Table 2.

Clinical trials using hymecromone (4-methylumbelliferone) in humans

Reference	Patient Type	Indication	Study Type	n	Dose	Primary and Secondary Outcome	Duration	Adverse Events
Walter and Seidel61	Patients requiring cholecystectomy, age older than 14 yr	Postsurgical revision of the biliary pathways	Double-blind, randomized, placebo-controlled	25	2400 mg/d×7.5 d, then 1200 mg×7 d	Postoperative gall bladder volume, residual pressure, and serum enzymes	2 wk	Decreased drain output and need for postoperative, two patients with mild headaches in the treatment group, three with decreased appetite and diarrhea in the placebo group
Camarri and Marchettini62	After cholecystectomy dyspepsia, age >16, mean 58.5 yr	Treatment of symptoms after surgery on bile ducts	Double-blind, randomized, placebo-controlled	13	800 mg twice daily	Pain and gastroenteric symptoms	3 wk	No unexpected symptoms, no abnormal laboratory results (CBC, Cr, BUN, AST, ALT, Alk phos, glucose, UA) by the end of the treatment
Trabucchi et al.63	Biliary dyskinesia	Biliary dyskinesia	RCT versus tiropramide 300 mg	20	1200 mg daily	Biliary pain attacks Dyspepsia symptoms	3 mo	NA
Quaranta et al.64	After cholecystectomy dyspepsia (motor disorders of the biliary tract), age >16, mean 59.5 yr (62 in the active drug group versus 56 in the placebo group)	Treatment of abdominal pain and gastroenteric symptoms because of motor disorders of the biliary tract after cholecystectomy	Placebo-controlled, double-blind, randomized	15	1200 mg/d	Abdominal pain and gastroenteric symptoms	3 wk	One patient developed renal colic/oliguria resolved after drug cessation. No other side effects reported including normal laboratory results after therapy (CBC, uric acid, glucose, UA, AST, ALT, bilirubin, alk phos, γ-GT, cholesterol, SPEP, and amylase)
Garretta and Venitz65	Healthy, age 21–35 yr	Pharmacokinetics	Pharmacokinetics	8	400 mg IV, 800 mg IV, 600 mg by mouth solution, 1200 mg by mouth solution, 1200 mg tablets	Pharmacokinetics	Once	NA
Krawzak et al.66	Healthy, age 22–30 yr	Common bile duct contraction after meal	Prospective, double-blind, randomized crossover study	20	400 mg IV	Common bile duct width while fasting and after meal	Once, after meal	NA
Abate et al.67	Biliary dyskinesia	Dyspepsia Biliary dyskinesia Cholelithiasis Hepatopathy	Placebo-controlled, multicenter, randomized	61	600 mg with lunch, 600 mg with dinner	Abdominal pain	2 wk	NA
Hoffmann et al.68	Healthy, age 25–37 yr	Healthy	4-MU by mouth and IV	20	800 mg ×1 (by mouth and IV)	Gall bladder volume Common bile duct diameter	Once, with meal	NA
Nersesov et al.69	Adults, age 18–65 yr	Primary functional disorders of the gallbladder or sphincter of oddi, after cholecystecomy syndrome	Multicenter, prospective, observational	877	Group A (n=89) 600 mg/d Group B (n=788) 1200 mg/d	Biliary pain severity on the basis of a ten-point visual analog scale	21 d	Treatment satisfaction was higher in group B
Rosser et al.59	Healthy adults, age 18–65 yr	Phase 1 Healthy adult volunteers	Dose response—phase 1 Open-label, nonrandomized	12	400 mg ×3, 800 mg ×3, or 1200 mg ×3	Safety Tolerability Dose response	4 d	Excellent safety and tolerability
Yang et al.60	Patients with COVID-19	COVID-19	Open-label random trial to assess clinical parameters	94	94 patients received 400 mg ×3 daily and 50 patients' control	Primary: changes in lymphocyte counts, CRP, fibrinogen, D-dimer Secondary: changes in pulmonary CT	35 d	None

Partially adapted, expanded, and updated from ref. 39 with permission. 4-MU, 4-methylumbelliferone; CBC, complete blood count; AST, aspartate aminotransferase; ALT, alanine aminotransferase; COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CT, computed tomography; GT, gamma-glutamyl transferase; UA, urinalysis; SPEP, serum protein electrophoresis; IV, intravenous; NA, not applicable.