46, P = 0.001) and OS (log rank = 7.63, P = 0.006) than the UI-low ones. At last, the UI was found to be an independent risk factor for DFS (HR: 0.52, 95% CI: 0.28-0.95, P = 0.034). CONCLUSIONS: The use of NSAIDs during radical resection in NSCLC patients correlated with the outcome and patients with a relative high UI has better outcome.

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We have designed a new compound from the non-steroidal anti-inflammatory drug (NSAID) ketoprofen (Ket) and 2-amino-2-(hydroxymethyl)-1,3-propanediol (Tris) precursors, with the aim to reduce the gastrointestinal (GI) side effects of NSAID therapies. We investigated mucosal reactions in a standard rat model of colitis together with methane generation as a possible indicator of pro-inflammatory activation under this condition (approval number: V./148/2013). Whole-body methane production (photoacoustic spectroscopy) and serosal microcirculation (intravital videomicroscopy) were measured, and mucosal damage was assessed (conventional histology; in vivo laser-scanning endomicroscopy). Inflammatory markers were measured from tissue and blood samples. Colitis induced an inflammatory response, morphological colonic damage and increased methane output. Ket treatment lowered inflammatory activation and colonic mucosal injury, but macroscopic gastric bleeding and increased methane output were present. Ket-Tris reduced inflammatory activation, methane emission and colonic mucosal damage, without inducing gastric injury. Conjugation with Tris reduces the GI side effects of Ket and still decreases the inflammatory response in experimental colitis. Methane output correlates with the mucosal inflammatory response and non-invasively demonstrates the effects of anti-inflammatory treatments.

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Prostaglandins, the bioactive lipids generated from the metabolism of arachidonic acid through cyclooxygenases, have potent effects on many constituents of tumor microenvironments. In this review, we will describe the formation and activities of prostaglandins in the context of the tumor microenvironment. We will discuss the regulation of cancer-associated fibroblasts and immune constituents by prostaglandins and their roles in immune escapes during tumor progression. The review concludes with future perspectives on improving the efficacy of immunotherapy through repurposing non-steroid anti-inflammatory drugs and other prostaglandin modulators.

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Delirium is an acute brain dysfunction. As one of the common psychiatric disorders in ICU, it can seriously affect the prognosis of patients. Hormones are important messenger substances found in the human body that help to regulate and maintain the function and metabolism of various tissues and organs. They are also one of the most commonly used drugs in clinical practice. Recent evidences suggest that aberrant swings in cortisol and non-cortisol hormones might induce severe cognitive impairment, eventually leading to delirium. However, the role of hormones in the pathogenesis of delirium still remains controversial. This article reviews the recent research on risk factors of delirium and the association between several types of hormones and cognitive dysfunction. These mechanisms are expected to offer novel ideas and clinical relevance for the treatment and prevention of delirium.

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Cyclooxygenase-2 (COX-2) is a key aspect of the physiology and pathogenesis of various cancer types. Overexpression of this enzyme is responsible for the elevated prostaglandin production and characteristic feature of breast cancer. Inhibition of COX-2 derived prostanoids facilitates anti-inflammatory, analgesic, and antipyretic effects of non-steroid anti-inflammation drugs. The overexpression of COX-2 is associated with inflammation, pain, and fever. The present study provides the updated relevant literature describing the role of well-characterized isoforms of cyclooxygenase with particular emphasis on COX-2, mechanism of action, the effect of the drug, combinatorial drugs, and microarray-based differential expression analysis and network analysis. We have discussed the currently used combinatorial treatments and their challenges in breast cancer. This article is categorized under: Cancer > Computational Models Cancer > Molecular and Cellular Physiology.

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Drug repurposing is a strategy used to develop new treatments based on approved or investigational drugs outside the scope of their original clinical indication. Since this approach benefits from the original toxicity data of the repurposed drugs, the drug-repurposing strategy is timesaving, and inexpensive. It has a higher success rate compared to traditional drug discovery. Several repurposing candidates have been identified in silico screening and in vitro methodologies. One of the best examples is non-steroidal anti-inflammatory drugs (NSAIDs). Tumor-promoting inflammation is one of the hallmarks of cancer, revealing a connection between inflammatory processes and tumor progression and development. This explains why using NSAIDs in the context of neoplasia has become a topic of interest. Indeed, identifying NSAIDs with antitumor activity has become a promising strategy for finding novel cancer treatment opportunities. Indeed, several commercial anti-inflammatory drugs, including aspirin, ibuprofen, diclofenac, celecoxib, tepoxalin and cyclovalone, naproxen, and indomethacin have presented antitumor activity, and some of them are already in clinical trials for cancer treatment. However, the benefits and complications of using NSAIDs for cancer treatment must be carefully evaluated, particularly for cancer patients with no further therapeutic options available. This review article provides insight into the drug repurposing strategy and describes some of the well-known NSAIDs that have been investigated as repurposed drugs with potential anticancer activity.

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Non-infectious uveitis represents a heterogenous group of immune-mediated ocular diseases, which can be associated with underlying systemic disease. While the initial choice of treatment of non-infectious uveitis depends on a number of factors such as anatomical location and degree of inflammation, topical therapies often remain the initial choice of non-invasive therapy. In this narrative review, we aim to describe the literature on non-infectious uveitis, with specific focus on the current perspective on topical anti-inflammatory therapy.

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BACKGROUND: De Quervain's disease is tenosynovitis of the first dorsal compartment causing severely painful radial-side wrist pain and impaired function. Steroids are effective in treating this condition due to their anti-inflammatory properties. However, this drug causes problems such as hypopigmentation, and is contradicted in diabetes mellitus patients. Non-steroidal anti-inflammatory drug (NSAID) which are efficacious in shoulder pathology and not contraindicated in diabetics and can be used to avoid the local effects of steroids could be beneficial for some patients. The present study was a randomized controlled trial to examine the differences in pain scores and functional response to local injections of a corticosteroid and the NSAID ketorolac. METHODS: Sixty-four patients with radial styloid tenosynovitis were randomized using a computer-generated random number table into two groups receiving either a ketorolac injection or a triamcinolone injection. We evaluated post-injection pain intensity using a verbal numerical rating scale (VNRS), functional outcomes using the Thai Disabilities of the Arm, Shoulder and Hand (DASH) scale, and evaluated grip and pinch strengths, recorded at baseline and 6 weeks after the injection. RESULTS: Thirty-one participants in the ketorolac group and 29 participants in the triamcinolone group completed the study and were included in the analysis. There were no significant differences in the assessments at baseline. At the 6-week conclusion of the study, patients in the triamcinolone group had a statistically lower average pain score than in the ketorolac group (0.7 ± 2.0 vs 5.3 ± 3.2, P < 0.001), higher DASH functional score (4.4 ± 6.5 vs 34.1 ± 20.2, P < 0.001), higher right grip strength (60.8 ± 16.8 vs 49.2 ± 18.6, P < 0.015), and higher left grip strength (59.8 ± 18.1 vs 50.3 ± 18.0, P < 0.04). However, there was no difference in pinch strength. CONCLUSIONS: Our study found that ketorolac injections resulted in inferior pain reduction, functional score and grip improvement than triamcinolone injection in patients with radial styloid tenosynovitis. Future studies are required to examine the effects of ketorolac in larger group and with longer follow-up periods to further elucidate the findings of this study. TRIAL REGISTRATION: The study was registered at Clinicaltrials.in.th (TCTR20200909006).

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Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.

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As a member of the nuclear receptor superfamily, the farnesoid X receptor (FXR) is a bile acid activated transcription factor. FXR is involved in many important metabolic processes and serves as a promising therapeutic target for nonalcoholic steatohepatitis (NASH). Since discovered, the first non-steroidal FXR agonist GW4064 has been widely used to explore the biological functions of FXR, however, the low pharmacokinetic limited its further clinical application. In current study, we designed a series of substituted isothiazoles as new FXR agonists. Among them, five compounds exhibited better FXR agonistic activity than GW4064. Specially, the most potent compound S5 possessed better pharmacokinetic profile and in vivo potency than lead compound.

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Neurodegenerative diseases (NDDs) are characterized by progressive deterioration of the structure and function of cells and their networks in the nervous system. There are currently no drugs or other treatments that can stop the progression of NDDs. NDDs have many similarities and common pathways, e.g., formation of misfolded amyloid proteins, intra- and extracellular amyloid deposits, and chronic inflammation. Initially, the inflammation process has a cytoprotective function; however, an elevated and prolonged immune response has damaging effects and causes cell death. Neuroinflammation has been a target of drug development for treating and curing NDDs. Treatment of different NDDs with non-steroid anti-inflammatory drugs (NSAIDs) has failed or has given inconsistent results. The use of NSAIDs in diagnosed Alzheimer's disease is currently not recommended. Sigma-1 receptor (Sig-1R) is a novel target for NDD drug development. Sig-1R plays a key role in cellular stress signaling, and it regulates endoplasmic reticulum stress and unfolded protein response. Activation of Sig-1R provides neuroprotection in cell cultures and animal studies. Clinical trials demonstrated that several Sig-1R agonists (pridopidine, ANAVEX3-71, fluvoxamine, dextrometorphan) and their combinations have a neuroprotective effect and slow down the progression of distinct NDDs.

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Certain combinations of acidic and basic drugs can cause significant changes in physicochemical properties through the formation of ionic liquids, eutectic mixtures, or deep eutectic solvents. In particular, combining indomethacin and lidocaine is known to result in apparent increases in both the partition coefficients (hydrophobicity) and aqueous solubilities (hydrophilicity). The physicochemical interactions between drugs change the water solubility of the drugs and affect the bio-availability of active pharmaceutical ingredients. Therefore, we need to clarify the mechanism of changes of water solubility of drugs through the physicochemical interactions. In the present study, we identified a thermodynamic factor that regulates the dissolution of a basic drug, in the presence of various acidic nonsteroidal anti-inflammatory drugs. The results demonstrated that enthalpy-entropy compensation plays a key role in the dissolution of drug mixtures and that relevant thermodynamic conditions should be considered.

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Conservative treatments for early osteoarthritis (OA) of the knee included the use of non-steroid anti-inflammatory drugs (NSAIDs) and intra-articular hyaluronic acid (HA) injection. Recently, several animal studies reported that extracorporeal shockwave therapy (ESWT) demonstrated chondroprotective effects on knee OA. The present study compared the efficacy of oral NSAIDs, HA injection, and noninvasive ESWT for early OA of the knee. Forty-five patients with early knee OA were randomized into three groups. NSAIDs group received celecoxib 200 mg daily for 3 weeks. HA group received intra-articular injection of HA once a week for 3 weeks. ESWT group received ESWT for 3 sessions at bi-weekly interval. All patients were followed up for one year. Evaluations included the visual analogue scale (VAS) score, serum enzyme-linked immunosorbent assay (ELISA), plain radiography, dual-energy X-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI). In addition, the functional scores were performed including, WOMAC (Western Ontario and McMaster Universities Arthritis Index) score, KOOS (knee injury and osteoarthritis outcome) score, and IKDC (International Knee Documentation Committee) score. All three groups showed significant improvement in VAS and functional scores as well as in the collected one-year follow-up data after treatments. ESWT group had better pain relief than NSAIDs and HA groups. ESWT group had better therapeutic effects in the functional scores than NSAIDs and HA groups. The bone mineral density (BMD) of proximal tibia is significantly increased after ESWT than others. In the serum ELISA, ESWT inhibited the expression of COMP in knee OA patients as compared with NSAIDs and HA groups. The parameters of MRI showed no significant differences between three groups after treatments. ESWT and intra-articular HA injection showed comparable results than NSAIDs. ESWT was superior in pain relief than HA and NSAIDs. The results demonstrated that ESWT was an effective and alternative therapy than HA and NSAIDs for early osteoarthritis of the knees.