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Frontiers in Pharmacology 2021Drug-induced liver injury (DILI) has become a serious public health problem. For the management of DILI, discontinuation of suspicious drug or medicine is the first... (Review)
Review
Drug-induced liver injury (DILI) has become a serious public health problem. For the management of DILI, discontinuation of suspicious drug or medicine is the first step, but the treatments including drugs and supporting approaches are needed. Reference to clinical patterns and disease severity grades of DILI, the treatment drugs were considered to summarize into hepatoprotective drugs (N-acetylcysteine and Glutathione, Glycyrrhizin acid preparation, Polyene phosphatidylcholine, Bicyclol, Silymarin), anticholestatic drug (Ursodeoxycholic acid, S-adenosylmethionine, Cholestyramine), immunosuppressants (Glucocorticoids) and specific treatment agents (L-carnitine, Anticoagulants). The current article reviewed the accumulated literature with evidence-based medicine researches for DILI in clinical practice. Also the drawbacks of the clinical studies involved in the article, unmet needs and prospective development for DILI therapy were discussed.
PubMed: 35069218
DOI: 10.3389/fphar.2021.806249 -
The Cochrane Database of Systematic... Jul 2020Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013.
OBJECTIVES
To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes.
SEARCH METHODS
For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies.
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy.
DATA COLLECTION AND ANALYSIS
The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach.
MAIN RESULTS
We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy.
AUTHORS' CONCLUSIONS
When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).
Topics: Charcoal; Cholagogues and Choleretics; Cholestasis; Cholestyramine Resin; Dexamethasone; Drugs, Chinese Herbal; Female; Fetal Distress; Galactans; Glucocorticoids; Humans; Mannans; Plant Gums; Pregnancy; Pregnancy Complications; Pruritus; Randomized Controlled Trials as Topic; S-Adenosylmethionine; Stillbirth; Ursodeoxycholic Acid
PubMed: 32716060
DOI: 10.1002/14651858.CD000493.pub3 -
Canadian Medical Association Journal Feb 1971
Review
Topics: Animals; Cholelithiasis; Cholestyramine Resin; Diarrhea
PubMed: 5544698
DOI: No ID Found -
The Cochrane Database of Systematic... Jul 2017Lymphocytic colitis is a cause of chronic diarrhea. It is a subtype of microscopic colitis characterized by chronic, watery, non-bloody diarrhea and normal endoscopic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Lymphocytic colitis is a cause of chronic diarrhea. It is a subtype of microscopic colitis characterized by chronic, watery, non-bloody diarrhea and normal endoscopic and radiologic findings. The etiology of this disorder is unknown.Therapy is based mainly on case series and uncontrolled trials, or by extrapolation of data for treating collagenous colitis, a related disorder. This review is an update of a previously published Cochrane review.
OBJECTIVES
To evaluate the efficacy and safety of treatments for clinically active lymphocytic colitis.
SEARCH METHODS
The MEDLINE, PUBMED and EMBASE databases were searched from inception to 11 August 2016 to identify relevant papers. Manual searches from the references of included studies and relevant review articles were performed.Abstracts from major gastroenterological meetings were also searched to identify research submitted in abstract form only. The trial registry web site www.ClinicalTrials.gov was searched to identify registered but unpublished trials. Finally, the Cochrane Central Register of Controlled Trials and the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Group Specialized Trials Register were searched for other studies.
SELECTION CRITERIA
Randomized controlled trials assessing medical therapy for patients with biopsy-proven lymphocytic colitis were considered for inclusion DATA COLLECTION AND ANALYSIS: Data was independently extracted by at least two authors. Any disagreements were resolved by consensus. Data were analyzed on an intention-to-treat (ITT) basis. The primary outcome was clinical response as defined by the included studies. Secondary outcome measures included histological response as defined by the included studies, quality of life as measured by a validated instrument and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. Data were combined for analysis if they assessed the same treatments. Dichotomous data were combined using a pooled RR along with corresponding 95% CI. A fixed-effect model was used for the pooled analysis.
MAIN RESULTS
Five RCTs (149 participants) met the inclusion criteria. These studies assessed bismuth subsalicylate versus placebo, budesonide versus placebo, mesalazine versus mesalazine plus cholestyramine and beclometasone dipropionate versus mesalazine. The study which assessed mesalazine versus mesalazine plus cholestyramine and the study which assessed beclometasone dipropionate versus mesalazine were judged to be at high risk of bias due to lack of blinding. The study which compared bismuth subsalicylate versus us placebo was judged as low quality due to a very small sample size and limited data. The other 3 studies were judged to be at low risk of bias. Budesonide (9 mg/day for 6 to 8 weeks) was significantly more effective than placebo for induction of clinical and histological response. Clinical response was noted in 88% of budesonide patients compared to 38% of placebo patients (2 studies; 57 participants; RR 2.03, 95% CI 1.25 to 3.33; GRADE = low). Histological response was noted in 78% of budesonide patients compared to 33% of placebo patients (2 studies; 39 patients; RR 2.44, 95% CI 1.13 to 5.28; GRADE = low). Forty-one patients were enrolled in the study assessing mesalazine (2.4 g/day) versus mesalazine plus cholestyramine (4 g/day). Clinical response was noted in 85% of patients in the mesalazine group compared to 86% of patients in the mesalazine plus cholestyramine group (RR 0.99, 95% CI 0.77 to 1.28; GRADE = low). Five patients were enrolled in the trial studying bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks versus placebo). There were no differences in clinical (P=0.10) or histological responses (P=0.71) in patients treated with bismuth subsalicylate compared with placebo (GRADE = very low). Forty-six patients were enrolled in the trial studying beclometasone dipropionate (5 mg/day or 10 mg/day) versus mesalazine (2.4 g/day). There were no differences in clinical remission at 8 weeks (RR 0.97; 95% CI 0.75 to 1.24; GRADE = low) and 12 months of treatment (RR 1.29; 95% CI 0.40 to 4.18; GRADE = very low). Although patients receiving beclometasone dipropionate (84%) and mesalazine (86%) achieved clinical remission at 8 weeks, it was not maintained at 12 months (26% and 20%, respectively). Adverse events reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, hyperhidrosis and headache. Nausea and skin rash were reported as adverse events in the mesalazine study. Adverse events in the beclometasone dipropionate trial include nausea, sleepiness and change of mood. No adverse events were reported in the bismuth subsalicylate study.
AUTHORS' CONCLUSIONS
Low quality evidence suggests that budesonide may be effective for the treatment of active lymphocytic colitis. This benefit needs to be confirmed by a large placebo -controlled trial. Low quality evidence also suggests that mesalazine with or without cholestyramine and beclometasone dipropionate may be effective for the treatment of lymphocytic colitis, however this needs to be confirmed by large placebo-controlled studies. No conclusions can be made regarding bismuth subsalicylate due to the very small number of patients in the study, Further trials studying interventions for lymphocytic colitis are warranted.
Topics: Anti-Inflammatory Agents; Antidiarrheals; Beclomethasone; Bismuth; Budesonide; Cholestyramine Resin; Colitis, Lymphocytic; Humans; Mesalamine; Organometallic Compounds; Randomized Controlled Trials as Topic; Salicylates
PubMed: 28702956
DOI: 10.1002/14651858.CD006096.pub4 -
British Heart Journal Feb 1975Hyperlipidaemia in children is most commonly expressed as hypercholesterolaemia. "Normal values" for serum cholesterol, if defined statistically, vary between... (Review)
Review
Hyperlipidaemia in children is most commonly expressed as hypercholesterolaemia. "Normal values" for serum cholesterol, if defined statistically, vary between communities, and levels of cholesterol in childhood above which an increased risk of coronary heart disease in adult life may be expected have not been firmly established. It is suggested that serum cholesterol concentration over 250 mg/dl (6.47 mmol/l) in a child over 1 year of age merits detailed investigation, including full lipoprotein analysis, and levels of serum cholesterol between230 and 250 mg/dl (5.95-6.47 mmol/l) should be repeated with further studies if indicated. Secondary hyperlipoproteinaemia rarely presents diagnostic problems but must always be excluded. The only primary hyperlipoproteinaemia likely to be encountered in childhood is familial hyperbetalipoproteinaemia in its common heterozygous form. The most effective means to date of lowering serum cholesterol in this condition is cholestyramine, but the long-term consequences of therapy are not known and treatment should at present be limited to children from high-risk families. Long-term follow-up is essential and until results of such studies are available population screening is unjustified.
Topics: Adolescent; Age Factors; Child; Child, Preschool; Cholestasis; Cholesterol; Cholestyramine Resin; Chylomicrons; Coronary Disease; Diabetes Complications; Electrophoresis; Fasting; Glycogen Storage Disease; Glycogen Storage Disease Type I; Humans; Hypercholesterolemia; Hyperlipidemias; Hypothyroidism; Infant; Lipoproteins; Liver Diseases; Nephrotic Syndrome; Puberty; Triglycerides; Xanthomatosis
PubMed: 164201
DOI: 10.1136/hrt.37.2.105 -
JCI Insight Oct 2022A high-fat diet (HFD) contributes to the increased incidence of colorectal cancer, but the mechanisms are unclear. We found that R-spondin 3 (Rspo3), a ligand for...
A high-fat diet (HFD) contributes to the increased incidence of colorectal cancer, but the mechanisms are unclear. We found that R-spondin 3 (Rspo3), a ligand for leucine-rich, repeat-containing GPCR 4 and 5 (LGR4 and LGR5), was the main subtype of R-spondins and was produced by myofibroblasts beneath the crypts in the intestine. HFD upregulated colonic Rspo3, LGR4, LGR5, and β-catenin gene expression in specific pathogen-free rodents, but not in germ-free mice, and the upregulations were prevented by the bile acid (BA) binder cholestyramine or antibiotic treatment, indicating mediation by both BA and gut microbiota. Cholestyramine or antibiotic treatments prevented HFD-induced enrichment of members of the Lachnospiraceae and Rumincoccaceae, which can transform primary BA into secondary BA. Oral administration of deoxycholic acid (DCA), or inoculation of a combination of the BA deconjugator Lactobacillus plantarum and 7α-dehydroxylase-containing Clostridium scindens with an HFD to germ-free mice increased serum DCA and colonic Rspo3 mRNA levels, indicating that formation of secondary BA by gut microbiota is responsible for HFD-induced upregulation of Rspo3. In primary myofibroblasts, DCA increased Rspo3 mRNA via TGR5. Finally, we showed that cholestyramine or conditional deletion of Rspo3 prevented HFD- or DCA-induced intestinal proliferation. We conclude that secondary BA is responsible for HFD-induced upregulation of Rspo3, which, in turn, mediates HFD-induced intestinal epithelial proliferation.
Topics: Animals; Anti-Bacterial Agents; Bile Acids and Salts; Cell Proliferation; Cholestyramine Resin; Deoxycholic Acid; Diet, High-Fat; Intestines; Leucine; Ligands; Mice; RNA, Messenger; Up-Regulation; beta Catenin
PubMed: 36099053
DOI: 10.1172/jci.insight.148309 -
Acta Gastro-enterologica Belgica 2019Pruritus is a common, troublesome symptom in patients with cholestatic liver diseases, especially frequent in intrahepatic cholestasis of pregnancy (ICP) and in primary... (Review)
Review
Pruritus is a common, troublesome symptom in patients with cholestatic liver diseases, especially frequent in intrahepatic cholestasis of pregnancy (ICP) and in primary biliary cholangitis (PBC). Cholestatic associated pruritus can have profound effects on the quality of life. The underlying mechanism is still poorly understood. Severe potential pruritogens have been discussed, such as bile salts, opioids, steroid and lysophosphatidic acid (LPA), but none of these are considered as key mediators. Because of this unraveling pathophysiology the treatment of hepatogenic pruritus often represents a clinical challenge. The EASL guidelines have suggested a step-wise approach, starting with elimination of pruritogens by bile acid sequestrants (cholestyramine), in second line managing the metabolism of pruritogens (rifampicin) and in third-line and fourth- line by modifying the itch perception with μ-opioid antagonist or selective serotonin reuptake inhibitors (SSRI). In treatment-refractory pruritus interruption of the enterohepatic cycle by molecular absorbent recirculating system (MARS), nasobiliairy drainage or experimental therapy such as Ultraviolet B light therapy can be considered. Liver transplantation may be reserved for intractable pruritus. Clinical trials with novel agents are ongoing, potentially providing efficacious options in the future.
Topics: Cholestasis; Cholestasis, Intrahepatic; Cholestyramine Resin; Female; Humans; Pregnancy; Pruritus; Quality of Life
PubMed: 30888758
DOI: No ID Found -
The Cochrane Database of Systematic... Nov 2017Collagenous colitis is a cause of chronic diarrhea. This updated review was performed to identify therapies for collagenous colitis that have been assessed in randomized... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Collagenous colitis is a cause of chronic diarrhea. This updated review was performed to identify therapies for collagenous colitis that have been assessed in randomized controlled trials (RCTs).
OBJECTIVES
The primary objective was to assess the benefits and harms of treatments for collagenous colitis.
SEARCH METHODS
We searched CENTRAL, the Cochrane IBD Group Specialized Register, MEDLINE and EMBASE from inception to 7 November 2016.
SELECTION CRITERIA
We included RCTs comparing a therapy with placebo or active comparator for the treatment of active or quiescent collagenous colitis.
DATA COLLECTION AND ANALYSIS
Data were independently extracted by two authors. The primary outcome was clinical response or maintenance of response as defined by the included studies. Secondary outcome measures included histological response, quality of life and the occurrence of adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The Cochrane risk of bias tool was used to assess bias. The overall quality of the evidence was assessed using the GRADE criteria.
MAIN RESULTS
Twelve RCTs (476 participants) were included. These studies assessed bismuth subsalicylate, Boswellia serrata extract, mesalamine, cholestyramine, probiotics, prednisolone and budesonide therapy. Four studies were low risk of bias. One study assessing mesalamine and cholestyramine was judged to be high risk of bias due to no blinding. The other studies had an unclear risk of bias for random sequence generation (five studies) allocation concealment (six studies), blinding (one study), incomplete outcome data (one study) and selective outcome reporting (one study). Clinical response occurred in 100% (4/4) of patients who received bismuth subsalicylate (nine 262 mg tablets daily for 8 weeks) compared to 0% (0/5) of patients who received placebo (1 study; 9 participants; RR 10.80, 95% CI 0.75 to 155.93; GRADE = very low). Clinical response occurred in 44% (7/16) of patients who received Boswellia serrata extract (three 400 mg/day capsules for 8 weeks) compared to 27% (4/15) of patients who received placebo (1 study; 31 participants; RR 1.64, 95% CI 0.60 to 4.49; GRADE = low). Clinical response occurred in 80% (24/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study; 55 participants; RR 1.82, 95% CI 1.13 to 2.93; GRADE = low). Histological response was observed in 87% (26/30) of budesonide patients compared to 44% (11/25) of mesalamine patients (1 study, 55 participants; RR 1.97, 95% CI 1.24 to 3.13; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 0.69, 95% CI 0.43 to 1.10; GRADE = low), withdrawals due to adverse events (RR 0.09, 95% CI 0.01 to 1.65; GRADE = low) and serious adverse events (RR 0.12, 95% CI 0.01 to 2.21; GRADE = low). Clinical response occurred in 44% (11/25) of mesalamine patients (3 g/day) compared to 59% (22/37) of placebo patients (1 study; 62 participants; RR 0.74, 95% CI 0.44 to 1.24; GRADE = low). Histological response was observed in 44% (11/25) and 51% (19/37) of patients receiving mesalamine and placebo, respectively (1 study; 62 participants; RR 0.86, 95% CI 0.50 to 1.47; GRADE = low). There was no difference between the two treatments with respect to adverse events (RR 1.26, 95% CI 0.84 to 1.88; GRADE = low), withdrawals due to adverse events (RR 5.92, 95% CI 0.70 to 49.90; GRADE = low) and serious adverse events (RR 4.44, 95% CI 0.49 to 40.29; GRADE = low). Clinical response occurred in 63% (5/8) of prednisolone (50 mg/day for 2 weeks) patients compared to 0% (0/3) of placebo patients (1 study, 11 participants; RR 4.89, 95% CI 0.35 to 68.83; GRADE = very low). Clinical response occurred in 29% (6/21) of patients who received probiotics (2 capsules containing 0.5 x 10 CFU each of L. acidophilus LA-5 and B. animalis subsp. lactis strain BB-12 twice daily for 12 weeks) compared to 13% (1/8) of placebo patients (1 study, 29 participants, RR 2.29, 95% CI 0.32 to 16.13; GRADE = very low). Clinical response occurred in 73% (8/11) of patients who received mesalamine (800 mg three times daily) compared to 100% (12/12) of patients who received mesalamine + cholestyramine (4 g daily) (1 study, 23 participants; RR 0.74, 95% CI 0.50 to 1.08; GRADE = very low). Clinical response occurred in 81% (38/47) of patients who received budesonide (9 mg daily in a tapering schedule for 6 to 8 weeks) compared to 17% (8/47) of placebo patients (3 studies; 94 participants; RR 4.56, 95% CI 2.43 to 8.55; GRADE = low). Histological response was higher in budesonide participants (72%, 34/47) compared to placebo (17%, 8/47) (RR 4.15, 95% CI 2.25 to 7.66; GRADE = low). Clinical response was maintained in 68% (57/84) of budesonide patients compared to 20% (18/88) of placebo patients (3 studies, 172 participants, RR 3.30 95% CI 2.13 to 5.09; GRADE = low). Histological response was maintained in 48% (19/40) of budesonide patients compared to 15% (6/40) of placebo patients (2 studies; 80 participants; RR 3.17, 95% CI 1.44 to 6.95; GRADE = very low). No difference was found between budesonide and placebo for adverse events (5 studies; 290 participants; RR 1.18, o95% CI 0.92 to 1.51; GRADE = low), withdrawals due to adverse events (5 studies, 290 participants; RR 0.97, 95% CI 0.43 to 2.17; GRADE = very low) or serious adverse events (4 studies, 175 participants; RR 1.11, 95% CI 0.15 to 8.01; GRADE = very low). Adverse effects reported in the budesonide studies include nausea, vomiting, neck pain, abdominal pain, excessive sweating and headache. Adverse effects reported in the mesalamine studies included nausea and skin rash. Adverse effects in the prednisolone study included abdominal pain, headache, sleep disturbance, mood change and weight gain.
AUTHORS' CONCLUSIONS
Low quality evidence suggests that budesonide may be effective for inducing and maintaining clinical and histological response in patients with collagenous colitis. We are uncertain about the benefits and harms of therapy with bismuth subsalicylate, Boswellia serrata extract, mesalamine with or without cholestramine, prednisolone and probiotics. These agents and other therapies require further study.
Topics: Bismuth; Boswellia; Budesonide; Cholestyramine Resin; Chronic Disease; Colitis, Collagenous; Diarrhea; Glucocorticoids; Humans; Mesalamine; Organometallic Compounds; Plant Extracts; Prednisolone; Probiotics; Randomized Controlled Trials as Topic; Salicylates
PubMed: 29127772
DOI: 10.1002/14651858.CD003575.pub6