1548 Letters to the Editor
Reply. We read with the interest the letter by Kantouros et al1 in response to our article.2 We agree with the authors that the systemic proinflammatory milieu can play a strong role in the development and progression of cirrhosis as well as hepatic encephalopathy.3 This could be worsened by concurrent bacterial infections and with gut dysbiosis that is prevalent in these patients.4 However, the relationship of health-related quality of life (HRQOL) with inflammation in cirrhotics without prior hepatic encephalopathy is unclear. We used the Sickness Impact Profile (SIP) as a measure of HRQOL and correlated it with systemic inflammation in cirrhotic patients.5 The SIP consists of 12 domains (home management, mobility, sleep/rest, communication, ambulation, body care/mobility, work, recreation/ pastimes, eating, emotional behavior, social interaction, and ambulation) with a total score. It inquires about symptoms related to health over the last 24 hours and a high score indicates worse HRQOL. We enrolled 115 outpatients with cirrhosis without prior hepatic encephalopathy. The mean age was 576 years with 75 men. The mean model for end-stage liver disease was 9.43 and the main etiology was hepatitis C virus (n ¼ 39) followed by non-alcoholic steatohepatitis (n ¼ 35) and alcoholic (n ¼ 32) cirrhosis. All patients underwent SIP and analysis of IL-6, IL-1b, IL-2 and TNFa using published techniques on the same day.4 We performed Pearson’s correlation between individual and total SIP scores and inflammatory cytokines. Significant correlations between cytokines and SIP domains were found in physical domains. Home management was positively correlated IL-1b (r ¼ 0.5, P < .001), IL-2 (r ¼ 0.5, P < .001), TNF-a (r ¼ 0.5, P < .001) and IL-6 (r ¼ 0.4, P < .001) while body care and mobility was linked with IL-1b (r ¼ 0.4, P ¼ .03), IL-2 (r ¼ 0.4, P ¼ .02), TNF-a (r ¼ 0.3, P ¼ .02) and IL-6 (r ¼ 0.3, P ¼ .03). There was a modest correlation between eating and cytokines IL-1b (r ¼ 0.2, P ¼ .05), IL-2 (r ¼ 0.3, P ¼ .02), TNF-a (r ¼ 0.2, P ¼ .05) and IL-6 (r ¼ 0.3, P ¼ .03). Interestingly, none of the other domains, including sleep/ rest were correlated with the systemic inflammation. We were intrigued by the notion offered by Kantourous et al, that Helicobacter pylori infection and inflammatory cytokines might be associated with the persistent neuropsychological impairment seen in cirrhotic patients. Unfortunately, in our experience with compensated patients, SIP domains placing a demand on attentional and executive functions (eg, work, communication, and social interaction) were not correlated with inflammatory cytokines. We conclude that in cirrhotic patients without prior hepatic encephalopathy, systemic inflammation is associated with physical domains and not related to sleep. Further research is required to evaluate the interaction of systemic inflammation and personal sleep assessment in this compensated cirrhotic population.
Clinical Gastroenterology and Hepatology Vol. 13, No. 8
JASMOHAN S. BAJAJ, MD Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and McGuire VA Medical Center Richmond, Virginia JAMES B. WADE, PhD Department of Psychiatry Virginia Commonwealth University and McGuire VA Medical Center Richmond, Virginia
References 1. 2.
Kountouras J, et al. Clin Gastroenterol Hepatol 2015. Bajaj JS, et al. Clin Gastroenterol Hepatol 2015;13:390–397.
3.
Shawcross DL, et al. J Hepatol 2004;40:247–254.
4.
Bajaj JS, et al. J Hepatol 2014;60:940–947.
5.
Bergner M, et al. Med Care 1981;19:787–805. http://dx.doi.org/10.1016/j.cgh.2015.06.012
Pinaverium in Irritable Bowel Syndrome: Old Drug, New Tricks? Dear Editor: We read with interest the randomized controlled trial by Zheng et al1 that compared the antispasmodic pinaverium with placebo for the treatment of diarrheapredominant irritable bowel syndrome (IBS-D). The authors reported that more than 75% of patients receiving pinaverium had either 30% reduction from baseline in abdominal pain or 50% reduction in the number of days with at least 1 stool with a Bristol stool score 6 at week 4, compared with 33.5% with placebo (P < .001). The proportion of dual responders, those who achieved both of these end points at week 4, was also significantly higher with pinaverium (38.1% vs 16.7%, P < .001). A previous systematic review and meta-analysis suggested that pinaverium was of benefit in irritable bowel syndrome (IBS),2 with a number needed to treat of 3, but this was based on only 3 trials,3–5 containing 188 patients, that were conducted in the 1970s and 1980s and lacked rigorous end points. We therefore commend the authors for conducting this randomized controlled trial by using state-of-the-art methodology. Previous experts in the field have pointed out the lack of clarity surrounding the effectiveness of traditional therapies for IBS because of small underpowered trials and a failure to assess efficacy by using currently accepted end points.6 This underlines the importance of the current study, which uses an old drug but judges its effect on IBS symptoms by using outcomes that are rigorous and closely mirror those recommended by the Food and Drug Administration.
August 2015
Letters to the Editor 1549
Patients with IBS-D demonstrate accelerated intestinal transit and reduced terminal ileum diameter on magnetic resonance studies,7 which suggests that antispasmodic drugs may be of greatest benefit in this patient group, but to date, most studies have failed to examine their efficacy according to IBS subtype. The findings of Zheng et al1 therefore allow targeting of antispasmodic therapy toward a specific IBS subtype, an approach that has been used with almost all novel agents developed for the treatment of IBS since alosetron, which is another strength of their study. The major concerns are that the trial was only 4 weeks in duration and was conducted entirely in China. Whether pinaverium will demonstrate similar efficacy beyond 4 weeks or in non-Chinese patients with IBS-D remains to be seen. The authors’ assertion that pinaverium can be considered as a first-line treatment for IBS may therefore be premature. Despite this, they are to be congratulated on a rigorous trial that is an important addition to our growing body of knowledge on the appropriate use of pharmacologic therapies in IBS. CATHERINE L. DAVIES, MBChB Leeds Gastroenterology Institute St James’s University Hospital Leeds, United Kingdom ALEXANDER C. FORD, MD Leeds Gastroenterology Institute St James’s University Hospital Leeds, United Kingdom
1998, whose duration was 8 weeks.7 However, we agree that a long-duration clinical trial on pinaverium is needed to test the offset of action of pinaverium; and our next clinical trial will reflect this (NCT02330029 at www. clinicaltrials.gov). Although a multicountry and multicenter clinical trial of pinaverium would have been superb, we believe that conducting such a clinical trial in China is more practical and sufficient for the purposes of testing the effectiveness of pinaverium. China has the world’s largest population. China’s population (1364 million) is more than 4 times the population of the United States (318 million), and almost 2 times the total population of all European countries combined (741 million).8 Therefore, it is of both clinical and social significance to test an old and inexpensive IBS drug in the world’s largest population. All of the previous clinical studies on pinaverium were conducted in a single country outside China (3 in France, 1 in Belgium, 1 in Mexico, and 1 in India).7 Pinaverium blocks calcium channels on smooth muscle cells of the gastrointestinal tract, resulting in a spasmolytic effect in the gut. No studies have suggested that these smooth muscle cell calcium channels are different among races, and all clinical studies from different countries have confirmed that pinaverium was effective in relieving IBS symptoms. Pinaverium is old and inexpensive, however, still effective in relieving IBS symptoms. BAIWEN LI, MD Department of Gastroenterology Shanghai First People’s Hospital Shanghai Jiao Tong University Hongkou, Shanghai, China
Leeds Institute of Biomedical and Clinical Sciences University of Leeds Leeds, United Kingdom
JUN XIAO, PharmD, PhD The Macrohard Institute of Health Roseville, Minnesota
References
References
1.
Zheng L, et al. Clin Gastroenterol Hepatol 2015;26:101–109.
2.
Ford AC, et al. Br Med J 2008;337:a2313.
1.
3. 4.
Delmont J. Med Chir Dig 1981;10:365–370. Virat J, et al. Prat Med 1987;43:32–34.
2.
Defrance P, et al. Ital J Gastroenterol 1991;23(suppl 1):64–66.
3.
Levy C, et al. Sem Hop Ther 1977;53:372–374.
5.
Levy C, et al. Sem Hop Ther 1977;53:372–374.
4.
Virat J, et al. Prat Med 1987;43:32–34.
6.
Camilleri M, et al. Gastroenterology 2009;137:766–769.
5.
Delmont J. Med Chir Dig 1981;10:365–370.
7.
Marciani L, et al. Gastroenterology 2010;138:469–477.
Awad R, et al. Acta Gastroenterol Latinoam 1995;25:137–144.
6.
Jayanthi V, et al. J Assoc Physicians India 1998;46:369–371.
7.
Zheng L, et al. Clin Gastroenterol Hepatol 2015;13:1285–1292.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.03.007
8.
Available at: http://www.prb.org/pdf14/2014-world-populationdata-sheet_eng.pdf. Accessed April 10, 2015.
Reply. We thank Drs Davies and Ford for their comment. We chose 4 weeks because pinaverium has a quick onset of action (1–3 days), and therefore 4 weeks seems to be long enough to test the effectiveness of pinaverium to quickly relieve irritable bowel syndrome (IBS) symptoms. Moreover, the duration of previous clinical trials on pinaverium have been 4 weeks or less (Awad et al,1 3 weeks; Defrance and Casini,2 15 days; Levy et al,3 2 weeks; Virat and Hueber,4 1 week; Delmont,5 4 weeks), except for the trial by Jayanthi et al6 in
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.05.005
Ultrasonography and Transmural Healing in Crohn’s Disease Dear Editor: We have read with interest the study by Zorzi et al1 regarding the usefulness of a new sonographic
Reply. We read with the interest the letter by Kantouros et al1 in response to our article.2 We agree with the authors that the systemic proinflammatory milieu can play a strong role in the development and progression of cirrhosis as well as hepatic encephalopathy.3 This could be worsened by concurrent bacterial infections and with gut dysbiosis that is prevalent in these patients.4 However, the relationship of health-related quality of life (HRQOL) with inflammation in cirrhotics without prior hepatic encephalopathy is unclear. We used the Sickness Impact Profile (SIP) as a measure of HRQOL and correlated it with systemic inflammation in cirrhotic patients.5 The SIP consists of 12 domains (home management, mobility, sleep/rest, communication, ambulation, body care/mobility, work, recreation/ pastimes, eating, emotional behavior, social interaction, and ambulation) with a total score. It inquires about symptoms related to health over the last 24 hours and a high score indicates worse HRQOL. We enrolled 115 outpatients with cirrhosis without prior hepatic encephalopathy. The mean age was 576 years with 75 men. The mean model for end-stage liver disease was 9.43 and the main etiology was hepatitis C virus (n ¼ 39) followed by non-alcoholic steatohepatitis (n ¼ 35) and alcoholic (n ¼ 32) cirrhosis. All patients underwent SIP and analysis of IL-6, IL-1b, IL-2 and TNFa using published techniques on the same day.4 We performed Pearson’s correlation between individual and total SIP scores and inflammatory cytokines. Significant correlations between cytokines and SIP domains were found in physical domains. Home management was positively correlated IL-1b (r ¼ 0.5, P < .001), IL-2 (r ¼ 0.5, P < .001), TNF-a (r ¼ 0.5, P < .001) and IL-6 (r ¼ 0.4, P < .001) while body care and mobility was linked with IL-1b (r ¼ 0.4, P ¼ .03), IL-2 (r ¼ 0.4, P ¼ .02), TNF-a (r ¼ 0.3, P ¼ .02) and IL-6 (r ¼ 0.3, P ¼ .03). There was a modest correlation between eating and cytokines IL-1b (r ¼ 0.2, P ¼ .05), IL-2 (r ¼ 0.3, P ¼ .02), TNF-a (r ¼ 0.2, P ¼ .05) and IL-6 (r ¼ 0.3, P ¼ .03). Interestingly, none of the other domains, including sleep/ rest were correlated with the systemic inflammation. We were intrigued by the notion offered by Kantourous et al, that Helicobacter pylori infection and inflammatory cytokines might be associated with the persistent neuropsychological impairment seen in cirrhotic patients. Unfortunately, in our experience with compensated patients, SIP domains placing a demand on attentional and executive functions (eg, work, communication, and social interaction) were not correlated with inflammatory cytokines. We conclude that in cirrhotic patients without prior hepatic encephalopathy, systemic inflammation is associated with physical domains and not related to sleep. Further research is required to evaluate the interaction of systemic inflammation and personal sleep assessment in this compensated cirrhotic population.
Clinical Gastroenterology and Hepatology Vol. 13, No. 8
JASMOHAN S. BAJAJ, MD Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University and McGuire VA Medical Center Richmond, Virginia JAMES B. WADE, PhD Department of Psychiatry Virginia Commonwealth University and McGuire VA Medical Center Richmond, Virginia
References 1. 2.
Kountouras J, et al. Clin Gastroenterol Hepatol 2015. Bajaj JS, et al. Clin Gastroenterol Hepatol 2015;13:390–397.
3.
Shawcross DL, et al. J Hepatol 2004;40:247–254.
4.
Bajaj JS, et al. J Hepatol 2014;60:940–947.
5.
Bergner M, et al. Med Care 1981;19:787–805. http://dx.doi.org/10.1016/j.cgh.2015.06.012
Pinaverium in Irritable Bowel Syndrome: Old Drug, New Tricks? Dear Editor: We read with interest the randomized controlled trial by Zheng et al1 that compared the antispasmodic pinaverium with placebo for the treatment of diarrheapredominant irritable bowel syndrome (IBS-D). The authors reported that more than 75% of patients receiving pinaverium had either 30% reduction from baseline in abdominal pain or 50% reduction in the number of days with at least 1 stool with a Bristol stool score 6 at week 4, compared with 33.5% with placebo (P < .001). The proportion of dual responders, those who achieved both of these end points at week 4, was also significantly higher with pinaverium (38.1% vs 16.7%, P < .001). A previous systematic review and meta-analysis suggested that pinaverium was of benefit in irritable bowel syndrome (IBS),2 with a number needed to treat of 3, but this was based on only 3 trials,3–5 containing 188 patients, that were conducted in the 1970s and 1980s and lacked rigorous end points. We therefore commend the authors for conducting this randomized controlled trial by using state-of-the-art methodology. Previous experts in the field have pointed out the lack of clarity surrounding the effectiveness of traditional therapies for IBS because of small underpowered trials and a failure to assess efficacy by using currently accepted end points.6 This underlines the importance of the current study, which uses an old drug but judges its effect on IBS symptoms by using outcomes that are rigorous and closely mirror those recommended by the Food and Drug Administration.
August 2015
Letters to the Editor 1549
Patients with IBS-D demonstrate accelerated intestinal transit and reduced terminal ileum diameter on magnetic resonance studies,7 which suggests that antispasmodic drugs may be of greatest benefit in this patient group, but to date, most studies have failed to examine their efficacy according to IBS subtype. The findings of Zheng et al1 therefore allow targeting of antispasmodic therapy toward a specific IBS subtype, an approach that has been used with almost all novel agents developed for the treatment of IBS since alosetron, which is another strength of their study. The major concerns are that the trial was only 4 weeks in duration and was conducted entirely in China. Whether pinaverium will demonstrate similar efficacy beyond 4 weeks or in non-Chinese patients with IBS-D remains to be seen. The authors’ assertion that pinaverium can be considered as a first-line treatment for IBS may therefore be premature. Despite this, they are to be congratulated on a rigorous trial that is an important addition to our growing body of knowledge on the appropriate use of pharmacologic therapies in IBS. CATHERINE L. DAVIES, MBChB Leeds Gastroenterology Institute St James’s University Hospital Leeds, United Kingdom ALEXANDER C. FORD, MD Leeds Gastroenterology Institute St James’s University Hospital Leeds, United Kingdom
1998, whose duration was 8 weeks.7 However, we agree that a long-duration clinical trial on pinaverium is needed to test the offset of action of pinaverium; and our next clinical trial will reflect this (NCT02330029 at www. clinicaltrials.gov). Although a multicountry and multicenter clinical trial of pinaverium would have been superb, we believe that conducting such a clinical trial in China is more practical and sufficient for the purposes of testing the effectiveness of pinaverium. China has the world’s largest population. China’s population (1364 million) is more than 4 times the population of the United States (318 million), and almost 2 times the total population of all European countries combined (741 million).8 Therefore, it is of both clinical and social significance to test an old and inexpensive IBS drug in the world’s largest population. All of the previous clinical studies on pinaverium were conducted in a single country outside China (3 in France, 1 in Belgium, 1 in Mexico, and 1 in India).7 Pinaverium blocks calcium channels on smooth muscle cells of the gastrointestinal tract, resulting in a spasmolytic effect in the gut. No studies have suggested that these smooth muscle cell calcium channels are different among races, and all clinical studies from different countries have confirmed that pinaverium was effective in relieving IBS symptoms. Pinaverium is old and inexpensive, however, still effective in relieving IBS symptoms. BAIWEN LI, MD Department of Gastroenterology Shanghai First People’s Hospital Shanghai Jiao Tong University Hongkou, Shanghai, China
Leeds Institute of Biomedical and Clinical Sciences University of Leeds Leeds, United Kingdom
JUN XIAO, PharmD, PhD The Macrohard Institute of Health Roseville, Minnesota
References
References
1.
Zheng L, et al. Clin Gastroenterol Hepatol 2015;26:101–109.
2.
Ford AC, et al. Br Med J 2008;337:a2313.
1.
3. 4.
Delmont J. Med Chir Dig 1981;10:365–370. Virat J, et al. Prat Med 1987;43:32–34.
2.
Defrance P, et al. Ital J Gastroenterol 1991;23(suppl 1):64–66.
3.
Levy C, et al. Sem Hop Ther 1977;53:372–374.
5.
Levy C, et al. Sem Hop Ther 1977;53:372–374.
4.
Virat J, et al. Prat Med 1987;43:32–34.
6.
Camilleri M, et al. Gastroenterology 2009;137:766–769.
5.
Delmont J. Med Chir Dig 1981;10:365–370.
7.
Marciani L, et al. Gastroenterology 2010;138:469–477.
Awad R, et al. Acta Gastroenterol Latinoam 1995;25:137–144.
6.
Jayanthi V, et al. J Assoc Physicians India 1998;46:369–371.
7.
Zheng L, et al. Clin Gastroenterol Hepatol 2015;13:1285–1292.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.03.007
8.
Available at: http://www.prb.org/pdf14/2014-world-populationdata-sheet_eng.pdf. Accessed April 10, 2015.
Reply. We thank Drs Davies and Ford for their comment. We chose 4 weeks because pinaverium has a quick onset of action (1–3 days), and therefore 4 weeks seems to be long enough to test the effectiveness of pinaverium to quickly relieve irritable bowel syndrome (IBS) symptoms. Moreover, the duration of previous clinical trials on pinaverium have been 4 weeks or less (Awad et al,1 3 weeks; Defrance and Casini,2 15 days; Levy et al,3 2 weeks; Virat and Hueber,4 1 week; Delmont,5 4 weeks), except for the trial by Jayanthi et al6 in
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2015.05.005
Ultrasonography and Transmural Healing in Crohn’s Disease Dear Editor: We have read with interest the study by Zorzi et al1 regarding the usefulness of a new sonographic
