Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Antibiotics are usually prescribed to cure infections but they also have significant modulatory effects on the gut microbiota. Several alterations of the intestinal bacterial community have been reported during antibiotic treatment, including the reduction of beneficial bacteria as well as of microbial alpha-diversity. Although after the discontinuation of antibiotic therapies it has been observed a trend towards the restoration of the original condition, the new steady state is different from the previous one, as if antibiotics induced some kind of irreversible perturbation of the gut microbial community. The poorly absorbed antibiotic rifaximin seem to be different from the other antibiotics, because it exerts non-traditional effects additional to the bactericidal/bacteriostatic activity on the gut microbiota. Rifaximin is able to reduce bacterial virulence and translocation, has anti-inflammatory properties and has been demonstrated to positively modulate the gut microbial composition. Animal models, culture studies and metagenomic analyses have demonstrated an increase in Bifidobacterium, Faecalibacterium prausnitzii and Lactobacillus abundance after rifaximin treatment, probably consequent to the induction of bacterial resistance, with no major change in the overall gut microbiota composition. Antibiotics are therefore modulators of the symbiotic relationship between the host and the gut microbiota. Specific antibiotics, such as rifaximin, can also induce eubiotic changes in the intestinal ecosystem; this additional property may represent a therapeutic advantage in specific clinical settings.     

Rifaximin, but not growth factor 1, reduces brain edema in cirrhotic rats

AIM: To compare rifaximin and insulin-like growth factor (IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS: Rats with CCl₄-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups: Cirrhosis; Cirrhosis + IGF-1; Cirrhosis + rifaximin; Controls; Controls + IGF-1; and Controls + rifaximin. An oral glutamine-challenge test was performed, and plasma and cerebral ammonia, glucose, bilirubin, transaminases, endotoxemia, brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS: Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups, and improved some liver function parameters (bilirubin, alanine aminotransferase and aspartate aminotransferase). These effects were associated with a significant reduction in cerebral water content. Blood and cerebral ammonia levels, and area-under-the-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals. By contrast, IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION: By reducing gut bacterial overgrowth, only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema, alterations associated with hepatic encephalopathy.     

Rifaximin in the treatment of inflammatory bowel disease

The gut microbiota plays a role in promoting and maintaining inflammation in inflammatory bowel diseases (IBD),hence the rationale for the use of antibiotics in the treatment of those disorders.Antibiotics,however, may induce untoward effects,especially during long- term therapy.Rifaximin polymer is an antibacterial agent that is virtually unabsorbed after oral adminis- tration and is devoid of systemic side effects.Rifaximin has provided promising results in inducing remission of Crohn's disease(up to 69%i...     

Rifaximin is associated with modest,transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome

Rifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D.

ClinicalTrials.gov identifier number: NCT01543178.     

腹水超滤浓缩回输腹腔术治疗肝硬化顽固性腹水疗效分析

目的 探讨腹水超滤浓缩回输腹腔术治疗肝硬化顽固性腹水的疗效。方法 将56例肝硬化顽固性腹水患者随机分为2组,均给予保肝、利尿及抗病毒治疗。在此基础上,对治疗组行腹水超滤浓缩回输腹腔术加小剂量人血白蛋白静脉滴注(静滴)(每滤出1000ml腹水,静滴人血白蛋白4g),对对照组行大量放腹水加大剂量人血白蛋白静滴(每抽出1000ml腹水,静滴人血白蛋白8g)。结果 术后第14天,治疗组患者24h尿量、血清ALB水平均高于对照组(P均<0.05),且治疗组总有效率高于对照组(P<0.05)。结论 腹水超滤浓缩回输腹腔术是一种安全有效的治疗肝硬化顽固性腹水的方法。     

Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications

Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint",characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined,and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover,in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis(SBP),hepatic encephalopathy(HE),and,portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic,immune-modulating and anti-inflammatory activity,a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE,and also to prevent the development of SBP,to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality,triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.     

Study confirms benefit of surgery for gastroesophageal reflux disease

Evaluation of: Pimentel M, Lembo A, Chey WD et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N. Engl. J. Med. 364(1), 22–32 (2011).

Alterations in gut flora may play an important role in the pathophysiology of bowel symptoms, especially in patients with irritable bowel syndrome (IBS). If so, antibiotics that affect gut flora may offer a novel approach for the management of patients with IBS. Here, we discuss the results of two identically designed, double-blind, placebo-controlled trials (TARGET 1 and TARGET 2) of a poorly absorbed antibiotic, rifaximin, in patients with IBS. In these studies, 1260 patients (females 76.1 and 72.1%, respectively) who had IBS without constipation were randomized to receive either rifaximin 550 mg or placebo, three-times daily for 2 weeks. Subsequently, daily symptoms were assessed and patients were followed up for 10 weeks. The primary outcome measure – adequate relief of global IBS symptoms during the first 4 weeks after treatment – was met in significantly more patients who received rifaximin than placebo (p < 0.001). In addition, more patients in the rifaximin group than in the placebo group (p < 0.001) reported an adequate relief of bloating, and an improvement in abdominal pain and stool consistency – secondary outcome measures. The incidence of adverse events with rifaximin was similar to placebo, and the drug was well tolerated. In summary, a 2-week course of rifaximin provided significant relief of IBS symptoms, as well as bloating and abdominal pain.     

Antibiotics for the treatment of hepatic encephalopathy

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.     

Rifaximin versus Other Antibiotics in the Primary Treatment and Retreatment of Bacterial Overgrowth in IBS

Purpose Previous studies demonstrate improvement in IBS after antibiotic therapy, with the greatest efficacy seen with the antibiotic, rifaximin. The purpose of this study was to compare the efficacy of rifaximin in both the treatment and retreatment of IBS. Methods A retrospective chart review was conducted on Rome I-positive IBS patients. Charts were reviewed to evaluate all antibiotic treatments (rifaximin, neomycin, doxycycline, amoxicillin/clavulanate, and ciprofloxacin), even those predating 1 July 2004. Data collection included symptoms, breath test results (pre- and post-treatment), antibiotics used, and clinical response to individual antibiotic treatments before and after rifaximin availability in the USA. Results Out of 98 eligible charts, 84 patients received one course of rifaximin. Fifty of these (60%) had a follow-up breath test. Among these, 31 (62%) were clinical responders and 19 (38%) were nonresponders. Of 31 responders, 25 (81%) had a normal follow-up breath test compared with only 3 of the 19 nonresponders (16%) (P < 0.001). Of participants given rifaximin, 69% (58 out of 84) had a clinical response compared with only 38% (9 out of 24) with neomycin (P < 0.01) and 44% (27 out of 61) with all non-rifaximin antibiotics (P < 0.01). Rifaximin was used as retreatment on 16 occasions, and all patients improved. Conclusions Rifaximin is more effective than other antibiotics in the treatment and retreatment of IBS.     

Transjugular intrahepatic portosystemic shunt versus paracentesis plus albumin in patients with refractory ascites who have good hepatic and renal function: a prospective randomized trial

Background

Transjugular intrahepatic portosystemic shunt (TIPS) has recently been reported to be effective in the treatment of cirrhotic patients with refractory ascites. However, the clinical utility of TIPS in the subset of refractory ascitic patients with good hepatic and renal function is uncertain. The aim of this study was to compare the efficacy of TIPS to that of large-volume paracentesis in cirrhotic patients with refractory ascites who have good hepatic and renal function.

Methods

Sixty cirrhotic patients with refractory ascites who presented with a Child?CPugh score of <11, serum bilirubin of <3?mg/dl and creatinine of <1.9?mg/dl were assigned randomly to TIPS (n?=?30) or large-volume paracentesis plus albumin (n?=?30). The primary endpoint was survival. The secondary endpoints were response to treatment and development of hepatic encephalopathy.

Results

The baseline characteristics were similar in the two groups. Seventeen patients treated with TIPS and 21 treated with paracentesis died during the study period. The cumulative probabilities of survival at 1 and 2?years were 80 and 64% in the TIPS group and 49 and 35% in the paracentesis group (p?<?0.005). TIPS was significantly superior to paracentesis in the control of ascites (p?<?0.005). Treatment failure was more frequent in the paracentesis group, whereas the frequency of hepatic encephalopathy was greater in the TIPS group.

Conclusions

In cirrhotic patients with refractory ascites who have good hepatic and renal function, TIPS improves survival and provides better control of ascites than large-volume paracentesis.     

Rifaximin,gut microbes and mucosal inflammation: unraveling a complex relationship

Rifaximin is a non-systemic, broad-spectrum antibiotic that acts against gram-positive, gram-negative, and anaerobic bacteria. Clinical studies indicate that rifaximin is beneficial in treating irritable bowel syndrome (IBS). The mechanism responsible for the beneficial effects of rifaximin is not clear. In a recent study, we reported that rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus species. These changes prevent gut inflammation and visceral hyperalgesia caused by chronic stress. To more closely mirror human clinical studies in which rifaximin is used to treat IBS symptoms, we performed additional studies and showed that rifaximin reversed mucosal inflammation and barrier dysfunction evoked by chronic stress. These beneficial effects were accompanied by a striking increase in the abundance of Lactobacillaceae and a marked reduction in the number of segmented filamentous bacteria after rifaximin treatment. These microbial changes may contribute to the antiinflammatory effects of rifaximin on the intestinal mucosa.     

Long-term clinical outcome of large volume paracentesis with intravenous albumin in patients with spontaneous bacterial peritonitis: a randomized prospective study

BACKGROUND AND AIM: Large volume paracentesis (LVP) with plasma volume expansion has been used for tense or refractory ascites. However, still in question is whether it is safe and effective for the treatment of spontaneous bacterial peritonitis (SBP). We addressed this issue and conducted a study to assess safety and long-term outcome of LVP in cirrhotic patients with SBP. METHODS: Forty-two randomly assigned cirrhotic patients with SBP were classified into two groups; Group 1 included 21 patients who were treated with LVP and intravenous albumin; and Group 2 included 21 patients who were treated with diuretics and intravenous albumin. RESULTS: The overall cumulative survival rate was poor in patients with SBP (42.5% and 22.5% at 6 and 12 months, respectively). At 7 days after treatment, the blood tests were similar between the two groups. In the ascitic fluid, the white blood cell counts decreased significantly and the protein concentrations tended to increase in both groups. In-hospital days, resolution rate of SBP, and in-hospital mortality rate were similar between the two groups. Although complication rates tended to be slightly higher in Group 1, long-term cumulative survivals were similar between Group 1 and Group 2. LVP was effective in removing abdominal discomfort in patients with tense ascites without serious complication. CONCLUSIONS: LVP with intravenous albumin was as effective as diuretics with intravenous albumin for the treatment of SBP with similar mortality. LVP with intravenous albumin might be feasible for the treatment of tense or refractory ascites in cirrhotic patients with SBP.     

Furosemide-induced natriuresis as a test to identify cirrhotic patients with refractory ascites

The diagnosis of refractory ascites in cirrhotic patients carries a poor prognosis and liver transplantation should always be considered in this situation. Identification of patients who will not respond to diuretic therapy usually requires several weeks of observation during which a trial of diuretics is instituted using stepwise increases in dosage in order to classify ascites as refractory. In the present study we evaluated the effect of a single dose of 80 mg intravenous furosemide on urinary sodium excretion over 8 hours in cirrhotic patients with ascites responsive to diuretic treatment (group 1; n = 14) and patients with refractory ascites (group 2; n = 15). The test was performed after 3 days without diuretics and patients were on a 80 mEq sodium/day diet. Refractory ascites was defined by the absence of response after 3 months of high doses of diuretics (spironolactone 200 mg/d + furosemide 80 mg/d + metolazone 2.5 mg/d) and the need for repeated paracentesis. The two groups had similar degrees of liver and renal dysfunction as assessed by the Pugh score and creatinine clearance. The effects of furosemide on 8-hour natriuresis was much higher in patients with responsive ascites as compared with patients with refractory ascites (125 +/- 46 vs. 30 +/- 16 mEq; mean +/- SD; P <.0001). A natriuresis lower than 50 mEq/8 hours was observed in all group-2 patients as compared with none from group 1. The present study shows that patients with refractory ascites can be identified quickly and accurately by using this simple furosemide-induced natriuresis test, which could be very useful to select patients for liver transplantation.     

Prognosis of patients with ascites after PleurX insertion: an observational study

Objective: To evaluate the safety of PleurX in cirrhotic patients with refractory ascites.

Methods: We prospectively registered patients who received a PleurX catheter cirrhosis-associated refractory ascites at our department from July 2015 to November 2016. Our control group consisted of matched cirrhotic patients with refractory ascites treated with large volume paracentesis (LVP) and patients with malignant ascites treated with PleurX during the same period.

Results: We included 25 patients with cirrhosis-related ascites (7 in PleurX group) and 17 with malignant ascites (14 in PleurX group). Of these, six patients had hepatocellular carcinoma and cirrhosis (5 in PleurX group). None were eligible for insertion of a TIPS or liver transplantation. The maximum duration of follow-up was (480 days) in the PleurX group and 366 days in the LVP group (median 84 and 173 days, respectively). There was no difference in mortality when comparing PleurX with LVP treatment (hazard ratios: 3.0 and 1.0, p?=?.23 and .96, respectively). Mortality was higher in patients with malignant ascites (p=?.01). We found no significant differences in adverse events (incl. spontaneous bacterial peritonitis) or in P-albumin, P-creatinine and P-sodium between the groups.

Conclusion: PleurX insertion for the treatment of refractory ascites in cirrhotic patients appears to be safe. Prospective randomized trials are necessary in order to confirm these findings.     

经肝动脉自体骨髓干细胞移植联合奥曲肽治疗肝硬化顽固性腹水14例

目的:研究经肝动脉自体骨髓干细胞移植联合奥曲肽治疗肝硬化顽固性腹水的临床疗效.方法:33例肝硬化顽固性腹水患者被随机分为两组,治疗组(14例)在常规治疗药物治疗上行经肝动脉自体骨髓干细胞移植后,再加用奥曲肽,对照组(19例)在常规治疗药物治疗上加奥曲肽.观察患者治疗后的腹围、食欲、尿量、双下肢浮肿、腹水消退情况及血清A...     

腹水超滤浓缩回输腹腔治疗肝硬化顽固性腹水疗效评价

目的 评估腹水超滤浓缩回输腹腔术治疗肝炎肝硬化顽固性腹水患者临床疗效。方法75例肝硬化顽固性腹水患者分为治疗组（50例）和对照组（25例）,两组患者均采用保肝、利尿、对症、支持等常规治疗,疗程4周。对照组在常规治疗基础上,采用多次治疗性腹穿放液治疗;治疗组在常规治疗基础上,采用腹水超滤浓缩回输腹腔治疗,观察并比较两组治疗后体重、腹围、24h尿量和尿钠排出量、肝功能、肾功能、血电解质及不良反应。结果治疗4周后治疗组腹围、体重、24h尿量优于对照组（P〈0．01）;血清白蛋白、肾小球滤过率及24h尿钠量高于对照组（P〈0．01）,肌酐、胱抑素c水平低于对照组（P〈0．05。P〈0．01）;治疗组显效率（48．0％）和总有效率（80．0％）明显好于对照组（24．0％和52．0％）（P〈0．05）：两组均未出现严重不良反应。结论腹水超滤浓缩回输腹腔术治疗肝硬化顽固性腹水患者临床疗效优于多次治疗性腹穿放液。     

术前穿刺置管持续腹水引流对肝硬化伴顽固性腹水患者肝移植效果的影响

目的 评价术前穿刺置管持续腹水引流对拟行肝移植的肝硬化伴顽固性腹水患者肝移植效果的影响.方法 将2003年2月-2005年12月在我院行肝移植术的肝硬化伴顽固性腹水患者随机分为对照组(单纯药物治疗)和实验组(术前加穿刺置管腹水引流),分析治疗效果,并对肝移植疗效(包括随访)进行比较.结果 实验组穿刺置管腹水引流操作中无并发症发生,治疗后症状缓解率明显高于对照组,体重降低,尿量增加,尿蛋白降低,移植后半年血肌酐明显低于治疗前.对照组治疗后较治疗前MELD评分分值显著性升高.结论 术前穿刺置管持续腹水引流技术安全稳定,相比单纯药物治疗,综合治疗能够提高肝硬化伴顽固性腹水患者的术前状况.     

Comparative pilot study of repeated large volume paracentesis vs the combination on clonidine-spironolactone in the treatment of cirrhosis-associated refractory ascites

OBJECTIVES: To study the usefulness of the combination of clonidine--spironolactone in refractory ascites. METHODS: Twenty cirrhotic patients with refractory ascites were randomly assigned to receive repeated large volume paracentesis plus intravenous albumin (group 1), or a combination of clonidine (0.075 mg twice daily) and spironolactone (200 to 400 mg daily) (group 2). RESULTS: During the first hospitalisation,, the mean weight loss in group 1 was higher than in group 2 (12.4 +/- 3.2 versus 4.3 +/- 1.1 kg, P < or = 0.01). Mean stay in hospital was shorter in group 2 (20 +/- 1.5 versus 10 +/- 2.8 days; P < or = 0.01). Paracentesis did not induce changes in neuro-hormonal measurements. Oppositely, clonidine induced a decreased sympathetic activity, an increased glomerular filtration rate and a delayed reduction of the renin-aldosterone levels. During the follow-up in group 1, the number of rehospitalisations for ascites was higher than in group 2 (37 versus 3; P < or = 0.01), and the mean time to the first readmission was shorter (10 +/- 2.7 versus 23.7 +/- 5.6 days; P < or = 0.01). The total duration spent in hospital were similar in both groups. CONCLUSION: Paracentesis is more effective for short-term treatment of ascites but clonidine-spironolactone association might provide better long-term control.     

Rifaximin improves systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites

Circulating levels of endotoxin, interleukin (IL)-6, and tumor necrosis factor (TNF)-α increase with intestinal bacterial overgrowth and translocation, and are believed to be involved in the pathogenesis of hyperdynamic circulatory syndrome and functional renal failure in patients with advanced cirrhosis. We investigated the effects of the antibiotic rifaximin on systemic hemodynamics and renal function in patients with alcohol-related cirrhosis and ascites. We measured mean arterial pressure, cardiac output (CO) by Doppler ultrasound, systemic vascular resistance (as the ratio of mean arterial pressure:CO), plasma renin activity, levels of plasma aldosterone, the glomerular filtration rate by plasma clearance of technetium-99m-DTPA, natriuresis, levels of plasma endotoxin, and serum levels of IL-6 and TNF-α in 13 patients at baseline and after 4 weeks of treatment with rifaximin. Rifaximin treatment significantly reduced CO and significantly increased systemic vascular resistance, in association with a significant decrease in plasma rennin activity. The therapy also significantly increased the glomerular filtration rate and natriuresis while reducing levels of endotoxin, IL-6, and TNF-α. Intestinal decontamination with rifaximin improved systemic hemodynamics and renal function in patients with advanced cirrhosis.     

The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function: a multicentric study

Ascites is a common complication of liver cirrhosis, occurring in more than 50-60% of the patients within 10 years of the diagnosis. In 5-10% of patients, ascites cannot be mobilized, or its early recurrence cannot be prevented by medical treatment. This condition is known as “refractory ascites”. The use of terlipressin in cirrhotic patients with refractory ascites and normal renal function has not been evaluated. This prospective study was aimed at evaluating whether terlipressin in addition to standard therapy (diuretics plus albumin) might improve the outcome of refractory ascites in cirrhotic patients without HRS.

Patients

26 cirrhotic patients with refractory ascites were prospectively enrolled in this study. All the patients had tense (grade 3) ascites, and 10/26 showed also massive peripheral edema. Patients received maximum diuretic treatment plus albumin and terlipressin.

Results

Complete response was seen in 16/26 patients. The higher response to therapy was seen during the 2nd week of treatment. 6 patients showed a decrease of at least two points in the ascites score. No differences in clinical response to treatment were seen according to the etiology of the disease.

Conclusions

In conclusion, our study shows a synergistic effect of terlipressin vs treatment with albumin plus diuretics in patients with refractory ascites. One could speculate that albumin might enhance the vasoconstrictive response to terlipressin, thus contributing to counterbalance the negative effects of systemic vasodilation, which characterizes the hyperdynamic circulation of cirrhotic patients.