morphinans and Liver-Diseases

Naloxegol is a peripherally acting µ-opioid receptor antagonist (PAMORA) in development for the treatment of opioid-induced constipation (OIC). The pharmacokinetics of a single oral 25-mg dose of naloxegol in plasma was assessed in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment and compared with healthy volunteers. Participants were matched for sex, age, and body mass index. Hepatically impaired patients exhibited a 17%-18% decrease in area under the plasma concentration versus time curve (AUC) despite similar maximum plasma concentrations (Cmax ). This was an unexpected finding given that naloxegol is primarily cleared by the hepatic route. Time to Cmax was shorter in patients with moderate impairment (0.6 hours) versus those with mild impairment (2.3 hours) or normal subjects (2.0 hours). Mean apparent terminal half-life (t½ ) was shorter in patients with mild (9.6 hours) and moderate (7.5 hours) hepatic impairment versus healthy subjects (11.3 hours). Reductions in enterohepatic recycling of naloxegol because of hepatic impairment may explain the observed decreases in AUC and t½ observed in these patients. Naloxegol was generally well tolerated, and mild or moderate hepatic impairment appeared to have minimal effect on its pharmacokinetics and safety.

Topics: Adult; Area Under Curve; Female; Humans; Liver Diseases; Male; Middle Aged; Morphinans; Narcotic Antagonists; Polyethylene Glycols

Nalfurafine hydrochloride, a selective κ-opioid receptor agonist has been approved for pruritus in patients with chronic liver disease. However, not all patients respond to nalfurafine hydrochloride. The aim of this study was to clarify the efficacy of nalfurafine hydrochloride. The subjects were patients with chronic liver disease complicated by pruritus who were treated with nalfurafine hydrochloride between May, 2015, and May, 2021. The degree of pruritus was evaluated based on the Visual Analog Scale (VAS) score and the Kawashima's pruritus score. Nalfurafine hydrochloride 2.5 μg was orally administered once a day for 12 weeks. A decrease in the VAS score of ≥ 25 mm or the Kawashima's pruritus score of ≥ 1 scores was designated as relevant response. The former of ≥ 50 mm or the latter of ≥ 2 scores as remarkable response. The 326 patients who were evaluated the efficacy at 12 weeks. The median time suffering from pruritus to administration of nalfurafine hydrochloride was 4 months. The median VAS score improved from 70.0 mm before administration to 40.0 and 30.0 mm at 4 and 12 weeks of treatment, respectively. On multivariate analysis, shorter itching period and lower FIB-4 index value were extracted as the independent factors related to remarkable responder. On multivariate analysis, shorter itching period was extracted as the only independent factor related to relevant responder. In conclusion, this study suggested nalfurafine hydrochloride treatment markedly improves pruritus in patients with chronic liver disease. A short pruritus period and less-advanced fibrosis were associated with response to nalfurafine hydrochloride.

Topics: Humans; Liver Diseases; Morphinans; Pruritus; Receptors, Opioid, kappa; Spiro Compounds

Ischemia-reperfusion (IR) injury is induced by an interrupted blood flow and succeeding blood restoration, which is common in the operation of liver transplantation. Serious IR injury is a major reason leading to transplant failure. Hepatic IR is featured by excessive inflammatory response, oxidative stress, and apoptosis. Sinomenine (SIN) is derived from the herb Sinomeniumacutum and shows properties of anti-inflammation and antiapoptosis in multiple IR-induced organ injuries. However, the effect of SIN in hepatic IR has not been investigated.. This study aims to investigate impacts of SIN on hepatic IR and the involved signaling pathway. An in vivo rat model of syngeneic orthotopic liver transplantation was constructed to induce the hepatic IR injury.. Results showed that SIN pretreatment provided a significant prevention against IR-induced hepatic injury as manifested by the downregulated activities of serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, the alleviatedoxidative stress as shown by increased activities of serum superoxide dismutase and glutathione peroxidase, and decreased serum level of malondialdehyde, the suppressed inflammatory responses as shown by downregulated serum tumor necrosis factor-α, interleukin (IL)-6, IL-8 levels, and upregulated IL-10 level, as well as attenuated apoptosis as shown by decreased protein expression of cleaved caspase-3 and -9. In line with these results, SIN pretreatment also alleviatedthe hepatic histopathological changes in IR rats and induced Nrf-2/HO-1 activation. The use of brusatol, a selective inhibitor for Nrf-2, effectively reversed SIN-induced above effects.. Altogether, our results demonstrate that SIN might be a useful therapeutic drug for preventing hepatic IR-induced injury during clinical liver transplantation.

Topics: Alanine; Alanine Transaminase; Animals; Aspartate Aminotransferases; Caspase 3; Glutathione Peroxidase; Interleukin-10; Interleukin-8; Lactate Dehydrogenases; Liver Diseases; Malondialdehyde; Morphinans; Rats; Reperfusion Injury; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Among various symptoms accompanied with chronic liver disease, pruritus affects the quality of life of patients, causing physical and mental stress, and worsens hepatic function. Recently, κ-opioid receptor agonist, nalfurafine hydrochloride was approved to treat central pruritus in patients with liver disease in Japan. This study aimed to assess the long-term efficacy and safety of nalfurafine hydrochloride on pruritus in chronic liver disease patients.. A patient-reported outcome using questionnaire-based methods was used for 41 liver disease patients with or without pruritus symptoms. Nalfurafine hydrochloride (2.5 μg/day) was orally administered to 18 patients suffering from pruritus symptoms and whose current treatment was not effective. The same questionnaires and visual analogue scales (VAS) were repeatedly followed up for the patients for the entire follow-up period, and biochemical analyses were performed to evaluate the safety of the treatment.. Pruritus completely disappeared in seven of 18 cases, and VAS scores showed a decreasing trend over time from the start of nalfurafine hydrochloride administration in all patients who received the medication. Among 11 patients who were followed up for more than 12 weeks, nine patients showed continuous improvement of symptoms, and this progress was still apparent at ≥20 weeks after starting administration (p < 0.0001). The medication was discontinued in four patients because of progression of primary disease, high cost, oral dryness, and anemia. No significant toxicity was observed on the serum biochemical analyses.. Nalfurafine hydrochloride contributed to long-term suppression of pruritus without significant safety problems.

Topics: Adult; Aged; Aged, 80 and over; Antipruritics; Chronic Disease; Female; Humans; Liver Diseases; Male; Middle Aged; Morphinans; Patient Reported Outcome Measures; Pruritus; Quality of Life; Spiro Compounds; Surveys and Questionnaires; Treatment Outcome

Topics: Administration, Oral; Animals; Carbon Isotopes; Carbon Tetrachloride; Carbon Tetrachloride Poisoning; Cystamine; Fatty Liver; Glucosephosphate Dehydrogenase; Injections, Intraperitoneal; Isocitrate Dehydrogenase; Kinetics; Lipid Metabolism; Liver; Liver Diseases; Male; Microsomes, Liver; Morphinans; Necrosis; Organ Size; Oxidation-Reduction; Oxidoreductases; Peroxides; Rats