rifampin and lysophosphatidic-acid

Pruritus is a common symptom with primary biliary cholangitis. Research has focused on refining understanding of the neurohumoral pathways involved in transduction of pruritus from peripheral cutaneous receptors to the central nervous system, and identifying modulating drugs. Current treatments have variable efficacy and safety. Because of the deleterious effects on quality of life or debilitation, many patients necessitate individualized therapeutic approaches; clinicians may need to consider invasive treatment options. This article highlights various therapeutic interventions, from general measures to invasive strategies, and novel agents under investigation, providing clinicians with the management tricks of the trade.

Topics: Anion Exchange Resins; Bile Acids and Salts; Cholestyramine Resin; Drainage; Filtration; Humans; Liver Cirrhosis, Biliary; Lysophospholipids; Narcotic Antagonists; Opioid Peptides; Phosphoric Diester Hydrolases; Plasmapheresis; Pruritus; Receptors, Opioid; Rifampin; Selective Serotonin Reuptake Inhibitors; Serotonin; Sertraline; Substance P

Cholestatic itch is a feature of numerous hepatobiliary disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, the inherited form of cholestasis, and intrahepatic cholestasis of pregnancy. Although undervalued by physicians, cholestatic itch can be a source of great discomfort to the patient and significantly affects quality of life. Many pruritogens such as bile salts, opioids, serotonin, and histamine have been implicated in the pathogenesis of cholestatic itch, but no causative link has ever been established. Recent findings indicate that the potent neuronal activator lysophosphatidic acid and autotaxin, the enzyme forming lysophosphatidic acid, may be key elements in its pathogenesis. Treatment options for patients with cholestatic itch include the anion exchange resin cholestyramine, bile acid ursodeoxycholic acid, PXR agonist rifampicin, opioid antagonist naltrexone, and the serotonin inhibitor sertraline. These drugs can be used as a stepwise therapeutic approach. The body of evidence for many of these options, however, is not very robust. Patients who do not respond to medical therapy can be candidates for interventional measures, such as albumin dialysis, plasmapheresis, or nasobiliary drainage, or certain experimental approaches such as UVB phototherapy. Research over the past decade has elucidated many of the receptors and neuropeptides involved in itch sensation and transmission; it is hoped that in the future this will lead to the development of novel antipruritic medication for cholestatic itch.

Topics: Anion Exchange Resins; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Naltrexone; Narcotic Antagonists; Plasmapheresis; Pregnane X Receptor; Pruritus; Receptors, Steroid; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Ultraviolet Therapy; Ursodeoxycholic Acid

The pathogenesis of itch during cholestasis is largely unknown and treatment options are limited. Lysophosphatidate, female steroid hormones, and endogenous opioids are among the agents discussed as potential pruritogens in cholestasis. The itch-alleviating action of guideline-based therapeutic interventions with anion exchanger resins, rifampicin, opioid antagonists, and serotonin reuptake inhibitors are studied to unravel the molecular pathogenesis of itch. Still, a considerable part of the patients is in need of alternative experimental therapeutic approaches (eg, UV-B phototherapy, extracorporeal albumin dialysis, nasobiliary drainage), providing additional information about the enigmatic pathophysiology of cholestatic pruritus.

Topics: Animals; Anion Exchange Resins; Antibiotics, Antitubercular; Bile Acids and Salts; Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Narcotic Antagonists; Pregnane X Receptor; Pruritus; Receptors, Steroid; Rifampin; Selective Serotonin Reuptake Inhibitors; Sertraline; Signal Transduction

Pruritus can occur as a severe complication of cholestasis. Several hypotheses suggest an important role for the accumulation of bile acids, endogenous opioids and - mire recently - lysophosphatidic acid. Bile acid sequestrants are the first-line therapeutic agents. In refractory cases, a stepwise approach using rifampicin, oral opiate antagonists and the selective serotonin reuptake inhibitor sertraline should be tested. Recent case series reported effective relief of pruritus using extracorporal liver support systems and plasmapheresis.

Topics: Cholestasis; Cholestyramine Resin; Humans; Lysophospholipids; Opioid Peptides; Plasmapheresis; Pruritus; Renal Dialysis; Rifampin; Sertraline; Sorption Detoxification; Ursodeoxycholic Acid

GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure-response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis.. Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300-1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure-response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily.. The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50-1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily.. Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis.

Topics: Adult; Aged; Antibiotics, Antitubercular; Biomarkers, Pharmacological; Case-Control Studies; Dose-Response Relationship, Drug; Drug Interactions; Female; Healthy Volunteers; Humans; Idiopathic Pulmonary Fibrosis; Imidazoles; Lysophospholipids; Male; Middle Aged; Phosphoric Diester Hydrolases; Pyrimidines; Rifampin