Drugs For Constipation Research Articles

Long-term prescribed drug use in stage I-III rectal cancer patients in Sweden, with a focus on bowel-regulating drugs after surgical and oncological treatment.

To describe long-term prescribed drug use after rectal cancer treatment. We identified 12,871 rectal cancer patients without distant metastasis between 2005 and 2016 and 64,341 matched population comparators using CRCBaSe (a Swedish nationwide register linkage of colorectal cancer patients). Mean defined daily doses (DDDs) of drug dispensing during relapse-free follow-up were calculated by Anatomical Therapeutic Chemical drug categories. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) from negative binomial regression were used to compare drug dispensing between patients and comparators. The overall pattern of drug dispensing was similar among cancer survivors and comparators, although patients had higher mean DDDs of drugs regulating the digestive system. Excess dispensing of drugs for constipation (IRR, 3.35; 95% CI, 3.12-3.61), diarrhea (IRR, 6.43; 95% CI, 5.72-7.22), functional gastrointestinal disorders (IRR, 3.78; 95% CI, 3.15-4.54), and vitamin and mineral supplements (IRR, 1.37; 95% CI, 1.24-1.50) was observed up to 10years after surgery. Treatment with Hartmann's procedure was associated with higher dispensing rates of digestive drugs compared to surgery with anterior resection and abdominoperineal resection but the association was attributed to higher use of diabetic drugs. Additionally, excess digestive drug dispensing was associated with more advanced cancer stage but not with (chemo)radiotherapy treatment. Excess drug use after rectal cancer is primarily driven by bowel-regulating drugs and is not modified by surgical or oncological treatment. The excess use of bowel-regulating drugs after rectal cancer indicated long-standing postsurgical gastrointestinal morbidity and need of prophylaxis. Reassuringly, no excess use of other drug classes was noted long term.

Yoga as an adjunct therapy in elderly patients of chronic constipation

Background: Constipation being very prevalent and common complaint in elderly people, an effective measure is needed to get the relief along with drugs for constipation used by clinicians. Our aim was to search out the potential applicability and effectiveness of yoga. Methods: 30 elderly patients visiting medicine OPD for chronic constipation were included in study. Yoga group (15) was offered selected yogic practices in addition to drugs and control group drugs only. Patients kept record of drug intake on paper for 2 months of study. Data was obtained by using CAS score and frequency of drug intake. Data were analysed using t test. Results: Baseline CAS scores for the yoga and control groups were 11.92±1.59 and 12.07±1.68 respectively. Post yoga CAS score for the yoga and control groups were 3.50±1.40 and 4.14±1.5 respectively. Frequency of drug intake in yoga and control groups in first month of yoga was 17.57±2.31 and 19.14±2.38 respectively. In 4th month of yoga practice frequency of drug intake in yoga and control groups was 11.07±2.16 and 18.35±2.56, which was highly significant. Conclusions: Selected yoga practices can be used as an adjuvant therapy to treat chronic constipation in case of elderly. They can be effective in decreasing drug requirement in patients of chronic constipation. Yoga practices should be advised for patients of chronic constipation.

Treatment of High Blood Pressure is associated with a Reduced Incidence of Parkinson’s disease (S42.007)

<h3>Objective:</h3> We performed an agnostic drug-wide association study (DWAS) in Norway estimating the association between all drugs prescribed in Norway and the subsequent incidence of Parkinson’s disease (PD). <h3>Background:</h3> Several drugs including treatments for cardiovascular diseases have been associated with a reduced incidence of PD. <h3>Design/Methods:</h3> We employed data on drug use in the entire Norwegian population from 2004 to 2019 (4.6 million) registered in the Norwegian Prescription Registry, including more than 600 million individual prescriptions. Drug classes were screened according to ATC codes at level 2, corresponding to therapeutic subgroups. Individuals who developed PD during the 15 years of follow-up (n=15,849) were identified using an algorithm based on drugs prescribed to treat the disease. Cox regression models with exposure as time-dependent variable were specified, and all p-values were corrected for multiple testing using the false discovery rate. <h3>Results:</h3> We found several novel associations between drug classes and the incidence of PD including a <i>decreased</i> incidence of PD among users of drugs acting on the renin-angiotensin system (0.86, 95%CI: 0.83–0.89). We also found an inverse association between calcium channel blockers and PD incidence, but we could not confirm the previously reported association between lipid-modifying agents and PD. Further, beta blocking agents and drugs for cardiac therapy were associated with an <i>increased</i> PD incidence. We also found increased PD incidence for drugs used in the treatment of prodromal symptoms of PD, including urologicals, drugs for constipation, anti-psychotics, and antidepressants. <h3>Conclusions:</h3> We observed two large drug classes of anti-hypertensives being associated with a subsequent reduced incidence of PD. The finding of two other cardiovascular drug classes being associated with an <i>increased</i> PD incidence calls for more detailed epidemiological studies and experimental studies to elucidate possible mechanisms. <b>Disclosure:</b> Trond Riise has nothing to disclose. Mr. Solheim has nothing to disclose. The institution of Dr. Bjornevik has received research support from Michael J. Fox Foundation. The institution of Dr. Bjornevik has received research support from National Multiple Sclerosis Society. The institution of Dr. Bjornevik has received research support from Department of Defense. Dr. Igland has nothing to disclose. Miss Tuominen has nothing to disclose. Dr. Abolpour Mofrad has nothing to disclose. Dr. Cortese has received personal compensation in the range of $500-$4,999 for serving as a speaker at educational event with Roche. Dr. Scherzer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. The institution of Dr. Scherzer has received research support from NIH. The institution of Dr. Scherzer has received research support from Michael J. Fox Foundation. The institution of Dr. Scherzer has received research support from American Parkinson’s Disease Association. Dr. Scherzer has received intellectual property interests from a discovery or technology relating to health care. Mrs. Romanowska has nothing to disclose.

Medicine use in people with intellectual disabilities: a Finnish nationwide register study

People with intellectual disability (ID) are a vulnerable group in our society; many of them depend on other people for assistance in their everyday lives. Compared with the general population, people with ID have poorer general health and, therefore, need more healthcare services and use more medicines. The aim of this study is to define the population of all Finnish people with ID using administrative data and to compare their medicine use and expenditure on medicines to those of the age-matched and sex-matched controls. People with ID and their age-matched and sex-matched controls (1:1) were extracted from nationwide healthcare and social allowance registers. Administrative register data on all prescription medicine purchases in 2019 were used to determine the prevalence of medicine use in both groups on a general level and by medicine categories. The differences in the prevalence of medicine use between the two groups were analysed using the logistic regression model. In addition, we studied the total expenditure on reimbursable medicine purchases covered by the National Health Insurance between people with ID and control group. The subpopulation of people with ID consisted 37 196 individuals, of whom 82.7% purchased prescription medicines in 2019. The corresponding share of individuals purchasing prescription medicines in the control group was 70.3%. The differences in the prevalence of medicine use between the two populations were highest in the younger age groups (0-6, 7-12 and 13-17). In the study population, 28.1% (OR=12.28; 95% CI: 11.54-13.07) of the people used antipsychotics, making it the most used medicine category in people with ID. In the control group, 3.3% of people used antipsychotics. Compared with the control group, the use of antiepileptics, drugs for constipation, mineral supplements and anxiolytics was four to seven times higher among people with ID. Furthermore, the median expenditure on medicine use among people with ID was four times higher than in the control group. Compared with the control group, people with ID used more medicines, especially psychotropics, and their expenditure on medicine use was higher.

Lubiprostone is non-selective activator of cAMP-gated ion channels and Clc-2 has a minor role in its prosecretory effect in intestinal epithelial cells.

Loss of prosecretory Cl- channel CFTR activity is considered as the key cause of gastrointestinal disorders in cystic fibrosis including constipation and meconium ileus. Clc-2 is proposed as an alternative Cl- channel in intestinal epithelia that can compensate for CFTR loss-of-function. Lubiprostone is an FDA-approved drug with Clc-2 activation as its presumed mechanism of action. However, relative contribution of Clc-2 in intestinal Cl- secretion and the mechanism of action of lubiprostone remain controversial due to lack of selective Clc-2 inhibitors. Using recently identified selective Clc-2 inhibitor AK-42, we characterized the roles of Clc-2 in Cl- secretion in human intestinal epithelial T84 cells. Clc-2 inhibitor AK-42 had minimal (15%) inhibitory effect on secretory short-circuit current (Isc) induced by cAMP agonists, where subsequently applied CFTR inhibitor (CFTRinh-172) caused 2-3 fold greater inhibition. Similarly, AK-42 inhibited lubiprostone-induced secretory Isc by 20%, whereas CFTRinh-172 caused 2-3 fold greater inhibition. In addition to increasing CFTR and Clc-2-mediated apical Cl- conductance, lubiprostone increased basolateral membrane K+ conductance, which was completely reversed by cAMP-activated K+ channel inhibitor BaCl2 All components of lubiprostone-induced secretion (Clc-2, CFTR and K+ channels) were inhibited by ~65% with the extracellular Ca2+-sensing receptor (CaSR) activator cinacalcet that stimulates cAMP hydrolysis. Lastly, EP4 prostaglandin receptor inhibitor GW627368 pretreatment inhibited lubiprostone-induced secretion by 40% without any effect on forskolin response. Our findings suggest that Clc-2 has minor role in cAMP-induced intestinal Cl- secretion; and lubiprostone is not a selective Clc-2 activator, but general activator of cAMP-gated ion channels in human intestinal epithelial cells. Significance Statement Cl- channel Clc-2 activation is the proposed mechanism of action of the FDA-approved constipation drug lubiprostone. Using first-in-class selective Clc-2 inhibitor AK-42, we showed that Clc-2 has minor contribution in intestinal Cl- secretion induced by lubiprostone and cAMP agonists. We also found that lubiprostone is a general activator of cAMP-gated ion channels in human intestinal epithelial cells (via EP4 receptors). Our findings clarify the roles of Clc-2 in intestinal Cl- secretion and elucidate the mechanism of action of approved-drug lubiprostone.

Repeated Use of Prescription Drugs in Pediatrics: Comprehensive Overview Based on German Claims Data.

Background: Investigating drug utilization in large and unselected samples of children and adolescents is an important component of public health monitoring. Most existing studies in this field focused on any drug use (i.e., ≥1 prescription of a certain drug) although chronic drug use may be more relevant. This study aimed to provide a comprehensive overview of prevalence and types of prescription drugs used repeatedly in children and adolescents in Germany in 2016. Methods: We used the German Pharmacoepidemiological Research Database (GePaRD)—a claims database covering ∼20% of the German population. We included children and adolescents aged 0–17 years and assessed repeated use of prescription drugs (≥3 prescriptions in 2016) on two levels: therapeutic subgroups (ATC 2nd level) and chemical substances (ATC 5th level). Analyses were stratified by sex and age groups (<2, 2–5, 6–12, and 13–17 years). Results: Overall, 2.5 million children and adolescents were included. In the age groups below 13 years, the prevalence rates of repeated use of prescription drugs (ATC 2nd level) were higher in boys than in girls (113–152 vs. 83–130 per 1,000 person-years), whereas in the age group 13–17 years, they were twice as high in girls than in boys (236 vs. 118 per 1,000 person-years). In boys and girls aged below six years, systemic antibiotics, topical ocular antibiotics, and drugs for constipation were among the most common drugs used repeatedly. For higher ages, methylphenidate, levothyroxine, and combined hormonal contraceptives, were among the most common drugs used repeatedly. Conclusions: Overall, about one in ten children in Germany repeatedly used prescription drugs. This proportion as well as the type of drugs used repeatedly markedly varied by sex and age. For certain drugs, our findings raise concerns regarding appropriateness of prescribing that should be addressed in future studies.

The different effects of Chinese Herb Solid Drink and lactulose on gut microbiota in rats with slow transit constipation induced by compound diphenoxylate

Slow transit constipation (STC) has become an epidemic medical problem. There are several kinds of drugs for constipation; however, each drug has its limitations. The gut microbiota has a close relationship with STC. Lactulose is an effective drug for constipation because it is a kind of bulking laxative and microbioecologic, and it relieves the syndromes of STC. We found that the Chinese Herb Solid Drink (CHSD), which contains medicine food homologous materials such as psyllium husk, sweetalmond, semen sesami nigrum, and hemp seed, has a similar effect on relieving constipation as lactulose, although it has different effects on the gut microbiota. We investigated the mechanisms of CHSD in rats with STC, induced by diphenoxylate, via constipation index and enzyme linked immunosorbent assay (ELISA) analyses using serum and 16S rDNA amplicon and gas chromatography-mass spectroscopy (GC–MS). CHSD enhanced the relative abundance of some types of gut microbiota, such as Blautia, Ruminococcus, Roseburia, Coprococcus, Lachnospira, and Phascolarctobacterium, while lactulose enhanced the relative abundance of Blautia, Phascolarctobacterium, Eubacterium, and Akkernansia in diphenoxylate-induced STC rats. Both CHSD and lactulose enhanced the level of short-chain fatty acids in the faeces of rats; however, the composition of those were different between the two drugs. From the perspective of the gut neuroendocrine system, both CHSD and lactulose could elevate neurotransmitters, such as motilin (MTL) and substance P (SP), which promote intestinal peristalsis and reduce the expression of vasoactive intestinal peptide, which inhibits intestinal peristalsis in the serum of STC rats. CHSD could elevate gastrin expression, which also promoted intestinal peristalsis in serum, while lactulose did not have this effect. Our findings suggest that CHSD may be an effective and safe therapeutic choice for STC.

Factors correlated with drug use for constipation: perspectives from the 2016 open Japanese National Database

BackgroundThe prevalence of chronic constipation is increased in females and with age or environmental (low temperature), racial, socioeconomic, and habitual risk factors. The impact of low outside temperature on constipation drug use remains unclear. Here, we investigated risk factors for constipation drug use by evaluating data from the Japanese National Database.MethodsThis ecological study used the 2016 open Japanese National Database of health insurance claims (prescriptions) to acquire the number of health insurance prescription claims in all 47 prefectures for drugs to relieve constipation, antihypertensives, vasodilators, as well as medical check-ups and questionnaire responses. Internet survey on room temperatures in 2010 were also used. Pearson correlation coefficients (r) between the number of population-based prescriptions for each item were calculated and multiple linear regression analysis (MLR) was performed.ResultsPrescriptions for magnesium laxatives significantly correlated with aging (r = 0.58), vasodilators (r = 0.53), being female (r = 0.43), antihypertensives (r = 0.39), and inversely with eating ≤2 h before bedtime (r = − 0.37), total crime rate (r = − 0.33), insomnia (r = − 0.33), and population density (r = − 0.31). Stimulant laxatives (sennoside and picosulfate) were significantly correlated with antihypertensives (r = 0.79), aging (r = 0.69), vasodilators (r = 0.67), and being female (r = 0.56), and were inversely associated with average outside temperature (r = − 0.62), total crime rate (r = − 0.52), average income (r = − 0.51), and 30-min of vigorous exercise (r = − 0.44). Fecal interventions were significantly correlated with aging (r = 0.55) and female (r = 0.59), and inversely correlated with population density (r = − 0.41) and total crime rate (r = − 0.38). MLR analysis identified aging as the only significant risk factor for magnesium laxative use (partial slope [β] = 1241.0). Female sex and antihypertensives were independent risk factors for stimulant laxative prescriptions (β = 44,547.0 and 0.2) and average outside temperature and 30-min of vigorous exercise were independent preventive factors (β = − 616.8 and − 219.1).ConclusionWe identified associations of magnesium laxatives with aging, stimulant laxatives with female sex, antihypertensives, low outside temperature and less 30 min of vigorous exercise.

P1440ASSOCIATION BETWEEN THE USE OF DRUGS FOR CONSTIPATION AND MORTALITY IN HEMODIALYSIS PATIENTS; FROM JAPAN-DIALYSIS OUTCOMES AND PRACTICE PATTERNS STUDY (J-DOPPS)

Abstract Background and Aims Hemodialysis patients have a high prevalence of constipation related to medication use, water restriction, insufficient dietary fiber intake, and reduced physical activity. Thus, these patients use drugs for constipation (DFC) more than five times that used by healthy individuals. In hemodialysis patients, two pathological factors, namely, reduced defecation function and DFC use itself, occur. These factors could be related to deteriorating life prognosis resulting from altered intestinal microbiota, gastrointestinal complications, or declining quality of life. In the general population, some reports have suggested that constipation and DFC use are risk factors of coronary artery disease, cardiovascular death, or all-cause death. However, whether such risk factors are appropriate for hemodialysis patients has not been clarified. This study aimed to investigate the association between DFC use and risk of death in hemodialysis patients. Method In this prospective cohort study based on the Japan-Dialysis Outcomes and Practice Patterns Study (J-DOPPS), we used J-DOPPS phase 1-5 (1998-2015) data. Hemodialysis patients enrolled in the J-DOPPS whose dialysis vintage was &amp;gt;3 months (n=12,217) were divided into two groups according to usage (DFC group;n=3,721) and non-usage (non-DFC group;n=8,496) of DFC. The primary endpoint was all-cause death. Secondary endpoints were deaths from infection, malignancy, and cardiovascular causes. Hazard ratio (HR) was calculated using multilevel Cox regression analysis with facility level. Potential confounders were adjusted by the inverse probability of treatment weighting using the propensity score. Rubin’s rule was used for combined data. Sensitivity analysis was conducted using instrumental variable method to assess the effect of unmeasured confounders. Missing data were imputed using multilevel multiple imputation repeated 20 times. Results DFCs were prescribed in 30.5% of patients at baseline. Over a median follow-up of 730 [418, 974] days, 1,240 deaths from any cause were noted. Overall data were analyzed first. Although DFC use was associated with increased mortality risk (adjusted HR, 1.12; 95% confidence interval [CI] 1.03, 1.21), proportional assumptions were not met (Figure). Then, we only analyzed data of patients with observation period &amp;gt;1.5 years. In this study, 8,345 patients had an observation period &amp;gt;1.5 years, DFCs were prescribed in 31.0% of patients at baseline, and 389 patients died from any cause. Marked difference was observed after 1.5 years from baseline (adjusted HR, 1.35; 95% CI, 1.17, 1.55). Risks for deaths from infections (adjusted HR 1.62; 95% CI 1.14, 2.29) and malignancy (adjusted HR 1.60; 95% CI, 1.08, 2.36) were higher in the DFC group, but no difference in cardiovascular death risk was found (adjusted HR 1.11; 95% CI, 0.91, 1.36). Conclusion In hemodialysis patients, DFC use was associated with an increased risk of death. Thus, it may be important to manage defecation habit without using DFC by modulating intake of dietary fibers, exercise, or use of medications that are less likely to cause constipation.

Elobixibat alleviates chronic constipation in hemodialysis patients: a questionnaire-based study

BackgroundHemodialysis patients are prone to constipation, which can adversely affect their quality of life (QOL). Elobixibat, a highly selective inhibitor of the ileal bile acid transporter, can increase the bile acid level in the colon and, subsequently, enhance colonic motility and secretion. In hemodialysis patients with chronic constipation, it may have a novel action mechanism. However, the effect of elobixibat on such patients’ QOL had not been reported. This study aimed to evaluate the effect of elobixibat on the QOL of hemodialysis patients with chronic constipation.MethodsThis was a multicenter, observational study that used the Japanese version of the Patient Assessment of Constipation-Quality of Life (PAC-QOL) questionnaire on 27 patients (18 men and nine women, age range 47–90 years), who satisfied the Rome 3 diagnostic criteria for functional constipation and were already taking other drugs for constipation. These patients were administered elobixibat 10 mg/day and were asked to respond to the PAC-QOL questionnaire at baseline and after 4 weeks. Bayesian statistics were used to confirm our results.ResultsThe number of spontaneous bowel movements per week increased significantly from 2.6 ± 1.2 to 4.1 ± 2.1 (p < 0.001), and the Bristol Stool Form Scale score significantly improved from 1.9 ± 0.8 to 3.6 ± 0.7 (p < 0.001). The Cronbach’s alpha was 0.95, and the Guttman split-half reliability coefficient was 0.90. There were significant decreases in the physical discomfort scores from 1.94 ± 0.79 to 0.97 ± 0.72 (p < 0.001); psychosocial discomfort from 1.16 ± 0.93 to 0.63 ± 0.58 (p < 0.001); worries/ concerns from 1.84 ± 0.73 to 1.27 ± 0.59 (p < 0.001), and satisfaction from 2.79 ± 0.61 to 1.98 ± 0.77 (p < 0.001). The total PAC-QOL score significantly decreased from 1.83 ± 0.79 to 1.17 ± 0.56 (p < 0.001). Bayesian statistics confirmed the results’ significance.ConclusionsElobixibat reduced the PAC-QOL scores for hemodialysis patients with chronic constipation and improved the patients’ QOL. It may serve as a new option for treating constipation in hemodialysis patients.

Pharmacovigilance, Adverse Drug Reactions and Future Aspects of Pharmacovigilance in India:A Review Article

Pharmacovigilance is useful toreassure the safety of drugs and protecting the consumers from their injuries effects. A number of single drugs as well as fixed dose combinations have been banned from manufacturing, marketing and distribution in India. An important issue about the availability of banned drugs over the counter in India is that sufficient adverse drug reactions data about these drugs have not been reported. The most common categories of drugs withdrawn in the last decade were non steroidal anti inflammatory drugs (28%), antidiabetics (14.28%), antiobesity (14.28%), antihistamines (14.28%), gastroprokinetic drugs (7.14%), breast cancer and infertility drugs (7.14%), irritable bowel syndrome and constipation drugs (7.14%) and antibiotics (7.14%). Drug withdrawals from market were made mainly due to safety issues involving cardiovascular events (57.14%), liver damage (14.28%), and carcinogenic reasons . Majority of drugs have been banned since 3-5 years in other countries but are still available for sale in India. The present study says about how to manage adverse drug reactions and to prevent it in advance and provides implications for developing a system that can ensure the safety and efficacy of drugs in India.There should be a multidisciplinary approach towards drug safety that should be implemented throughout the entire duration spanning from drug discovery to usage by consumers.

薬物相互作用（45―経口便秘薬の薬物相互作用）

薬物相互作用（45―経口便秘薬の薬物相互作用）

Mallinckrodt spins off generics, APIs

Mallinckrodt plans to spin off its specialty generics and active pharmaceutical ingredient (API) business to shareholders, creating two independent companies: Sonorant Therapeutics, focused on branded pharmaceuticals, and Mallinckrodt, focused on generics and APIs. Sonorant will retain the constipation drug Amitiza, which was originally to go with specialty generics. Mallinckrodt said in December that it was considering separating the generics business.

Burden of drug use for gastrointestinal symptoms and functional gastrointestinal disorders in France: a national study using reimbursement data for 57 million inhabitants

Background:Gastrointestinal therapeutic drugs (GTDs) are extensively prescribed. The aim of this study was to investigate the characteristics of GTD use in a large population: the French general health scheme beneficiaries (87% of the 66 million inhabitants) in 2016.Methods:The national health data system was used to identify individual characteristics, diseases and GTD classes reimbursed, together with the costs, using anatomical therapeutic chemical class.Results:Among the 57.5 million individuals included, 45% received at least one reimbursement among the 130 million prescriptions reimbursed (90% prescribed by a general practitioner): proton-pump inhibitors (PPI; A02BC: 24%), drugs for functional gastrointestinal disorders (A03: 20%), drugs for constipation (A06: 10%), antidiarrheals, intestinal anti-inflammatory/anti-infective agents (A07: 10%), antiemetics and antinauseants (A04: 7%), other drugs for acid-related disorders (A02X: 6%), other drugs for peptic ulcer and gastro-oesophageal reflux disease (A02BX: 4.5%), antacids (A02A: 1.5%). The overall cost of reimbursed GTDs was €707 million and the mean cost per user was €28. Marked variations were observed according to age, sex, and disease. The rates of at least one reimbursement among infants were A07: 28%, A03: 17%, A02BX: 9%, A02X: 7%, A02BC: 6% and A06: 5%. Women more frequently received a reimbursement than men for each GTD class. Reimbursement rates also varied according to health status (end-stage renal disease A02BC: 66%, pregnancy A03: 53%, A04: 11%), treatments (people with at least six reimbursements for nonsteroidal anti-inflammatory drugs in 2016 A02BC: 62%). Chronic GTD use (>10 reimbursements/year) was observed in 19% of people with at least one A02BC reimbursement, A02BX: 11%, A03: 7%, A04: 2%, A06: 17% and A07: 3%.Conclusions:This study demonstrates extensive and chronic use of GTD in France, raising the question of their relevance according to current guidelines. They must be disseminated to general practitioners, who are the main prescribers of these drugs.

Role and Effect of Plecanatide vs Lactulose Affects in Compensated Cirrhosis With Constipation Efficacy: A Randomized Open Level Prospective Clinical Pilot Study - REPLACE Trial

Introduction: Cirrhosis of liver carries multiple clinical morbidities; portal Hypertension, Minimal and overt Encephalopathy, renal Insufficiency, Esophageal and rectal Varies, Small bowel Ischemia, ascetics and constipation. Usage of lactulose to regulate bowel movements was optimal to relief constipation lowering Encephalopathy. Disaccharides cause Glucose Intolerance and Diarrhea depleting electrolyte provoking Hepato Renal Syndrome. Rifaximin is the standard of care for MHE or OHE, further precipitates constipation. Plecanatide is a natural Uroguanyle Agonist without systemic Absorption, a Ph dependent drug for constipation with minimal side effects. This clinical study evaluates the efficacy of Plecanatide in compensated cirrhosis. Methods: The total study population (n = 60) comprised of Sixty Compensated cirrhotics with a mean MELD 0f 8 were randomized in two groups: A (Lactulose 30 cc Bid with Rifaximin 550 mg BID for 12 weeks) and B (Plecanatide 3 mg orally plus Rifaximin 550 mg bid for 12 weeks). All groups had a washout time two weeks from all existing medications for Constipation or Enemas or Suppository. The daily diet contained Total 3000 cal/day, Total protein 150 gm/day (vegetable), Total Fat 30 gm/day, Total fiber 100 gm/day, Total salt of 2 grams and total fluid 1000cc. All HE was measured by Flicker test and Trial Test Block test. Satisfactory Bowel Movement score was calculated for all the patients (0 - dissatisfactory, 4 -Satisfactory). Modified QOL was obtained. (0-Poor, 1- Good, 2 & 3 - Very good, 4 - Excellent) Exclusion Criteria: Renal failure, TIPS, HCC, post-Transplant, sepsis, HRS, CHF, IBD, Dialysis, Severe Ascites, Uncontrolled DM Cardiac Arrhythmia, BMI Drugs: Calcium Blocker, Anticholinergic medication, Herbal and OTC for Constipation, Miralax, suppositories, Enema, Prostaglandin analogs and other prescription drugs for constipation. Patient Characteristics: Table1 Results: Primary endpoint: Complete Spontaneous Bowel Movement (CSBM) in 24 hours Secondary endpoint: Sustained bowel movement post 12 weeks Table 2 Side Events Table 3 Conclusion: Clinical pilot reveals higher Efficacy of Plecanatide on Complete Spontaneous Bowel movements and Sustained Bowel Movements without drop out. No difference in regard to Overall HE in both groups. Large cohort studies required to validate.910_A Figure 1 No Caption available.910_B Figure 2 No Caption available.910_C Figure 3 No Caption available.

Cytotoxicity of Structurally Diverse Anthranoids and Correlation with Mechanism of Action and Side Effects.

The purpose of this contribution is to evaluate the cytotoxicity and apoptosis inducing ability of structurally diverse anthraquinones to establish a relationship between structure and toxicity. Besides the wide spread use of anthraquinones in pharmacological drugs for constipation and non-prescription dietary supplements for weight loss, extracts are still commercialized as crude extracts and long-term side effects are still relevant. In this work we developed a method to quantify the cascarosides isolated from Rhamnus purshiana (Cascara Sagrada) using LC-MS/MS and evaluated the effects of this extract and isolated compounds on cellular viability using NOK-SI, HeLa, and T98G cell lineages. Apoptosis inducing ability was also analyzed via evaluating key-proteins involved in apoptosis pathways. Using cascarosides isolated from bark extracts, we found that the presence of glucose moieties in the chemical structure reduced the toxicity. This communication reviewed the mechanisms of action, toxicity of anthraquinones and correlated the toxicity with chemical structures of cascarosides. Results indicate that cascarosides-enriched cascara extract, as well as glycosylated anthraquinones, may have some beneficial effects for laxative action of herbal medicines. Considering our results, a cascarosides-enrichment in cascara extract is recommended.

Elobixibat, an ileal bile acid transporter inhibitor, induces giant migrating contractions during natural defecation in conscious dogs.

Chronic constipation affects 14%-17% of the population. Elobixibat, a novel, ileal bile acid transporter (IBAT) inhibitor, has been approved as a new chronic constipation drug in Japan in January 2018. The present study aimed to examine the pharmacological effects of elobixibat on colonic motility in conscious dogs using a telemetry system. Six male beagle dogs were surgically implanted with strain gauge force transducers for gastrointestinal (GI) motility recording. The motility index was calculated from GI motility at each recording site in conscious and nonrestraint dogs. The fasted dogs were orally administered elobixibat (3, 10, or 30mg kg-1 ) or 30mg kg-1 of sennoside as positive control or vehicle using a crossover design and washout period of more than 6days. One hour after drug administration, the dogs were fed chow, and GI motility and defecation were observed for 10hours; GI motility was quantified to calculate giant migrating contractions (GMCs). Fecal bile acids (BAs) were determined as well. Elobixibat and sennoside significantly increased the number of defecations, fecal wet weight, and water content within 10hours after administration. Elobixibat dose-dependently decreased the time to first bowel movement, increased the amount of total fecal BAs, and rapidly induced mild GMCs during defecation; however, higher strength of GMCs was observed with sennoside. Elobixibat induces bowel movements faster than sennoside through a different mechanism. Elobixibat locally inhibits IBAT in the ileal lumen, leading to elevated fecal BAs in the colon and induced mild GMCs during defecation.

Non-bleeding Adverse Events with the Use of Direct Oral Anticoagulants: A Sequence Symmetry Analysis.

IntroductionPostmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases.ObjectiveThe aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA).MethodsSSA was performed using nationwide data from the French National Healthcare databases (Régime Général, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA).ResultsThis study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3 = 2.71, 95% confidence interval (CI) 1.79–4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3 = 1.31, 95% CI 1.27–1.36; and 1.17, 95% CI 1.12–1.22, respectively); and kidney diseases (aSR3 = 1.33, 95% CI 1.29–1.37).ConclusionResults of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded.Electronic supplementary materialThe online version of this article (10.1007/s40264-018-0668-9) contains supplementary material, which is available to authorized users.

2018: Targeting the Pusher: Beyond Going Beyond Senna and Colace for the Management of Constipation in Hospice (SA502)

•Understand the pathophysiology of functional bowel disorders vs opioid induced bowel dysfunction.•Learn how to classify bowel disorders and tailor therapies according to disorder.•Learn mechanisms of action of new drugs for constipation. Constipation occurs in the majority of patients who are in hospice and palliative care patients. Frequencies range from 70% to 87% according to studies. Surprisingly research suggests that opioid are responsible for constipation in only 25% of cases and that there is a significant large populations of patients, who we are likely to encounter in hospice with functional disorders that may not respond to the mantra of “Senna and Colace.” Add the growing number of elderly in the population who have a high prevalence of functional bowel disorders one has to consider better approaches to evaluating constipation. Complicating the management of constipation are the ever growing list of medications which may work for functional bowel disorders but not for opioid induced bowel dysfunction. Sorting out proper evaluation and proper application of therapies enhances therapeutic success and avoids inappropriate use of laxatives and lowers the risk for polypharmacy. This session will be presented by a panel of hospice/ palliative care specialists, and experts in palliative pharmacotherapeutics. Attendees will walk away with a new perspective on constipation. They will understand the proper applications of the new therapies for constipation. The session will by way of didactics, case presentation and audience participation help attendees: 1.) Recognize and classify types of constipation likely to occur in the hospice setting. 2.) Refine and improve methods of constipation evaluation. 3.) Understand differences in the pathophysiology of functional disorders versus opioid bowel dysfunction. 4.) Get a detailed overview of new drugs and where they fit therapeutically in the spectrum of constipation disorders. 5.) Get a perspective on the cost of new and old medications for constipation.

Managing Constipation in Adults With Cancer

Constipation is common in individuals with cancer, occurring in almost 60% of patients overall. The incidence increases in patients with advanced disease, particularly in those receiving opioid analgesics or medications with anticholinergic properties. Constipation is not uniformly assessed and therefore not recognized and appropriately managed in many instances. This can increase patients' physical and psychological distress. Furthermore, there is scant research to support current management strategies for constipation. The objectives of this review are to explore the incidence of and risk factors for constipation in patients with cancer, to discuss the extent of the problem, to explore the nonpharmacologic and pharmacologic measures for constipation and fecal impaction, and to synthesize a laxative management. An extensive review of medical, pharmacy, and nursing literature was done to explore the physiology and pathogenesis of constipation; detail the mechanisms of action, onset of effect, approximate costs, and adverse effects of drugs for constipation; and condense clinical expert consensus recommendations for constipation, particularly in patients with cancer. Advanced practitioners (APs) and other clinicians play crucial roles in identifying individuals at risk for and experiencing constipation to help them use effective regimens, including over-the-counter laxatives, and perhaps adjunctive nondrug measures. Clinicians and patients must develop an agreed-upon language for identifying the severity and effects of constipation. In addition, both should understand which laxatives are most appropriate and which should be avoided for particular patients. Two prescription agents are also available, and understanding when they should be used is important for APs.