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Hoilat GJ, Suhail FK, Adhami T, John S. Evidence-based approach to management of hepatic encephalopathy in adults. World J Hepatol 2022; 14:670-681. [PMID: 35646276 PMCID: PMC9099111 DOI: 10.4254/wjh.v14.i4.670] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 08/07/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a reversible syndrome of impaired brain function and represents one of the many complications of portal hypertension and decompensated liver disease. Although ammonia is clearly implicated in the pathogenesis of HE, the pathogenesis of HE is multifactorial with numerous mechanisms that results in functional impairment of neuronal cells. The initial management of HE focuses on supportive care and stabilization which includes providing appropriate nutritional support. Thereafter, focus should be on identifying and treating the precipitating factors. There are many therapeutic agents available for the management of HE, most of which are directed towards lowering the gut nitrogen load and thus the serum ammonia level. This review aims to provide an update on the conventional and emerging treatment options for HE.
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Affiliation(s)
- Gilles Jadd Hoilat
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States.
| | - Fathima Keshia Suhail
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, United States
| | - Talal Adhami
- Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH 44195, United States
| | - Savio John
- Department of Gastroenterology, SUNY Upstate Medical University, Syracuse, NY 13210, United States
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Brigo S, Mancuso E, Pellicano R. Dentistry and oral and maxillofacial surgery in the patient with liver disease: key messages for clinical practice. MINERVA STOMATOLOGICA 2019; 68:192-199. [PMID: 31140770 DOI: 10.23736/s0026-4970.19.04216-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The recent changes in terms of both epidemiology of chronic liver disease (CLD) and long-term survival of patients with CLD have had a great impact in the field of dentistry and oral and maxillofacial surgery. In this context, compared with the previous decades, today it is more probable to cure patients with CLD also at advanced stage (cirrhosis), that could remain asymptomatic for long, before the appearance of signs of decompensation. Hence, it is crucial to identify the patient with CLD and to define the stage of the latter. The main risks are the viral acquisition on the part of the operator or of the other patients, the risk of bleeding due to the impaired coagulation status or the risk of liver decompensation due to alterations in the metabolism of certain drugs leading to hepatotoxicity. Generally, it is appropriate to treat patients with CLD not yet evolved in cirrhosis or with compensated cirrhosis, in a primary care setting, whilst secondary care management should be reserved to those patients with decompensated cirrhosis (Child-Turcotte-Pugh's grade B or C) or compensated cirrhosis but with signs of thrombocytopenia or previous episodes of decompensation. In the latter case it is mandatory to quantify the perioperative risk. In this updated review the authors describe the practical approach to the patient with CLD.
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Affiliation(s)
- Selvaggia Brigo
- Bow Lane Dental Group, St George's Hospital, Bupa Dental Care, London, UK
| | - Enrico Mancuso
- General Surgery, Peterborough City Hospital, North West Anglia Foundation Trust, Peterborough, UK
| | - Rinaldo Pellicano
- Unit of Gastroenterology, Molinette - San Giovanni Antica Sede Hospital, Turin, Italy -
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Kornerup LS, Gluud LL, Vilstrup H, Dam G. Update on the Therapeutic Management of Hepatic Encephalopathy. Curr Gastroenterol Rep 2018; 20:21. [PMID: 29644492 PMCID: PMC5895665 DOI: 10.1007/s11894-018-0627-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
PURPOSE OF REVIEW Hepatic encephalopathy (HE) is a common and devastating complication to chronic liver disease. In this paper, we summarize the latest research and evidence of both conventional and up-coming treatments. RECENT FINDINGS Meta-analyses report beneficial effects of lactulose, branched-chain amino acids, rifaximin, and to some degree L-ornithine L-aspartate on the manifestations of HE in patients with cirrhosis, and generally the numbers needed to treat are low. Recent studies on newer HE treatments including ornithine phenylacetate, spherical carbon, and fecal microbiota transplant also report potentially beneficial effects on HE manifestations. The conventional treatments benefit patients with HE. Newer treatments are under study and more research is needed for their validation.
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Affiliation(s)
- Linda Skibsted Kornerup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark.
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital, Kettegaard Allé 30, Hvidovre, 2650, Denmark
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark
| | - Gitte Dam
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, 44 Norrebrogade, 8000, Aarhus, Denmark
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Zhu GQ, Shi KQ, Huang S, Wang LR, Lin YQ, Huang GQ, Chen YP, Braddock M, Zheng MH. Systematic review with network meta-analysis: the comparative effectiveness and safety of interventions in patients with overt hepatic encephalopathy. Aliment Pharmacol Ther 2015; 41:624-635. [PMID: 25684317 DOI: 10.1111/apt.13122] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 10/21/2014] [Accepted: 01/26/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Interventional treatment for overt hepatic encephalopathy (OHE), includes non-absorbable disaccharides, neomycin, rifaximin, L-ornithine-L-aspartate and branched chain amino acids (BCAA). However, the optimum regimen remains inconclusive. AIM To compare interventions in terms of patients' adverse events and major clinical outcomes. METHODS Literature search of PubMed, Embase, Scopus, and Cochrane Library studies published up to July 31 2014. RCTs of above interventions in OHE patients were included. Network meta-analysis combined direct and indirect evidence to estimate odds ratios (ORs) and mean difference (MD) between treatments and the probabilities of ranking for treatment based on clinical outcomes. RESULTS Twenty eligible RCTs were included. When compared with observation, only L-ornithine-L-aspartate (OR 3.71, P < 0.001) and BCAA (OR 3.37, P < 0.001) improved clinical efficacy significantly. However, when L-ornithine-L-aspartate was compared with BCAA, non-absorbable disaccharides and neomycin, there was a trend suggesting that L-ornithine-L-aspartate may be the most effective intervention with respect to clinical improvement (OR 1.10), rifaximin (OR 1.31), non-absorbable disaccharides (OR 2.75), neomycin (OR 2.22). In addition, L-ornithine-L-aspartate (MD -20.18, 95% CI -40.12 to -0.27) provided a significant reduction in blood ammonia concentration compared with observation. Neomycin appeared to be associated with more adverse events in comparison with non-absorbable disaccharides (OR 10.15), rifaximin (OR 17.31), L-ornithine-L-aspartate (OR 3.16) or BCAA (OR 7.69). CONCLUSIONS L-ornithine-L-aspartate treatment may show a trend in superiority for clinical efficacy among standard interventions for OHE. Rifaximin shows the greatest reduction in blood ammonia concentration, and treatment with neomycin demonstrates a higher probability in causing adverse effects among the five compared interventions.
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Affiliation(s)
- G-Q Zhu
- Department of Infection and Liver Diseases, Liver Research Center, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; School of the First Clinical Medical Sciences, Wenzhou Medical University, Wenzhou, China
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Kimer N, Krag A, Bendtsen F, Møller S, Gluud LL. Rifaximin for people with hepatic encephalopathy. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2015. [DOI: 10.1002/14651858.cd011585] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Nina Kimer
- Medical Division, Copenhagen University Hospital Hvidovre; Gastrounit; Kettegaards Alle 30 Hvidovre Denmark
| | - Aleksander Krag
- Odense University Hospital; Department of Gastroenterology S; Sdr. Boulevard 29, indgang 126 Odense C Denmark 5000
| | - Flemming Bendtsen
- Copenhagen University Hospital Hvidovre; Gastrounit, Medical Division; Kettegårds alle 30 Hvidovre Denmark DK-2650
| | - Søren Møller
- Centre for Functional and Diagnostic Imaging and Research; Department of Clinical Physiology and Nuclear Medicine; Copenhagen University Hospital Hvidovre Copenhagen Denmark
| | - Lise Lotte Gluud
- Copenhagen University Hospital Hvidovre; Gastrounit, Medical Division; Kettegårds alle 30 Hvidovre Denmark DK-2650
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Rifaximin versus Nonabsorbable Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-Analysis. Gastroenterol Res Pract 2013; 2013:236963. [PMID: 23653636 PMCID: PMC3638683 DOI: 10.1155/2013/236963] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Revised: 03/07/2013] [Accepted: 03/07/2013] [Indexed: 02/07/2023] Open
Abstract
Background. Many studies have found that the antibiotic rifaximin is effective for the treatment of hepatic encephalopathy. However, there is no uniform view on the efficacy and safety of rifaximin. Methods. We performed a meta-analysis through electronic searches to evaluate the efficacy and safety of rifaximin in comparison with nonabsorbable disaccharides. Results. A total of 8 randomized controlled trials including 407 patients were included. The efficacy of rifaximin was equivalent to nonabsorbable disaccharides according to the statistical data (risk ratio (RR): 1.06, 95% CI: 0.94–1.19; P = 0.34). Analysis showed that patients treated with rifaximin had better results in serum ammonia levels (weighted mean difference (WMD): −10.63, 95% CI: −30.63–9.38; P = 0.30), mental status (WMD: −0.32, 95% CI: −0.67–0.03; P = 0.07), asterixis (WMD: −0.12, 95% CI: −0.31–0.08; P = 0.23), electroencephalogram response (WMD: −0.21, 95% CI: −0.34–−0.09; P = 0.0007), and grades of portosystemic encephalopathy (WMD: −2.30, 95% CI: −2.78–−1.82; P < 0.00001), but only the last ones had statistical significance. The safety of rifaximin was better than nonabsorbable disaccharides (RR: 0.19, 95% CI: 0.10–0.34; P < 0.00001). Conclusion. Rifaximin is at least as effective as nonabsorbable disaccharides, maybe better for the treatment of hepatic encephalopathy. And the safety of rifaximin is better.
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Eltawil KM, Laryea M, Peltekian K, Molinari M. Rifaximin vs conventional oral therapy for hepatic encephalopathy: A meta-analysis. World J Gastroenterol 2012; 18:767-77. [PMID: 22371636 PMCID: PMC3286139 DOI: 10.3748/wjg.v18.i8.767] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 06/16/2011] [Accepted: 06/23/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To characterize the efficacy of rifaximin in the management of hepatic encephalopathy (HE) as several randomized controlled studies have shown contradictory results on its effectiveness in comparison to other oral agents.
METHODS: We performed a systematic review and random effects meta-analysis of all eligible trials identified through electronic and manual searches. Twelve randomized controlled trials met the inclusion criteria with a total of 565 patients.
RESULTS: The clinical effectiveness of rifaximin was equivalent to disaccharides or other oral antibiotics [odds ratio (OR) 0.96; 95% CI: 0.94-4.08] but with a better safety profile (OR 0.27; 95% CI: 0.12-0.59). At the completion of treatment protocols, patients receiving rifaximin showed lower serum ammonia levels [weighted mean difference (WMD) = -10.65; 95% CI: -23.4-2.1; P = 0.10], better mental status (WMD = -0.24; 95% CI: -0.57-0.08; P = 0.15) and less asterixis (WMD -0.1; 95% CI -0.26-0.07; P = 0.25) without reaching statistical significance. On the other hand, other psychometric outcomes such as electroencephalographic response and grades of portosystemic encephalopathy were superior in patients treated with rifaximin in comparison to the control group (WMD = 0.21, 95% CI: -0.33-0.09, P = 0.0004; and WMD = -2.33, 95% CI: -2.68-1.98, P = 0.00001, respectively). Subgroup and sensitivity analysis did not show any significant difference in the above findings.
CONCLUSION: Rifaximin appears to be at least as effective as other conventional oral agents for the treatment of HE with a better safety profile.
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8
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Rivkin A, Gim S. Rifaximin: new therapeutic indication and future directions. Clin Ther 2011; 33:812-27. [PMID: 21741091 DOI: 10.1016/j.clinthera.2011.06.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Rifaximin is a nonabsorbable oral antibiotic that acts locally in the gastrointestinal tract with minimal systemic adverse effects. Rifaximin received new labeling for reduction in the risk of the recurrence of overt hepatic encephalopathy (HE) in patients with advanced liver disease in March of 2010. OBJECTIVE This article reviews the pharmacology, pharmacokinetics, and pharmacodynamics of rifaximin. The efficacy and safety of rifaximin in reducing the risk of the recurrence of overt HE in patients with advanced liver disease, the new US Food and Drug Administration-approved indication, is the focus of this review. Emerging data on the use of rifaximin in irritable bowel syndrome (IBS) and Clostridium difficile infection (CDI) are also evaluated. METHODS MEDLINE and International Pharmaceutical Abstracts from 1983 to January 31, 2011, were searched using the key terms rifaximin, L/105, secondary hepatic encephalopathy, irritable bowel syndrome, and Clostridium difficile. Ongoing trials were identified using the clinicaltrials.gov Web site. Abstracts from the annual meetings of the American College of Gastroenterology and Digestive Disease Week from 2004 to 2010 and references from relevant articles were reviewed. Only trials examining use of rifaximin in secondary prophylaxis of HE were included. Studies on the efficacy and safety of rifaximin in the treatment of acute episodes of HE have been recently summarized elsewhere and are not reviewed here. RESULTS Literature search identified one trial on rifaximin use in secondary prevention of HE, six trials in patients with IBS, and six small studies and case reports in patients with CDI. In a trial of 299 patients, use of rifaximin 550 mg by mouth twice daily for 6 months for prevention of recurrent HE was associated with significantly fewer breakthrough HE episodes compared with placebo (rifaximin 22%, placebo 46%; P < 0.001), with a hazard ratio of 0.42 (95% CI, 0.28-0.64). The rifaximin group also had fewer hospitalizations involving HE compared with placebo (rifaximin 13.6%, placebo 22.6%; P = 0.01), with a hazard ratio of 0.50 (95% CI, 0.29-0.87). Rifaximin improved IBS symptom management in ∼9% more patients than placebo in 2 prospective, randomized, double-blind, placebo-controlled trials of 1260 patients (in the rifaximin group, 40.8% patients reported IBS symptom improvement compared with 31.7% in the placebo group; P < 0.001). The efficacy of rifaximin has been reported for the treatment of refractory or recurrent CDI in small studies, case series, and a case report. Optimal dosing, duration, and role of rifaximin for CDI management is unclear. In clinical trials of rifaximin for prevention of recurrent HE and for nonconstipated IBS, its safety profile was comparable to placebo. In the trial of rifaximin for prevention of recurrent HE, the most common adverse events occurring in 10% to 15% of patients were ascites, dizziness, fatigue, and peripheral edema. Most common adverse effects in IBS trials included abdominal pain, diarrhea, bad taste, headache, and upper respiratory tract infection, occurring in <10% of patients. CONCLUSIONS Rifaximin can be an effective option for reduction in the risk of the recurrence of HE in patients with advanced liver disease. Studies suggest that rifaximin provides relief of global symptoms of diarrhea-predominant IBS and bloating. Use of rifaximin in CDI requires further study.
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Affiliation(s)
- Anastasia Rivkin
- Pharmacy Practice, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York, USA
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Portale Hypertension. PRAXIS DER VISZERALCHIRURGIE. GASTROENTEROLOGISCHE CHIRURGIE 2011. [PMCID: PMC7123479 DOI: 10.1007/978-3-642-14223-9_38] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Während die Pathologie, die zur portalen Hypertension führt, im prähepatischen, hepatischen und posthepatischen venösen Gefäßbett liegen kann, machen die intrahepatischen Erkrankungen mit Abstand den Großteil aus. In unseren Breitengraden ist es die durch Alkoholabusus bedingte ethyltoxische Leberzirrhose, weltweit die durch Infektionen (HCV, HBV) bedingten Zirrhosen. Die chronische Hepatitis C mit ihren Komplikationen (Leberzellversagen, portale Hypertension und hepatozelluläres Karzinom) wird in den kommenden Jahren trotz moderner Therapieverfahren noch an Bedeutung gewinnen.
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Wang AH, Duan ZJ, Tian G, Zhang WJ, He GH. Targeted removal of ammonia from the colon using ammonia-removing microemulsion. Shijie Huaren Xiaohua Zazhi 2009; 17:2821-2824. [DOI: 10.11569/wcjd.v17.i27.2821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether ammonia-removing microemulsion (ARM) can specifically remove ammonia from artificial colonic fluid and explore the potential role of ARM in the prevention and treatment of hepatic encephalopathy.
METHODS: ARM was mixed with artificial colonic fluid containing different concentrations of ammonia for ten hours. Meanwhile, ARM was successively mixed with artificial gastric juice for 2 h, artificial small intestinal juice for 3 h and artificial colonic fluid for 10 h to mimic gastrointestinal transit and pH environment. Ammonia concentrations in the fluid were then measured using a standard technique, and the ammonia removal rate was calculated. The ammonia removal efficiency achieved using ARM was compared with that achieved using empty microemulsion, water and lactulose.
RESULTS: After mixing with ARM, the ammonia concentrations decreased to 0 g/L in the artificial colonic fluid initially containing 5 g/L or 10 g/L of ammonia, and to 0.521 ± 0.135 g/L in the fluid containing 20 g/L of ammonia. The ammonia removal rate achieved in artificial colonic fluid containing 10 or 20 g/L of ammonia was significantly higher than that in the artificial gastric juice and small intestinal juice containing enzymes (100% ± 0.00% vs 96.41% ± 0.84%, and 97.29% ± 2.67% vs 86.42% ± 2.63%, respectively; both P < 0.05). ARM achieved a higher ammonia removal efficiency than empty microemulsion, water and lactulose.
CONCLUSION: ARM shows a very good ammonia-removing effect and thus provides a new approach for removal of colonic ammonia. However, the digestive fluids in the stomach and small intestine may weaken such ammonia-removing effect.
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Baraldi M, Avallone R, Corsi L, Venturini I, Baraldi C, Zeneroli ML. Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy. Metab Brain Dis 2009; 24:81-93. [PMID: 19082698 DOI: 10.1007/s11011-008-9111-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2008] [Accepted: 10/28/2008] [Indexed: 12/15/2022]
Abstract
Benzodiazepines of natural origin (NBZDs) have been found in human blood and brains as well as in medicinal plants and foods. In plasma and brain tissue there are i.e. diazepam and nordiazepam equal to commercial drugs but there are also other benzodiazepine-like compounds termed "endozepines", which act as agonists at the benzodiazepine receptors of central type (CBR). A synthetic pathway for the production of NBZDs has not yet been found, but it has been suggested that micro-organisms may synthesize molecules with benzodiazepine-like structures. Hence NBZDs could be of both endogenous and exogenous source and be considered as natural anxyolitic and sedative. Interestingly there are also natural compounds, such as the polypeptide Diazepam Binding Inhibitor (DBI) acting as an "inversive agonist" implicated in fair and panic disorders. It has been suggested that NBZDs may play a role in the pathogenesis of hepatic encephalopathy (HE). Multidirectional studies evaluated NBZDs levels (1) in the blood of normal subjects, of cirrhotic with or without HE and in commercial benzodiazepine consumers; (2) in the blood of cirrhotic treated or not with a non-absorbable antibiotic; (3) in several constituents of our diet. In conclusion, NBZDs increase sometime in cirrhotics with or without HE but they reach concentrations not higher than those found in commercial benzodiazepines consumers. Hence NBZDs must be considered as occasional precipitating factor of HE and benzodiazepine antagonists only symptomatic drugs. The finding that NBZDs may be in part synthesized by intestinal bacterial flora and in part constituent of our diet underlines the importance to feed cirrhotic patients with selected food.
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Affiliation(s)
- M Baraldi
- Department of Biomedical Sciences (Section of Pharmacology), University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italy.
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Moye PM, Yunker NS. Rifaximin for Hepatic Encephalopathy. J Pharm Technol 2009. [DOI: 10.1177/875512250902500207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objective: To evaluate the efficacy of rifaximin for the treatment of hepatic encephalopathy (HE). Data Sources: All articles were accessed via PubMed (January 1960–December 2008), Cochrane Library, and Iowa Drug Information Service (1966–December 2008) using the terms rifaximin and hepatic encephalopathy. In addition, reference citations from publications identified were reviewed. Study Selection and Data Extraction: All articles in English identified from the data sources were evaluated. Fifteen studies that evaluated the efficacy, safety, and/or cost-effectiveness of rifaximin for the treatment of HE are reviewed in this article. Data Synthesis: HE is a neuropsychiatric syndrome that develops in patients with acute or chronic liver failure. There are a number of accepted theories explaining the pathophysiology of HE. Currently, pharmacologic therapies include nonabsorbable disaccharides (lactulose) and antibiotics (neomycin and metronidazole). Recent studies have shown a possible benefit with a newer, nonabsorbable rifamycin derivative, rifaximin. It has a broad spectrum of activity against aerobic and anaerobic gram-positive and gram-negative organism. Clinical trials have compared rifaximin with lactulose, neomycin, or metronidazole for the treatment of HE. There have also been review articles addressing the cost-effectiveness of rifaximin compared with lactulose, including the cost of hospitalization. To date there have been no randomized, placebo-controlled studies that have assessed the efficacy and long-term safety outcomes of rifaximin in the treatment of HE; however, rifaximin has demonstrated similar efficacy and better safety profiles compared with other therapies, in particular, neomycin and lactulose. Conclusions: Patients with HE who are refractory to lactulose therapy or who have decreased tolerability to lactulose therapy may benefit from rifaximin as either adjunct therapy or salvage therapy. ACPE Universal Program Numbers: 407-000-09-053-H01-P (Pharmacists); 407-000-09-053-H01-T (Technicians)
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Affiliation(s)
- Pamela M Moye
- PAMELA M MOYE PharmD BCPS, Clinical Assistant Professor, Department
of Pharmacy Practice, College of Pharmacy and Health Sciences, Mercer University,
Atlanta, GA
| | - Nancy S Yunker
- NANCY S YUNKER PharmD BCPS, Assistant Professor, Department of
Pharmacy, School of Pharmacy, Virginia Commonwealth University, Richmond, VA
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Jiang Q, Jiang XH, Zheng MH, Jiang LM, Chen YP, Wang L. Rifaximin versus nonabsorbable disaccharides in the management of hepatic encephalopathy: a meta-analysis. Eur J Gastroenterol Hepatol 2008; 20:1064-1070. [PMID: 19047837 DOI: 10.1097/meg.0b013e328302f470] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE To compare the positive and negative effects of rifaximin and nonabsorbable disaccharides in patients with hepatic encephalopathy. METHODS We used the method recommended by The Cochrane Collaboration to perform a meta-analysis of comparative randomized trials of rifaximin and nonabsorbable disaccharides. RESULTS Seven randomized controlled trials were identified, but only five trials involving 264 patients met all the inclusion criteria. There was no significant difference between rifaximin and nonabsorbable disaccharides on improvement in patients with hepatic encephalopathy [relative risk (RR) 1.08; 95% confidence interval (CI), 0.85-1.38; P=0.53]. RR was 0.98 (95% CI: 0.85-1.13; P=0.74) for acute hepatic encephalopathy in 157 patients and 0.87 (95% CI: 0.40-1.88; P=0.72) for chronic hepatic encephalopathy in 96 patients, respectively. There was no significant difference between rifaximin and nonabsorbable disaccharides on diarrhea (RR=0.90; 95% CI: 0.17-4.70; P=0.90). However, a significant difference in favor of rifaximin on abdominal pain (RR=0.28; 95% CI: 0.08-0.95; P=0.04) was identified. CONCLUSION Rifaximin is not superior to nonabsorbable disaccharides for acute or chronic hepatic encephalopathy in the long-term or short-term treatment except that it may be better tolerated. Further studies on larger populations are required to provide more sufficient evidence for assessment of the use of rifaximin.
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Affiliation(s)
- Qian Jiang
- Department of Clinical Pharmacy, West China School of hepatic encephalopathy, Sichuan University, Chengdu, China
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14
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van de Poll MCG, Ligthart-Melis GC, Olde Damink SWM, van Leeuwen PAM, Beets-Tan RGH, Deutz NEP, Wigmore SJ, Soeters PB, Dejong CHC. The gut does not contribute to systemic ammonia release in humans without portosystemic shunting. Am J Physiol Gastrointest Liver Physiol 2008; 295:G760-5. [PMID: 18703642 DOI: 10.1152/ajpgi.00333.2007] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The gut is classically seen as the main source of circulating ammonia. However, the contribution of the intestines to systemic ammonia production may be limited by hepatic extraction of portal-derived ammonia. Recent data suggest that the kidney may be more important than the gut for systemic ammonia production. The aim of this study was to quantify the role of the kidney, intestines, and liver in interorgan ammonia trafficking in humans with normal liver function. In addition, we studied changes in interorgan nitrogen metabolism caused by major hepatectomy. From 21 patients undergoing surgery, blood was sampled from the portal, hepatic, and renal veins to assess intestinal, hepatic, and renal ammonia metabolism. In seven cases, blood sampling was repeated after major hepatectomy. At steady state during surgery, intestinal ammonia release was equaled by hepatic ammonia uptake, precluding significant systemic release of intestinal-derived ammonia. In contrast, the kidneys released ammonia to the systemic circulation. Major hepatectomy led to increased concentrations of ammonia and amino acids in the systemic circulation. However, transsplanchnic concentration gradients after major hepatectomy were similar to baseline values, indicating the rapid institution of a new metabolic equilibrium. In conclusion, since hepatic ammonia uptake exactly equals intestinal ammonia release, the splanchnic area, and hence the gut, probably does not contribute significantly to systemic ammonia release. After major hepatectomy, hepatic ammonia clearance is well preserved, probably related to higher circulating ammonia concentrations.
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Affiliation(s)
- Marcel C G van de Poll
- Univ. Hospital Maastricht, Dept. of Surgery, PO Box 5800, 6200 AZ Maastricht, the Netherlands
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15
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González Reimers E, Santolaria Fernández F. Benzodiacepinas, alcohol y deterioro neuropsicológico. Med Clin (Barc) 2008; 130:696-7. [DOI: 10.1157/13120779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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16
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Abdel-Hady H, Zaki A, Badra G, Lotfy M, Selmi C, Giorgini A, El-Sayed M, Badr R. Helicobacter pylori infection in hepatic encephalopathy: Relationship to plasma endotoxins and blood ammonia. Hepatol Res 2007; 37:1026-33. [PMID: 17610507 DOI: 10.1111/j.1872-034x.2007.00146.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM Hepatic encephalopathy (HE) is frequently observed in patients with advanced liver disease and manifests a wide variety of neuropsychiatric signs and symptoms. Ammonia toxicity and bacterial endotoxins have been suggested as key determinants of HE onset whereas a role for Helicobacter pylori infection has not been established. We investigated the correlation between H. pylori infection and HE severity (evaluated through functional tests) in 60 outpatients with established liver cirrhosis and 20 non-cirrhotic controls. METHODS Fasting arterial blood ammonia, plasma endotoxins, and H. pylori infection status were investigated in all subjects. RESULTS H. pylori infection was documented in 35/60 (58%) patients and in 6/20 (30%) controls (P = 0.039). Significant differences were observed between patients with and withoutHE for age, presence of ascites, fasting arterial blood ammonia, plasma endotoxin, and H. pylori infection. Further, a significant increase in fasting arterial blood ammonia and plasma endotoxin was associated with H. pylori infection in cirrhotic patients. Last, medical treatment of H. pylori infection led to a significant decrease in HE severity and fasting arterial blood ammonia levels. CONCLUSION In conclusion, we submit that H. pylori infection might, in fact, play a role in increasing the circulating levels of ammonia and endotoxins in cirrhotic patients, thus facilitating the onset of HE.
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Affiliation(s)
- Hassan Abdel-Hady
- Department of Internal Medicine, Faculty of Medicine, Minufiya University, Minufiya, Egypt
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17
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Neff GW, Kemmer N, Zacharias VC, Kaiser T, Duncan C, McHenry R, Jonas M, Novick D, Williamson C, Hess K, Thomas M, Buell J. Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 2007; 38:3552-5. [PMID: 17175328 DOI: 10.1016/j.transproceed.2006.10.107] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2006] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Patients with end-stage liver disease often develop hepatic encephalopathy. The loss in cognitive abilities results in marked economic loss to the patient and health care community. We report hospital admission rates and economic impact of patients with end-stage liver disease suffering from hepatic encephalopathy. METHODS The medical records were reviewed involving liver transplant patients started on lactulose or rifaximin therapy after presenting with stage 2 hepatic encephalopathy from January 2004 to November 2005. Information collected included demographics, hospitalizations required for hepatic encephalopathy, economic data, and Model for End-stage Liver Disease (MELD) score. RESULTS Thirty-nine patients met study criteria: 24 patients treated with lactulose (group one) and 15 with rifaximin (group two). Group one included 18 men and six women of mean age 48 (range 39 to 58), average MELD 14 (range 10 to 19). Group two included 10 men and five women of mean age 47 (range 42 to 58), average MELD 15 (range 10 to 19). Group one patients required 19 hospitalizations overall: three patients with three hospitalizations, four patients with two hospitalizations, and two patients required one hospitalization. Total drug cost per month was 50 dollars(group one) and 620 dollars(group two). The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 13,284.96 dollars for a total of 318,839 dollars (range 5005 dollars to 26,255 dollars, including drug cost and hospital care). Group two required three hospitalizations, all three with one visit. The average annual cost of hospitalization, emergency room visit, and drug per patient treated was 7958.13 dollars for a total of 119,372 dollars (range 6005 dollars to 19,255 dollars, including drug cost and hospital care). The total cost of therapy per patient per year was 13,285 dollars (group one) versus 7958 dollars (group two). The average length of stay was shorter in group two [3.5 days (range 3 to 4)] versus group 1 [5.0 days (range 3 to 10); P < .0001]. CONCLUSION These pilot data demonstrate the marked difference in economic costs for the treatment of hepatic encephalopathy. The results also show that in comparative groups, the economic gains are quickly lost when using lactulose.
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Affiliation(s)
- G W Neff
- Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0595, USA.
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18
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Abstract
Hepatic encephalopathy (HE) is a major complication for acute and chronic liver failure. Despite several decades of intensive clinical and basic research, the pathogenesis of HE is still incompletely understood, and the precise mechanisms causing brain dysfunction in liver failure are still not fully established. Several theories concerning the pathogenesis of HE have been previously suggested, including the ammonia theory, which received the most attention. These theories are not mutually exclusive and the validity of none of them has been definitely proved experimentally. In this review article, an attractive theory concerning the pathogenesis of HE, the tumour necrosis factor-alpha (TNF) theory, is presented and comprehensively discussed after accumulation of sufficient data which indicate that the pro-inflammatory cytokine, TNF, is strongly involved in the pathogenesis of HE associated with both acute and chronic liver failure. This theory seems to be superior to all other previous theories in the pathogenesis of HE, and may induce development of other beneficial therapeutical modalities for HE directed towards inhibition of TNF production and/or action, and towards enhancement of its degradation.
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Affiliation(s)
- M Odeh
- Bnai Zion Medical Centre, and Faculty of Medicine, Technion, Haifa 31063, Israel.
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19
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Gasbarrini A, Lauritano EC, Nista EC, Candelli M, Gabrielli M, Santoro M, Zocco MA, Cazzato A, Finizio R, Ojetti V, Cammarota G, Gasbarrini G. Rifaximin-based regimens for eradication of Helicobacter pylori: a pilot study. Dig Dis 2006; 24:195-200. [PMID: 16699278 DOI: 10.1159/000090330] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Triple therapy is the treatment of choice for Helicobacter pylori-infected patients with an eradication rate ranging from 70 to 85%. Poor compliance and antibiotic resistance are the main causes of treatment failure. The aim of the present study was to assess the efficacy of rifaximin, a poorly absorbed antibiotic, for H. pylori eradication. METHODS We enrolled 48 consecutive H. pylori-positive patients affected. They were randomized to receive two 7-day rifaximin-based triple therapies: rifaximin tablets 400 mg t.i.d., esomeprazole 40 mg o.d. and clarithromycin 500 mg b.i.d. (CRE) or levofloxacin 500 mg o.d. (LRE). H. pylori eradication was assessed using a (13)C-urea breath test 4 weeks after the end of therapy. Treatment compliance and the incidence of side effects were also evaluated. RESULTS No dropouts were observed. The eradication rate both on intention-to-treat and per-protocol analysis did not show significant differences between groups: 58% (14/24 patients) in group 1 and 42% (10/24 patients) in group 2 (p = 0.24, OR 1.96, 95% CI 0.62-6.18). No significant differences in patients' compliance and incidence of side effects were found between groups. CONCLUSIONS Rifaximin-based therapy showed optimal compliance but a limited eradication rate compared to standard first-line treatment. Further investigations are needed to evaluate different dosages and combinations.
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Affiliation(s)
- Antonio Gasbarrini
- Department of Internal Medicine, Gemelli University Hospital, Catholic University of the Sacred Heart, Rome, Italy.
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20
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Scarpignato C, Pelosini I. Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential. Chemotherapy 2005; 51 Suppl 1:36-66. [PMID: 15855748 DOI: 10.1159/000081990] [Citation(s) in RCA: 164] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Rifaximin (4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo- [5,4-c]-rifamycin SV) is a synthetic antibiotic designed to modify the parent compound, rifamycin, in order to achieve low gastrointestinal (GI) absorption while retaining good antibacterial activity. Both experimental and clinical pharmacology clearly show that this compound is a nonsystemic antibiotic with a broad spectrum of antibacterial action covering Gram-positive and Gram-negative organisms, both aerobes and anaerobes. Being virtually nonabsorbed, its bioavailability within the GI tract is rather high with intraluminal and fecal drug concentrations that largely exceed the minimal inhibitory concentration values observed in vitro against a wide range of pathogenic organisms. The GI tract represents, therefore, the primary therapeutic target and GI infections the main indication. The appreciation of the pathogenic role of gut bacteria in several organic and functional GI diseases has increasingly broadened its clinical use, which is now extended to hepatic encephalopathy, small intestine bacterial overgrowth, inflammatory bowel disease and colonic diverticular disease. Potential indications include the irritable bowel syndrome and chronic constipation, Clostridium difficile infection and bowel preparation before colorectal surgery. Because of its antibacterial activity against the microorganism and the lack of strains with primary resistance, some preliminary studies have explored the rifaximin potential for Helicobacter pylori eradication. Oral administration of this drug, by getting rid of enteric bacteria, could also be employed to achieve selective bowel decontamination in acute pancreatitis, liver cirrhosis (thus preventing spontaneous bacterial peritonitis) and nonsteroidal anti-inflammatory drug (NSAID) use (lessening in that way NSAID enteropathy). This antibiotic has, therefore, little value outside the enteric area and this will minimize both antimicrobial resistance and systemic adverse events. Indeed, the drug proved to be safe in all patient populations, including young children. Although rifaximin has stood the test of time, it still attracts the attention of both basic scientists and clinicians. As a matter of fact, with the advancement of the knowledge on microbial-gut interactions in health and disease novel indications and new drug regimens are being explored. Besides widening the clinical use, the research on rifaximin is also focused on the synthesis of new derivatives and on the development of original formulations designed to expand the spectrum of its clinical use.
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Affiliation(s)
- Carmelo Scarpignato
- Laboratory of Clinical Pharmacology, Department of Human Anatomy, Pharmacology and Forensic Sciences, School of Medicine and Dentistry, University of Parma, Parma, Italy.
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