Antibiotic Therapy in the Management of Hepatic Coma

Fast, Bernhard B.; Wolfe, Sidney M.; Stormont, James M.; Davidson, Charles S.

doi:10.1001/archinte.1958.00260140299041

Cited by 22 publications

(4 citation statements)

References 17 publications

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“…The longstanding evidence for the importance of intestinally generated ammonia and the observation that antibiotic treatment can lower systemic and portal ammonia (31)(32)(33) have led to the clinical development of therapeutic agents aimed at decreasing gut microbial activity or adsorbing colonic ammonia for the treatment of HE (22,23). Those drugs include the antibiotic rifaximin, which may reduce activity of ureaseproducing bacteria, and the laxative lactulose, a nonabsorbable disaccharide that acidifies the colon and decreases transit time, resulting in increased fecal elimination of ammonia (34).…”

Section: Introductionmentioning

confidence: 99%

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

et al. 2019

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The intestine is a major source of systemic ammonia (NH3); thus, capturing part of gut NH3 may mitigate disease symptoms in conditions of hyperammonemia such as urea cycle disorders and hepatic encephalopathy. As an approach to the lowering of blood ammonia arising from the intestine, we engineered the orally delivered probiotic Escherichia coli Nissle 1917 to create strain SYNB1020 that converts NH3 to l-arginine (l-arg). We up-regulated arginine biosynthesis in SYNB1020 by deleting a negative regulator of l-arg biosynthesis and inserting a feedback-resistant l-arg biosynthetic enzyme. SYNB1020 produced l-arg and consumed NH3 in an in vitro system. SYNB1020 reduced systemic hyperammonemia, improved survival in ornithine transcarbamylase–deficient spfash mice, and decreased hyperammonemia in the thioacetamide-induced liver injury mouse model. A phase 1 clinical study was conducted including 52 male and female healthy adult volunteers. SYNB1020 was well tolerated at daily doses of up to 1.5 × 1012 colony-forming units administered for up to 14 days. A statistically significant dose-dependent increase in urinary nitrate, plasma 15N-nitrate (highest dose versus placebo, P = 0.0015), and urinary 15N-nitrate was demonstrated, indicating in vivo SYNB1020 activity. SYNB1020 concentrations reached steady state by the second day of dosing, and excreted cells were alive and metabolically active as evidenced by fecal arginine production in response to added ammonium chloride. SYNB1020 was no longer detectable in feces 2 weeks after the last dose. These results support further clinical development of SYNB1020 for hyperammonemia disorders including urea cycle disorders and hepatic encephalopathy.

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Section: Introductionmentioning

confidence: 99%

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

et al. 2019

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“…In clinical practice, encephalopathic patients may be improved by administration of lactulose (Bircher et al, 1966) acid enemas (Jackson et al, 1974) and broad spectrum antibiotics, which inhibit urea-splitting organisms in the colon (Fast et al, 1958;Stormont et al, 1958) and also by resection of the colon or its exclusion (Walker et al, 1965;Resnick et al, 1968). All these procedures reduce the production and/or absorption of ammonia, and frequently, although not always, the concentration of ammonia in the blood falls following the successful administration of these treatments.…”

Section: Discussionmentioning

confidence: 99%

Ammonia absorption from the canine colon after portacaval shunt

Harrison

Smith

Shields

1977

British Journal of Surgery

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Ammonia absorption was studied from Thirty-Vella colon loops in 6 dogs. Four underwent an end-to-side portacaval shunt and it was shown that absorption of ammonia from the colon significantly increased postoperatively. Absorption of ammonia from various solutions was also measured before and after portacaval shunt and it was shown taht absorption was increased from a high pH solution and from a solution with a high bicarbonate content and reduced from a low pH, low osmolality and high osmolality solution. Increased deposits of stainable iron were demonstrated in the livers of dogs following portacaval shunt.

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“…Antibiotic therapy was the first approach proposed for the treatment of HE, even on the basis of non-controlled clinical studies [30]. Suppression of intestinal flora and its metabolic activities will translate into decrease of production of ammonia and other bacteria-derived toxins.…”

Section: Treatment Of Hepatic Encephalopathymentioning

confidence: 99%

Management of Hepatic Encephalopathy: Focus on Antibiotic Therapy

Festi

Vestito²,

Mazzella³

et al. 2006

Digestion

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Hepatic encephalopathy (HE) is a major neuropsychiatric complication of both acute and chronic liver failure. Symptoms of HE include attention deficits, alterations of sleep patterns and muscular incoordination progressing to stupor and coma. The pathogenesis of HE is still unknown, although ammonia-induced alterations of cerebral neurotransmitter balance, especially at the astrocyte-neurone interface, may play a major role. Treatment of HE is therefore directed at reducing the production and absorption of gut-derived neurotoxic substances, especially ammonia. The non-absorbable disaccharides lactulose and lactitol were long considered as a first-line pharmacological treatment of HE, but a recent systematic review questioned their efficacy, pointing out that there is insufficient high-quality evidence to support their use. Oral antibiotics are regarded as a suitable therapeutic alternative. However, the prolonged use of antimicrobials is precluded by the possible occurrence of adverse events. Rifaximin, a synthetic antibiotic structurally related to rifamycin, displays a wide spectrum of antibacterial activity against Gram-negative and Gram-positive bacteria, both aerobic and anaerobic, and a very low rate of systemic absorption. Available evidence suggests that rifaximin – thanks to its efficacy and remarkable safety – has the highest benefit-risk ratio in the overall treatment of HE.

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Antibiotic Therapy in the Management of Hepatic Coma

Cited by 22 publications

References 17 publications

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans

Ammonia absorption from the canine colon after portacaval shunt

Management of Hepatic Encephalopathy: Focus on Antibiotic Therapy

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