morphinans and Chemical-and-Drug-Induced-Liver-Injury

A combination of conventional disease-modifying anti-rheumatic drugs improves the treatment of rheumatoid arthritis but with high side-effects. Methotrexate (MTX) combination therapy that with high therapeutic efficacy and low toxicity is in demand in many countries to replace the use of expensive biological agents.. This study was an open-label, 24-week, parallel randomized controlled trial conducted between November 2015 and December 2017.. Patients were randomly assigned at a 3:2 ratio to receive MTX combined with sinomenine (SIN) at a dose of 120 mg twice daily, or leflunomide (LEF) at a dose of 20 mg once daily. Efficacy and safety were assessed at weeks 4, 12 and 24. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology (ACR)50 response and a European League Against Rheumatism (EULAR) good response at week 24.. A total of 101/120 (84.2%) patients completed 24 weeks of observation. In the intention-to-treat (ITT) analysis, 65.3% of patients treated with MTX + SIN showed improved disease activity as determined by the ACR50 response at week 24 compared to 69.6% of patients treated with MTX + LEF. A similar insignificant pattern was found for the ACR20 and ACR70 responses, as well as the clinical disease activity index, EULAR response, and remission and low disease activity rates between these two treatment groups. The per-protocol analysis showed results consistent with those of the ITT analysis. Notably, significant reductions in gastrointestinal adverse reactions and liver toxicity were found in patients treated with MTX + SIN compared to patients treated with MTX + LEF (p < 0.05).. Considering the balance of efficacy and toxicity, the current study provides evidence that MTX + SIN combination therapy is probably one of the choices for treating patients with active rheumatoid arthritis in addition to MTX + LEF combination therapy.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Humans; Leflunomide; Male; Methotrexate; Middle Aged; Morphinans; Treatment Outcome

Topics: Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Inflammation; Liver; Male; Mice; Mice, Inbred BALB C; Morphinans; Oxidative Stress

Liver disease is common and often life-threatening. Sinomenine (SIN) is an active ingredient extracted from . In vivo experiments, mice were randomly divided into six groups (n=10): control group, model group, SIN (25 mg/kg) group, SIN (50 mg/kg) group, SIN (100 mg/kg) group and SIN (100 mg/kg) + SRI-011381 group. Alanine transaminases (ALT), aspartate transaminases (AST) and alkaline phosphatase (ALP) were detected. The pathological lesion was measured by HE staining. Apoptosis was measured by TUNEL staining. In vitro experiments, BRL-3A cells were treated with APAP (7.5 mM) and then subjected to various doses of SIN (10, 50 and 100 μg/mL) at 37°C for 24 h. Inflammatory factors and oxidative stress index were measured by ELISA. The expression of proteins was detected by Western blot.. The results showed that compared with the control group, the levels of ALT, AST and ALP in the serum of APAP-induced mice were significantly increased, followed by liver histological damage and hepatocyte apoptosis. Besides, APAP reduced the activity of SOD and GSH-Px, while increasing the content of MDA and LDH. Notably, APAP also promoted the expression of NLRP3, ASC, caspase-1 and IL-1β. Interestingly, SIN treatment dose-dependently reduced APAP-induced liver injury and oxidative stress, inhibited the activation of NLRP3 inflammasomes, and reduced the levels of inflammatory cytokines. In vitro studies have shown that SIN treatment significantly reduced the viability of BRL-3A cells and oxidative stress and inflammation. In addition, the Western blotting analysis showed that SIN inhibited the activation of TGF-β/Smad pathway in a dose-dependent manner in vitro and in vivo. These effects were significantly reversed by TGF-β/Smad activator SRI-011381 or TGF-β overexpression.. The study indicates that SIN attenuates APAP-induced acute liver injury by decreasing oxidative stress and inflammatory response via TGF-β/Smad pathway in vitro and in vivo.

Topics: Acetaminophen; Animals; Apoptosis; Cells, Cultured; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Inflammation; Mice; Mice, Inbred C57BL; Morphinans; Oxidative Stress; Smad Proteins; Structure-Activity Relationship; Transforming Growth Factor beta

A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Conditioning, Operant; Ethanol; Male; Morphinans; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Self Administration; Thioamides

Hepatic fibrosis is characterized by excess type I collagen deposition and exacerbated inflammatory response. Naltrexone, an opioid receptor antagonist used for treating alcohol abuse, attenuates hepatocellular injury in fibrotic animal models, which can be accompanied by deleterious side effects. Additionally, opioid neurotransmission is upregulated in patients with inflammatory liver disease. Several derivatives of Naltrexone, Nalmefene (Nal) and JKB-119, exert immunomodulatory activity; however, unlike Nal, JKB-119 does not show significant opioid receptor antagonism. To delineate the potential hepatoprotective effects of these compounds, we investigated if JKB-119 and Nal could modulate activation of hepatic stellate cells (HSCs), primary effector cells that secrete type I collagen and inflammatory mediators during liver injury. Our results demonstrated that Nal or JKB-119 treatment decreased smooth muscle α-actin, a marker of HSC activation, mRNA and protein expression. Despite decreased collagen mRNA expression, both compounds increased intracellular collagen protein expression; however, inhibition of collagen secretion was observed. To address a possible mechanism for suppressed collagen secretion or retention of intracellular collagen, endoplasmic (ER) protein expression and matrix metalloproteinase (MMP) activity were examined. While no change in ER protein expression (Grp78, PDI, Hsp47) was observed, MMP13 mRNA expression was dramatically increased. In an acute LPS inflammatory injury animal model, JKB-119 treatment decreased liver injury (ALT), plasma TNFα and PMN liver infiltration. Overall, these results suggest that JKB-119 can directly inhibit HSC activation attributed to anti-inflammatory activity and may, therefore, attenuate inflammation associated with HSC activation and liver disease.

Topics: Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Proliferation; Cell Survival; Cells, Cultured; Chemical and Drug Induced Liver Injury; Collagen; Disease Models, Animal; Hepatic Stellate Cells; Immunoblotting; Liver Cirrhosis; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 2; Morphinans; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred WKY; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction

Topics: Animals; Carbon Tetrachloride Poisoning; Cattle; Chemical and Drug Induced Liver Injury; Cytochrome c Group; Cytochrome P-450 Enzyme System; Cytochrome Reductases; Dealkylation; Enzyme Induction; Female; Hexobarbital; Liver; Microscopy, Electron; Microsomes, Liver; Morphinans; NAD; Organ Size; Phenobarbital; Pregnenolone Carbonitrile; Proteins; Rats; Serum Albumin, Bovine; Time Factors

Topics: Animals; Carbon Isotopes; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Cytochrome Reductases; Endoplasmic Reticulum; Glucose-6-Phosphatase; Lipid Metabolism; Liver; Male; Morphinans; Protein Binding; Rats; Ribosomes

Topics: Analgesics; Biliary Tract; Chemical and Drug Induced Liver Injury; Humans; Intestines; Liver; Methadone; Morphinans; Spasm