Formulation Studies with Cyclodextrins for Novel Selenium NSAID Derivatives.

Commercial cyclodextrins (CDs) are commonly used to form inclusion complexes (ICs) with different molecules in order to enhance their water solubility, stability, and bioavailability. Nowadays, there is strong, convincing evidence of the anticancer effect of selenium (Se)-containing compounds. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their further evaluation and clinical use. In this work, we study the enhancement of solubility with CD complexes for a set of different nonsteroidal anti-inflammatory drug (NSAID) derivatives with Se as selenoester or diacyl diselenide chemical forms, with demonstrated antitumoral activity. The CD complexes were analyzed via nuclear magnetic resonance (NMR) spectroscopic techniques. In order to obtain additional data that could help explain the experimental results obtained, 3D models of the theoretical CD-compound complexes were constructed using molecular modeling techniques. Among all the compounds, I.3e and II.5 showed a remarkable increase in their water solubility, which could be ascribed to the formation of the most stable interactions with the CDs used, in agreement with the in silico studies performed. Thus, the preliminary results obtained in this work led us to confirm the selection of ß and γ-CD as the most suitable for overcoming the pharmaceutical drawbacks of these Se derivatives.

Enhancing therapeutic efficacy in triple-negative breast cancer and melanoma: synergistic effects of modulated electro-hyperthermia (mEHT) with NSAIDs especially COX-2 inhibition in in vivo models.

Triple-negative breast cancer (TNBC) is a leading cause of cancer mortality and lacks modern therapy options. Modulated electro-hyperthermia (mEHT) is an adjuvant therapy with demonstrated clinical efficacy for the treatment of various cancer types. In this study, we report that mEHT monotherapy stimulated interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6) expression, and consequently cyclooxygenase 2 (COX-2), which may favor a cancer-promoting tumor microenvironment. Thus, we combined mEHT with nonsteroid anti-inflammatory drugs (NSAIDs): a nonselective aspirin, or the selective COX-2 inhibitor SC236, in vivo. We demonstrate that NSAIDs synergistically increased the effect of mEHT in the 4T1 TNBC model. Moreover, the strongest tumor destruction ratio was observed in the combination SC236 + mEHT groups. Tumor damage was accompanied by a significant increase in cleaved caspase-3, suggesting that apoptosis played an important role. IL-1ß and COX-2 expression were significantly reduced by the combination therapies. In addition, a custom-made nanostring panel demonstrated significant upregulation of genes participating in the formation of the extracellular matrix. Similarly, in the B16F10 melanoma model, mEHT and aspirin synergistically reduced the number of melanoma nodules in the lungs. In conclusion, mEHT combined with a selective COX-2 inhibitor may offer a new therapeutic option in TNBC.

Nonsteroidal anti-inflammatory drug "allergy" labeling is associated with increased postpartum opioid utilization.

BACKGROUND: Current guidelines recommend a stepwise approach to postpartum pain management, beginning with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids added only if needed. Report of a prior NSAID-induced adverse drug reaction (ADR) may preclude use of first-line analgesics, despite evidence that many patients with this allergy label may safely tolerate NSAIDs. OBJECTIVE: We assessed the association between reported NSAID ADRs and postpartum opioid utilization. METHODS: We performed a retrospective cohort study of birthing people who delivered within an integrated health system (January 1, 2017, to December 31, 2020). Study outcomes were postpartum inpatient opioid administrations and opioid prescriptions at discharge. Statistical analysis was performed on a propensity score-matched sample, which was generated with the goal of matching to the covariate distributions from individuals with NSAID ADRs. RESULTS: Of 38,927 eligible participants, there were 883 (2.3%) with an NSAID ADR. Among individuals with reported NSAID ADRs, 49.5% received inpatient opioids in the postpartum period, compared to 34.5% of those with no NSAID ADRs (difference = 15.0%, 95% confidence interval 11.4-18.6%). For patients who received postpartum inpatient opioids, those with NSAID ADRs received a higher total cumulative dose between delivery and hospital discharge (median 30.0 vs 22.5 morphine milligram equivalents [MME] for vaginal deliveries; median 104.4 vs 75.0 MME for cesarean deliveries). The overall proportion of patients receiving an opioid prescription at the time of hospital discharge was higher for patients with NSAID ADRs compared to patients with no NSAID ADRs (39.3% vs 27.2%; difference = 12.1%, 95% confidence interval 8.6-15.6%). CONCLUSION: Patients with reported NSAID ADRs had higher postpartum inpatient opioid utilization and more frequently received opioid prescriptions at hospital discharge compared to those without NSAID ADRs, regardless of mode of delivery.

Non-steroidal Anti-inflammatory Drugs and Osteopathic Manipulative Treatment for Pain Management in Patients With Osteoarthritis: A Literature Review.

The pathophysiology of osteoarthritis (OA) involves the destruction of articular cartilage and the overgrowth of bone with lipping and spur formation. Nerve endings in the joint capsule and adjacent tissues play a major role in the pain mechanisms of osteoarthritis. This often requires patients to seek pain control measures beyond over-the-counter drugs, such as local anesthetics. Osteopathic manipulation treatment (OMT) is a conservative, non-pharmacological treatment that can be used to help treat chronic pain associated with OA. Other non-pharmacologic therapies include weight loss, exercise, physical therapy (PT), and assistive devices. However, pharmacologic management may be added synergistically to control flares and maintain baseline activities of daily living. While oral non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for pain and inflammation associated with OA, they have a non-selective inhibitory action that often results in negative side effects when used chronically. The possibility of minimizing these complications through alternate treatments such as topical NSAIDs provides an opportunity for patients to receive adequate pain relief from OA without suffering unnecessary consequences. This literature review seeks to assess the state of research regarding topical NSAIDs and OMT as alternatives to the current gold-standard treatment of OA. The significant inclusion criteria consisted of articles that described the effects of OMT on OA or the use of topical NSAIDs such as Voltaren on OA. Due to the limited articles found, a qualitative analysis was performed, and the salient conclusions are outlined. Alternative pharmacological and non-pharmacological treatments, such as topical diclofenac gel and OMT, have shown promising results in the treatment of pain in OA. It is seen that a majority of patients achieve pain management using NSAIDs, acetaminophen, or topical analgesics. Both diclofenac sodium and OMT have individually been shown to be effective treatments of OA when compared to the use of oral NSAIDs. A holistic treatment approach that utilizes both topical diclofenac sodium and OMT may provide OA patients with an effective option to reduce their moderate to severe chronic pain with limited side effects. Further, high-quality randomized controlled trials are needed to identify whether synergistic effects occur when combining diclofenac sodium gel and OMT for pain relief in patients with OA.

Unusual worm-like radiopacities in the radiographs of patients with cervical spondylosis.

This report describes three patients with cervical spondylosis whose diagnostic radiographs showed worm-like, irregularly curved radiopaque lines and strings in the head and neck region during routine chiropractic examinations. Such artifacts are frequently misinterpreted as parasitic infection, electrostatic discharges, detector image lag, fracture, or ligature wires. All three patients with worm-like radiopacities disclosed their 15-20 years of history of acupuncture treatment to relieve neck pain. The present cases of unexpected and coincidental findings may suggest a possible acupuncture-caused radiographic artifacts in the neck and jaw bones. In particular, the patient had previous gold thread treatments possibly associated with the observed radiographic artifacts. These cases may emphasize the importance of having a thorough understanding of patient history regarding unexpected radiographic artifacts.

Contribution of Symptomatic, Herbal Treatment Options to Antibiotic Stewardship and Microbiotic Health.

Epithelial surfaces in humans are home to symbiotic microbes (i.e., microbiota) that influence the defensive function against pathogens, depending on the health of the microbiota. Healthy microbiota contribute to the well-being of their host, in general (e.g., via the gut-brain axis), and their respective anatomical site, in particular (e.g., oral, urogenital, skin, or respiratory microbiota). Despite efforts towards a more responsible use of antibiotics, they are often prescribed for uncomplicated, self-limiting infections and can have a substantial negative impact on the gut microbiota. Treatment alternatives, such as non-steroidal anti-inflammatory drugs, may also influence the microbiota; thus, they can have lasting adverse effects. Herbal drugs offer a generally safe treatment option for uncomplicated infections of the urinary or respiratory tract. Additionally, their microbiota preserving properties allow for a more appropriate therapy of uncomplicated infections, without contributing to an increase in antibiotic resistance or disturbing the gut microbiota. Here, herbal treatments may be a more appropriate therapy, with a generally favorable safety profile.

Updates in biologic therapy for chronic rhinosinusitis with nasal polyps and NSAID-exacerbated respiratory disease.

Chronic rhinosinusitis with nasal polyps (CRSwNP) associated with type 2 inflammation and non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (N-ERD) can be difficult to control with standard medical therapy and sinus surgery. In this group, biologicals are potentially promising treatment options. The phase III clinical trials for omalizumab, dupilumab, mepolizumab and benralizumab in CRSwNP have demonstrated favourable outcomes. Moving forward, direct comparisons among biologicals, refining patient selection criteria for specific biologicals, determining optimal treatment duration and monitoring long-term outcomes are areas of emerging interest. This review summarizes the clinical evidence from the recent 2 years on the role of biologicals in severe CRSwNP and N-ERD, and proposes an approach towards decision-making in their use.

Ingredients of a Natural Oral Nutritional Supplement and Their Role in the Treatment of Osteoarthritis.

Osteoarthritis is a prevalent degenerative disease affecting a large portion of the world's aging population. Currently, nonsteroidal anti-inflammatory drugs and acetaminophen are first-line medications for treating osteoarthritis patients' pain. However, several studies have noted that while these medications control pain they do not halt progressive degeneration and tend to have an unfavorable side-effect profile with prolonged use. Recently, due to their more favorable side-effect profiles, herbal alternatives for controlling osteoarthritis symptoms and for alleviating the progression of the disease are being increasingly studied. Synogesic is a newly developed herbal supplement blend by renowned orthopedic surgeons and physiatrists consisting of turmeric, rutin, ginger root, vitamin C, vitamin D, and boswellia extracts. A study by Sharkey et al. has commented on the efficacy of the blend on the patients with knee osteoarthritis. So far, a review on the ingredients of the blend has not yet carried outbeen. By exploring prominent literature databases including PubMed and ScienceDirect, our aim is to write a narrative review to explore the individual ingredients of this blend and delve into their characteristics, as well as the most recent literature on their mechanism and efficacy in patients with osteoarthritis. Through this, we hope to inform clinicians and patients alike on relevant up-to-date research on the supplement and provide insight on the potential for this supplement for alleviating the disease course of patients with osteoarthritis.

Herb-Drug Interaction in Inflammatory Diseases: Review of Phytomedicine and Herbal Supplements.

Many people worldwide use plant preparations for medicinal purposes. Even in industrialized regions, such as Europe, where conventional therapies are accessible for the majority of patients, there is a growing interest in and usage of phytomedicine. Plant preparations are not only used as alternative treatment, but also combined with conventional drugs. These combinations deserve careful contemplation, as the complex mixtures of bioactive substances in plants show a potential for interactions. Induction of CYP enzymes and pGP by St John's wort may be the most famous example, but there is much more to consider. In this review, we shed light on what is known about the interactions between botanicals and drugs, in order to make practitioners aware of potential drug-related problems. The main focus of the article is the treatment of inflammatory diseases, accompanied by plant preparations used in Europe. Several of the drugs we discuss here, as basal medication in chronic inflammatory diseases (e.g., methotrexate, janus kinase inhibitors), are also used as oral tumor therapeutics.

Long-term exposure to environmental diclofenac concentrations impairs growth and induces molecular changes in Lymnaea stagnalis freshwater snails.

As pharmaceutical substances are highly used in human and veterinary medicine and subsequently released in the environment, they represent emerging contaminants in the aquatic compartment. Diclofenac (DCF) is one of the most commonly detected pharmaceuticals in water and little research has been focused on its long-term effects on freshwater invertebrates. In this study, we assessed the chronic impacts of DCF on the freshwater gastropod Lymnaea stagnalis using life history, behavioral and molecular approaches. These organisms were exposed from the embryo to the adult stage to three environmentally relevant DCF concentrations (0.1, 2 and 10 µg/L). The results indicated that DCF impaired shell growth and feeding behavior at the juvenile stage, yet no impacts on hatching, locomotion and response to light stress were noted. The molecular findings (metabolomics and transcriptomic) suggested that DCF may disturb the immune system, energy metabolism, osmoregulation and redox balance. In addition, prostaglandin synthesis could potentially be inhibited by DCF exposure. The molecular findings revealed signs of reproduction impairment but this trend was not confirmed by the physiological tests. Combined omics tools provided complementary information and enabled us to gain further insight into DCF effects in freshwater organisms.

Appraisal of the Real-World Effectiveness of Biologic Therapies in Aspirin-Exacerbated Respiratory Disease.

BACKGROUND: There are no head-to-head studies for patients with aspirin-exacerbated respiratory disease (AERD) comparing any of the 5 Food and Drug Administration-approved respiratory biologic therapies. OBJECTIVE: Explore outcomes in subjects with AERD using biologic therapies in a real-world clinic setting. METHODS: A retrospective pilot study was conducted for subjects with AERD who had been prescribed omalizumab (anti-IgE), mepolizumab (anti-IL-5), reslizumab (anti-IL-5), benralizumab (anti-IL-5 receptor alpha [anti-IL-5Rα]), or dupilumab (anti-IL-4 receptor alpha [anti-IL-4Rα]). Clinical outcomes pre- versus postinitiation of biologic therapy were explored including symptoms, 22-item sino-nasal outcome test scores, systemic corticosteroid and antibiotic prescriptions, and emergency room visits related to AERD. RESULTS: Of the 74 subjects, 58.1% (n = 43) had used 1 biologic, though many (41.9%, n = 31) trialed more than 1 biologic. Of the 50 subjects who had used anti-IL-4Rα therapy, 98% (49 of 50) still had this therapy prescribed at study completion compared with 48.6% (17 of 35) and 26.9% (7 of 26) of those who used anti-IgE and anti-IL-5 and anti-IL-5 receptor alpha (anti-IL-5/IL-5Rα) therapy, respectively. Among those on anti-IL-4Rα therapy, there was a significant reduction in median total 22-item sino-nasal outcome test scores (51 to 19, P = .0002), corticosteroid bursts (2 to 0, P < .0001), and median number of antibiotic courses for respiratory disease (1 to 0, P = .0469) prebiologic versus postbiologic initiation. No statistically significant difference in those outcomes was observed for individuals on anti-IgE or anti-IL-5/IL-5Rα therapy. CONCLUSIONS: Anti-IL-4Rα therapy led to significantly higher rates of clinical improvement in AERD when compared with anti-IL-5/IL-5Rα and anti-IgE biologic therapies. Prospective studies would help clarify best practices for the use of biologic therapies in AERD.

Dehydroevodiamine ameliorates indomethacin-induced gastric injury via inhibition of ERK and p38 signaling pathway.

BACKGROUND: Dehydroevodiamine (DHE), a pivotal quinazoline alkaloid isolated from Fructus Evodiae (Tetradium ruticarpum (A. Juss.) Hartley), has various pharmacological effects. However, the effect of DHE on gastric injury is still uncharted. PURPOSE: To clarify the pharmacological effect and mechanism of DHE on gastric injury (GI) induced by indomethacin (IDO). STUDY DESIGN: The gastric injury was induced in rat by oral administration of 5 mg/kg IDO for 7 days. Then the rats were treated with DHE (10, 20, 40 mg/kg, ig) for 7 days. METHODS: The changes of food intake, body weight, gastric pH and general state observation were determined. And HE staining and AB-PAS staining was analyzed. Then, the inflammatory infiltration of gastric tissue was observed through MPO immunohistochemical approach, and the expression of TNF-α, IL-6 and IL-10 were measured. Furthermore, the levels of proteins ERK, p-ERK, P38, p-P38, JNK and p-JNK were determined to elucidate the molecular mechanism of DHE. RESULTS: DHE alleviated food intake reduction, weight loss and gastric injury induced by IDO and made gastric pH and mucosal thickness return to normal. In addition, DHE could down regulate the expression of MPO, TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage induced by inflammatory, and create a healing environment. Furthermore, DHE could significantly inhibit the phosphorylation of ERK and p38 not JNK. CONCLUSION: DHE ameliorated dyspepsia, inflammatory infiltration and tissue damage induced by IDO through ERK and p38 signaling pathways rather than JNK pathway.

Gasdermin D in pyroptosis.

Pyroptosis is the process of inflammatory cell death. The primary function of pyroptosis is to induce strong inflammatory responses that defend the host against microbe infection. Excessive pyroptosis, however, leads to several inflammatory diseases, including sepsis and autoimmune disorders. Pyroptosis can be canonical or noncanonical. Upon microbe infection, the canonical pathway responds to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), while the noncanonical pathway responds to intracellular lipopolysaccharides (LPS) of Gram-negative bacteria. The last step of pyroptosis requires the cleavage of gasdermin D (GsdmD) at D275 (numbering after human GSDMD) into N- and C-termini by caspase 1 in the canonical pathway and caspase 4/5/11 (caspase 4/5 in humans, caspase 11 in mice) in the noncanonical pathway. Upon cleavage, the N-terminus of GsdmD (GsdmD-N) forms a transmembrane pore that releases cytokines such as IL-1ß and IL-18 and disturbs the regulation of ions and water, eventually resulting in strong inflammation and cell death. Since GsdmD is the effector of pyroptosis, promising inhibitors of GsdmD have been developed for inflammatory diseases. This review will focus on the roles of GsdmD during pyroptosis and in diseases.

The Indian Network of Drug-Induced Liver Injury: Etiology, Clinical Features, Outcome and Prognostic Markers in 1288 Patients.

BACKGROUND: Etiology of and outcomes following idiosyncratic drug-induced liver injury (DILI) vary geographically. We conducted a prospective study of DILI in India, from 2013 to 2018 and summarize the causes, clinical features, outcomes and predictors of mortality. METHODS: We enrolled patients with DILI using international DILI expert working group criteria and Roussel Uclaf causality assessment method. Follow-up was up to 3 months from onset of DILI or until death. Multivariate logistics regression was carried out to determine predictors of non-survival. RESULTS: Among 1288 patients with idiosyncratic DILI, 51.4% were male, 68% developed jaundice, 68% required hospitalization and 8.2% had co-existing HIV infection. Concomitant features of skin reaction, ascites, and encephalopathy (HE) were seen in 19.5%, 16.4%, and 10% respectively. 32.4% had severe disease. Mean MELD score at presentation was 18.8 ± 8.8. Overall mortality was 12.3%; 65% in those with HE, 17.6% in patients who fulfilled Hy's law, and 16.6% in those that developed jaundice. Combination anti-TB drugs (ATD) 46.4%, complementary and alternative medicines (CAM) 13.9%, anti-epileptic drugs (AED) 8.1%, non-ATD antimicrobials 6.5%, anti-metabolites 3.8%, anti-retroviral drugs (ART)3.5%, NSAID2.6%, hormones 2.5%, and statins 1.4% were the top 9 causes. Univariate analysis identified, ascites, HE, serum albumin, bilirubin, creatinine, INR, MELD score (p < 0.001), transaminases (p < 0.04), and anti-TB drugs (p = 0.02) as predictors of non-survival. Only serum creatinine (p = 0.017), INR (p < 0.001), HE (p < 0.001), and ascites (p = 0.008), were significantly associated with mortality on multivariate analysis. ROC yielded a C-statistic of 0.811 for MELD and 0.892 for combination of serum creatinine, INR, ascites and HE. More than 50 different agents were associated with DILI. Mortality varied by drug class: 15% with ATD, 13.6% with CAM, 15.5% with AED, 5.8% with antibiotics. CONCLUSION: In India, ATD, CAM, AED, anti-metabolites and ART account for the majority of cases of DILI. The 3-month mortality was approximately 12%. Hy's law, presence of jaundice or MELD were predictors of mortality.

Zuojin Pill ameliorates inflammation in indomethacin-induced gastric injury via inhibition of MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury. MATERIALS AND METHODS: GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP. RESULTS: Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa. CONCLUSION: ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

Ameliorative activity of aqueous leaf extract from Madhuca longifolia against diclofenac-administered toxicity on rat stomach and intestine.

Madhuca longifolia, a tropical tree used as medicine and food, is known to have a beneficial effect against stomach gastric toxicity. Madhuca longifolia is used in treating cough, skin disease and nerve disorders. Diclofenac, a non-steroidal anti-inflammatory drug (NSAID), with overdosage and prolonged use, is known to cause gastric toxicity. Silymarin (SLY), a polyphenolic antioxidant flavonoid, is a derivative of Silybum marianum extracted from milk thistle seeds and fruits, has been widely used in the treatment of gastric ulcer. SLY was used as the standard drug to compare the effects with the Madhuca longifolia aqueous leaf extract treatment. The aim of the current study is to understand the effect of Madhuca longifolia aq. leaf extract on rat stomach and intestine against diclofenac-administered toxicity. Rats (n = 30) were divided into Group I normal control, Group II treated with diclofenac, Group III treated with diclofenac and Madhuca longifolia leaf extract, Group IV treated with diclofenac and silymarin, and Group V was treated with Madhuca longifolia leaf extract alone. After the study duration, rats were euthanized and tissue samples were analyzed for antioxidant, cytokine, protein expression levels and histopathological changes. Diclofenac treated rats had significant (p < 0.05) changes in levels of antioxidants, cytokines, protein expression and pathological changes as compared to rats treated with Madhuca longifolia. This study demonstrated that Madhuca longifolia leaf extract had gastroprotective activity in rats treated with diclofenac.

Outcomes and Predictors of Mortality in Patients With Drug-Induced Liver Injury at a Tertiary Hospital in South India: A Single-Centre Experience.

INTRODUCTION: Drug-induced liver injury (DILI) is an important cause of acute liver failure with significant morbidity and mortality. The outcome of DILI varies widely according to the drug implicated and the type of liver injury. Owing to the heterogeneous nature of liver injury, knowledge on clinical course and prognosis of DILI is limited. We had undertaken this study to determine the clinical characteristics, outcomes, and predictors of mortality in patients with DILI. MATERIALS AND METHODS: This prospective study was conducted from January 2015 through December 2018. We analyzed the drugs implicated, clinical course, and the outcome. Causality assessment was performed by using Roussel Uclaf Causality Assessment Method scoring. Patients were followed for 6 months until recovery/death or liver transplantation. RESULTS: There were 133 cases with DILI. The mean age was 47.6 years, and 51.9% of them were men. Drugs causing DILI were antitubercular drugs (37.5%) followed by neuropsychiatric drugs (16.5%), antibiotics/antifungals (12%), complementary and alternative medicine (10.5%), immunomodulatory/chemotherapeutic drugs (10.5%), and nonsteroidal antiinflammatory drugs (7.5%). Eighty-two (61.6%) patients were classified as hepatocellular, 30 (22.5%) as mixed and 21 (15.7%) as cholestatic type of injury. There was no significant difference in the mortality and morbidity between the three types of liver injury. There were 18 deaths (13.5%), of which antitubercular drugs constituted the majority (55.5%) followed by neuropsychiatric drugs (27.7%) and complementary and alternative medicine (16.6%). Based on receiver operating characteristic curve analysis, model for end-stage liver disease (MELD) score >28, mean international normalized ratio (INR) >1.97, mean bilirubin level >15.6 mg/dl, and creatinine level >1.35 mg/dl were associated with mortality. CONCLUSION: Although DILI is uncommon, it has significant morbidity and mortality. Antitubercular drugs were the most common cause for DILI and DILI-related mortality in our study. Variables such as MELD, INR, bilirubin, albumin, and creatinine help in predicting severity of liver injury and may help in triaging the patient for referral for liver transplantation.

Glycine and L-Arginine supplementation ameliorates gastro-duodenal toxicity in a rat model of NSAID (Diclofenac)-gastroenteropathy via inhibition of oxidative stress.

OBJECTIVES: This study examined the possible protective roles of exogenous glycine (Gly) and L-Arginine (l-Arg) against Diclofenac (DIC)-induced gastro-duodenal damage in rats. METHODS: Rats were divided into Group A (control), Group B (DIC group) and Groups C-F which were pre-treated for five days with Gly1 (250 mg/kg), Gly2 (500 mg/kg), l-Arg1 (200 mg/kg) and l-Arg2 (400 mg/kg), respectively, before co-treatment with DIC for another three days. Hematological, biochemical and histopathological analyses were then carried out. RESULTS: DIC produced significant (p<0.05) reduction in PCV (13.82%), Hb (46.58%), RBC (30.53%), serum total protein (32.72%), albumin (28.44%) and globulin (38.01%) along with significant (p<0.05) elevation of serum MPO activity (83.30%), when compared with control. In addition, DIC increased gastric H2O2 and MDA levels by 33.93 and 48.59%, respectively, while the duodenal levels of the same parameters increased by 19.43 and 85.56%, respectively. Moreover, SOD, GPx and GST activities in the DIC group were significantly (p<0.05) reduced in the stomach (21.12, 24.35 and 51.28%, respectively) and duodenum (30.59, 16.35 and 37.90%, respectively), compared to control. Treatment with Gly and l-Arg resulted in significant amelioration of the DIC-induced alterations although l-Arg produced better amelioration of RBC (29.78%), total protein (10.12%), albumin (9.93%) and MPO (65.01%), compared to the DIC group. The protective effects of both amino acids against oxidative stress parameters and histological lesions were largely similar. CONCLUSIONS: The data from this study suggest that Gly or l-Arg prevented DIC-induced gastro-duodenal toxicity and might, therefore be useful in improving the therapeutic index of DIC.

Influence of ß-D-mannuronic Acid, as a New Member of Non-steroidal Anti- Inflammatory Drugs Family, on the Expression Pattern of Chemokines and their Receptors in Rheumatoid Arthritis.

BACKGROUND: Based on the encouraging results of phase III clinical trial of ß-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. METHODS: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 µg/mL) of M2000 and optimum dose (1 µg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. RESULTS: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac. CONCLUSION: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

Individual responses to topical ibuprofen gel or capsaicin cream for painful knee osteoarthritis: a series of n-of-1 trials.

OBJECTIVES: To determine individual responses to ibuprofen gel or capsaicin cream for painful, radiographic knee OA using a series of n-of-1 trials. METHODS: Twenty-two participants were allocated 5% ibuprofen gel (A) and 0.025% capsaicin cream (B) in random sequence (AB or BA). Patients underwent up to 3 treatment cycles, each comprising one treatment for 4 weeks, an individualized washout period (maximum 4 weeks), then the other treatment for 4 weeks. Differential (ibuprofen or capsaicin) response was defined when change-from-baseline pain intensity scores (0-10 NRS) differed by ≥1 between treatments in ≥2 cycles within a participant. RESULTS: A total of 104 treatment periods were aggregated. Mean pain reduction was 1.2 (95% CI: 0.5, 1.8) on ibuprofen and 1.6 (95% CI: 0.9, 2.4) on capsaicin (P = 0.221). Of 22 participants, 4 (18%) had a greater response to ibuprofen, 9 (41%) to capsaicin, 4 (18%) had similar responses, and 5 (23%) were undetermined. CONCLUSION: Irrespective of equal efficacy overall, 59% of people displayed a greater response to one treatment over the other. Patients who do not benefit from one type of topical treatment should be offered to try another, which may be more effective. N-of-1 trials are useful to identify individual response to treatment. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov, NCT03146689.