Review article: anthranoid laxatives and their potential carcinogenic effects.

INTRODUCTION: Pseudomelanosis coli is the brown-black pigmentation of colon and rectum as a consequence of laxative use secondary to increasing dependency on narcotics. However, there are reports of Pseudomelanosis in the absence of laxatives and pigmentation in areas other than colon. Recently it has also been linked to colon cancer. METHODS: A selective review of existing literature on Psuedomelanosis coli was performed in PubMed. RESULTS: Early studies speculated that the pigment is melanin or an anthracene derivative. Now it is widely accepted that the pigment is actually lipofuscin. Lipofuscin predominantly accumulates in the macrophages of the lamina propria, usually in the colon. Electron microscopic examination of the pigment granules in the duodenum has revealed lysosomal bodies containing iron sulfide with traces of minerals from antacids, food additives and dental fillings. Electron microscopy of ileum revealed the pigment granule laden macrophages containing predominantly magnesium and aluminum-rich silicates. Pseudomelanosis is characteristically absent in colonic neoplasms. The area of the melanotic colon with cancer association has reduced or even lack of pigment laden macrophages. Pseudomelanosis is sometimes encountered in colonoscopy without a history of laxative use. This means that either chronic inflammation or a rapid intestinal transit in inflammation can cause pigmentation. Based on studies in guinea pigs, it is hypothesized that non-anthraquinone laxatives have the potential to cause microscopic pigment deposition, which may not result in gross discoloration on endoscopic evaluation. CONCLUSION: Pseudomelanosis coli has increased in incidence in the United States due to increasing incidence of chronic pain syndromes causing opioid dependence and secondary laxative use and with abundant purine intake. Non-anthracene Pseudomelanosis coli has a different pathogenesis and may be missed by endoscopists due to the grossly normal appearing colon. The pathogenesis of Pseudomelanosis coli in the setting of laxative naïve patients is not well understood. Interestingly, chronic colitis may have an association with Pseudomelanosis coli. There is no established correlation between Pseudomelanosis coli and cancer, but it is unclear if chronic colitis causing Pseudomelanosis has any role in carcinogenesis in these patients. Lastly, melanosis can occur in other parts of the gastrointestinal system, but is usually due to other pigments rather than lipofuscin. Further studies are needed.

Retrospective study on laxative use and melanosis coli as risk factors for colorectal neoplasma.

The habitual use of laxative containing anthraquinone glycosides is considered to be the main cause of melanosis coli (MC). In the past, most scholars considered MC to be a benign and reversible disease. However, new evidence has emerged that MC may increase the risk of colon cancer. Here, we report a case of a 48-year-old woman diagnosed with MC and colon cancer. Through a literature review of previous basic and clinical studies, we summarize existing evidence that reveals the possible association between MC and colon cancer. Although this case cannot establish causality between MC and colon cancer, a high level of clinical vigilance for occurrence of colon cancer in patients with MC should be maintained.

Contrary to short-term use, long-term benzodiazepine use is undesirable. Nevertheless, its prevalence is high. To prevent long-term use, it is important to know which short-term users are at risk of becoming long-term users. The purpose of the present study was to identify patient-related factors of long-term versus short-term use of benzodiazepines. A cross-sectional study was carried out in family practices among users of benzodiazepines with regard to DSM-IV diagnosis, coping and psychosocial characteristics,. In a multivariate logistic regression analysis, long-term use of benzodiazepines was the dependent variable. A total of 164 short-term and 158 long-term benzodiazepine users participated in the study. Having a DSM-IV disorder and psychiatric co-morbidity, being older, less educated, lonely and using more avoidance coping behaviour was associated with long-term use of benzodiazepines compared with short-term use. The associations found point to possibilities to reduce long-term benzodiazepine use, for example if patients with these characteristics are treated with the alternatives to benzodiazepines or are monitored closely for a short period after being prescribing benzodiazepines.

Melanosis coli is a condition in which the colon develops a brown to black discoloration. It is associated with chronic laxative use and frequently diagnosed incidentally during colonoscopy or histopathologic evaluation. A 74-year-old woman presented to the Emergency Department with severe abdominal pain and bilious emesis. During a cecal volvulus repair, her melanosis coli was nearly misdiagnosed as bowel ischemia. Melanosis coli is a diagnostic finding that can easily be confused with bowel ischemia, which may create a dilemma for the surgeon who is attempting to make a decision regarding the extent of a colonic resection. As such, a pathology consult is warranted in any patient with suspected ischemic colitis and concerns for concomitant melanosis coli.

Background: Melanosis coli is a benign pigmentation of the colonic mucosa, most commonly associated with chronic laxative use. The condition is caused by accumulation of lipofuscin within macrophages in the lamina propria. Although often incidental, its recognition is important to avoid misinterpretation as more serious colonic pathology. Case Presentation: We report the case of a 70-year-old man with chronic constipation for several years, who developed colonic melanosis while using an inulin-based laxative daily. Colonoscopy revealed diffuse brown-black pigmentation predominantly in the right colon, confirmed histologically as melanosis coli. After discontinuation of the laxative and implementation of dietary and lifestyle changes, the patient’s bowel function improved and pigmentation regressed over time. Conclusion: This case illustrates melanosis coli related to prolonged use of an inulin-based laxative. Awareness of this benign and reversible entity is crucial to prevent unnecessary alarm and to emphasize rational laxative use in elderly patients with chronic constipation.

Temporal discounting (TD) represents the mental devaluation of rewards that are available after a delay. Whether the hippocampus is critical for TD remains unclear, with marked discrepancies between animal and human studies: although animals with discrete hippocampal lesions display impaired TD, human participants with similar lesions show intact performance on classic intertemporal choice tasks. A candidate explanation for this discrepancy is that delays and rewards are experienced in the moment in animal studies but tend to be hypothetical in human studies. We tested this hypothesis by examining the performance of amnesic participants with hippocampal lesions (one female, six males) on a novel experiential intertemporal choice task that used interesting photographs occluded by thick lines as rewards (Patt et al., 2021). Using a logistic function to model indifference points data, we compared performance to that on a classic intertemporal choice task with hypothetical outcomes. Participants with hippocampal lesions displayed impaired patterns of choices in the experiential task but not in the hypothetical task. Specifically, hippocampal lesions were associated with decreased amplitude of the delay-reward trade-off, with persistent choice of the delayed option despite delay increase. These results help explain previous discrepancies across animal and human studies, indicating that the hippocampus plays a critical role in temporal discounting when the outcomes of decisions are experienced in the moment, but not necessarily when they are hypothetical.SIGNIFICANCE STATEMENT Impaired temporal discounting (TD) has been related to maladaptive behaviors, including substance dependence and nonadherence to medical treatment. There is consensus that TD recruits the brain valuation network but whether the hippocampal memory system is additionally recruited remains unclear. This study examined TD in hippocampal amnesia, providing a unique opportunity to explore the role of the hippocampus in cognition. Whereas most human studies have used hypothetical outcomes, this study used a novel experiential task with real-time delays and rewards. Results demonstrated hippocampal involvement in the experiential task, but not in a classic hypothetical task administered for comparison. These findings elucidate previous discrepancies between animal and human TD studies. This reconciliation is critical as animals serve as models of human neurocognition.

This study aims to examine possible differences in the effect on the course characteristics of the disease in cases of no use, short-term use and long-term use of benzodiazepines in patients with schizophrenia. In this retrospective observational study, the sample comprised patients with schizophrenia who were admitted to our psychiatric clinics from January 2015 to January 2019. Patients were also retrospectively tracked from the date of the first admission during the specified time until the end of the observation period (24 months) for clinical course characteristics. Data for 1710 patients with schizophrenia were included in the analyses. Patients with short-term benzodiazepines use had fewer psychiatric hospitalizations and shorter lengths of stay at psychiatric services than patients with no use or long-term use. Rates of antipsychotic drug discontinuation and suicidal behavior were also significantly lower among short-term benzodiazepines users than among those with no use or long-term use. In conclusion, our study indicates that short-term benzodiazepines use is associated with a better clinical course in patients with schizophrenia. Future studies should evaluate the effects of different benzodiazepines use patterns on disease prognosis with longer-term follow-up and prospective methodology and should concomitantly examine psychopathological variables.

Chimeric antigen receptor T-cell (CAR-T) therapy targeting for B-cell maturation antigen (BCMA) is used to treat patients with multiple myeloma (MM). To investigate gastrointestinal changes associated with CAR-T therapy, we performed a retrospective study. A total of 10 patients with 26 gastrointestinal biopsy specimens who underwent CAR-T therapy for MM were identified. Except for one patient with residual multiple myeloma, all specimens demonstrated markedly reduced or absent plasma cells. The most prominent biopsy findings occurred in the small intestine, primarily the duodenum, and included lamina propria lymphocytic infiltration, villous atrophy, foveolar metaplasia, an absence of plasma cells, and an increase in intraepithelial lymphocytes. There was an average of 7 apoptotic bodies per 10 high-power fields (hpf). The terminal ileum was also notable for increase in apoptotic bodies (average of 9.5 apoptotic bodies/10 hpf), villous atrophy, and lamina propria lymphocytic infiltration. The stomach biopsies overall typically showed mild inflammation with no increase in apoptotic bodies. A few colonic specimens demonstrated active colitis and prominent apoptotic bodies, while the majority of the colonic biopsies did not have significant findings other than melanosis coli, and an absence or reduction of plasma cells. The disproportionately greater injury in the duodenum versus the colon highlights the importance of upper endoscopic evaluation in symptomatic patients after CAR-T therapy. The mechanisms for these patterns of injury and differential anatomic findings are unknown; however, an immune-mediated injury associated with CAR-T therapy is suspected. Our study identifies a unique pattern of intestinal injury in patients with MM who received BCMA-targeted CAR-T therapy; this encompasses histologic findings more profound in the small intestine, which include absence of plasma cells, an increase in apoptotic bodies, lymphocytic infiltration, and villous atrophy.

The aim of this review is to provide an overview of the clinical assessment and evidence-based treatment options for managing diabetes-associated chronic constipation. A literature search of published medical reports in English language was performed using the OVID Portal, from PUBMED and the Cochrane Database of Systematic Reviews, from inception to October 2015. A total of 145 abstracts were identified; duplicate publications were removed and 95 relevant full-text articles were retrieved for potential inclusion. Chronic constipation is one of the most common gastrointestinal symptoms in patients with diabetes, and occurs more frequently than in healthy individuals. Treatment goals include improving symptoms and restoring bowel function by accelerating colonic transit and facilitating defecation. Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor. Lactulose, polyethylene glycol and lactitol are the most frequently prescribed osmotic agents. Lactulose has a prebiotic effect and a carry-over effect (continued laxative effect for at least 6 to 7days, post cessation of treatment). Stimulants such as bisacodyl, sodium picosulphate and senna are indicated if osmotic laxatives are not effective. Newer agents such as chloride-channel activators and 5-HT4 agonist can be considered for severe or resistant cases. The primary aim of intervention in diabetic patients with chronic constipation is to better manage the diabetes along with management of constipation. The physician should explain the rationale for prescribing laxatives and educate patients about the potential drawbacks of long-term use of laxatives. They should contact their physician if short-term use of prescribed laxative fails to provide relief.

Improved understanding of temporal trends in short- and long-term opioid prescribing may inform efforts to curb the opioid epidemic. To characterize the prevalence of short- and long-term opioid prescribing in the Veterans Health Administration (VHA) from 2010 to 2016. Observational cohort study using VHA databases. All patients receiving at least one outpatient prescription through the VHA during calendar years 2010 through 2016. Prevalence of opioid use from 2010 through 2016, stratified by short-term, intermediate-term, and long-term use. Temporal trends in discontinuation among existing long-term users and initiation of new long-term use and the net impact on rates of long-term opioid use. Relative likelihood of transitioning to long-term opioid use contrasted with use patterns in the prior year. The prevalence of opioid prescribing was 20.8% in 2010, peaked at 21.2% in 2012, and declined annually to 16.1% in 2016. Between 2010 and 2016, reductions in long-term opioid prescribing accounted for 83% of the overall decline in opioid prescription fills. Comparing data from 2010-2011 to data from 2015-2016, declining rates in new long-term use accounted for more than 90% of the decreasing prevalence of long-term opioid use in the VHA, whereas increases in cessation among existing long-term users accounted for less than 10%. The relative risk of transitioning to long-term use during 2016 was 6.5 (95% CI: 6.4, 6.7) among short-term users and 35.5 (95% CI: 34.8, 36.3) among intermediate users, relative to patients with no opioid prescriptions filled during 2015. Opioid prescribing trends followed similar trajectories in VHA and non-VHA settings, peaking around 2012 and subsequently declining. However, changes in long-term opioid prescribing accounted for most of the decline in the VHA. Recent VA opioid initiatives may be preventing patients from initiating long-term use. This may offer valuable lessons generalizable to other healthcare systems.

Background/AimsConstipation is a common gastrointestinal problem in the elderly. Because of the limitations of life style modifications and the comorbidity, laxative use is also very common. Therefore, this study reviews the latest literature on the effect and safety of laxative in the elderly.MethodsA systematic review of randomized controlled trials investigating the effectiveness and safety of laxatives for constipation in elderly patients over 65 years old were performed using the following databases PubMed, EMBASE, and the Cochrane Library.ResultsTwenty-three randomized controlled trials were included in this review. Among the selected studies, 9 studies compared laxative with placebo and 5 studies compared laxatives of the same type. Four studies compared different types of laxatives or compared combination agents. Five studies compared novel medications such as prucalopride, lubiprostone, and elobixibat with placebo. Psyllium, calcium polycarbophil, lactulose syrup, lactitol, polyethylene glycol, magnesium hydroxide, stimulant laxative with or without fiber, and other medications were more effective than placebo in elderly constipation patients in short-term. Generally, the frequency and severity of adverse effects of laxative were similar between the arms of studies.ConclusionsBulk laxative, osmotic laxative, stimulant laxative with or without fiber, and other medications can be used in elderly patients in short-term within 3 months with reasonable safety. However, the quality of included studies was not high and most of studies was conducted in a small number of patients. Among these laxatives, polyethylene glycol seems to be safe and effective in long-term use of about 6 months in elderly patients.

We read with great interest the excellent meta-analysis by Marret et al. 1and the accompanying editorial by Professor Kehlet2on the effects of combined opioid and nonsteroidal antiinflammatory drugs (NSAIDs) use to relieve postsurgical pain. Marret et al. conclude that NSAIDs (cyclooxygenase 2 [COX-2] selective and nonselective), in the aggregate, provide approximately 30% reduction in morphine consumption, with associated reductions in postoperative nausea and vomiting and sedation, but not pruritus, urinary retention, and respiratory depression. Although the efficacy data support the use of multimodal analgesia involving opioids and COX-2 selective NSAIDs, we believe the safety data on the short-term perioperative use of COX-2 selective inhibitors are less than clear for the following reasons.First, the US New Drug Application for rofecoxib was based almost exclusively on studies in patients with chronic pain. Studies to directly support the postsurgical pain indication consisted of 741 patients, of whom 85% received one dose for dental pain and 15% received five doses for orthopedic pain.*Marret et al. note that the cardiovascular risk of rofecoxib was associated with “long-term use.” However, in the absence of robust studies in high-risk surgical patients and based on data on parecoxib, one cannot preclude similar safety risks with short-term postsurgical use of rofecoxib.Second, although parecoxib (the injectable prodrug of the now withdrawn valdecoxib) is an effective analgesic, there remain serious unanswered questions about the safety of short-term use in the postsurgical setting. An important early adverse postsurgical safety signal came from a coronary artery bypass graft study included in the original US New Drug Application.†In the parecoxib and valdecoxib group, 19.0% had serious adverse events, versus 9.9% in the placebo group. Citing deficiencies in the data, including a numerically higher incidence of myocardial infarctions (1.9% vs. 0.7%) and cerebrovascular events (2.6% vs. 0.7%) and deaths (4 vs. 0), parecoxib received a nonapprovable letter from the Food and Drug Administration in 2001. The Food and Drug Administration concluded that “the adverse event profile of parecoxib was generally worse than that of placebo in this trial. Although not statistically significantly different, the number of deaths, myocardial infarctions, cerebrovascular accidents, pulmonary embolisms, along with renal and pulmonary complications were also numerically more frequent for parecoxib during this IV dosing period than placebo. In fact, during the entire study period, the incidence of these clinically relevant adverse events associated with parecoxib/valdecoxib was statistically significantly different than placebo. Similarly, during the entire study period, more patients in the parecoxib/valdecoxib versus the placebo group withdrew from the study due to an adverse event.”†Third, follow-up studies conducted with parecoxib have raised additional safety issues. In one trial,3cardiovascular events (including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism) occurred significantly more frequently in the parecoxib and valdecoxib group than with placebo (2.0% vs. 0.5%; P = 0.03). In another trial,4there were significantly more sternal wound infections with parecoxib than with placebo (3.2% vs. 0%; P = 0.03).Fourth, 3 yr ago, the European Medicines Evaluation Agency issued a public statement on parecoxib regarding the risk of serious hypersensitivity and skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, and exfoliative dermatitis, as well as anaphylaxis and angioedema.5The European Medicines Evaluation Agency has since contraindicated the use of parecoxib in patients with ischemic heart disease and stroke. Excluding individuals with silent ischemia, this translates to approximately 20 million at-risk patients in the United States. Immediately before its withdrawal in the United States, the Food and Drug Administration required a similarly worded box warning for valdecoxib. Notably, the warning indicated (1) a higher risk of serious skin reactions within the first 2 weeks, (2) a greater propensity for such reactions with valdecoxib than other COX-2 inhibitors, and (3) a recommendation to discontinue valdecoxib at the first appearance of skin rash. Since self-limiting pruritus and hypersensitivity are common in the postsurgical setting, causality assessment in patients with early signs of serious and unrelated skin reactions may prove difficult.Fifth, there are indications that the increased COX-2 levels observed under pathologic conditions in endothelial cells and atherosclerotic lesions provides atheroprotection and modulates vascular remodeling through its principal metabolite, prostacyclin.6In addition, in patients with acute pain, there is considerable spinal up-regulation of COX-1, which may provide a further rationale for the use of drugs that inhibit both isoforms of COX in acute pain.Finally, survey data continue to support the view that postsurgical pain is undertreated. Although the efficacy of COX-2 selective NSAIDs such as parecoxib is comparable to nonselective NSAIDs, further safety data are required to support their short-term use in the perioperative setting.‡TheraQuest Biosciences, Blue Bell, Pennsylvania. nbabul@theraquestinc.com

We report the case of a 74-year-old female with an extreme picture of melanosis coli of the whole colon after chronic use of anthraquinone laxatives for the treatment of constipation over many decades. Endoscopic work-up revealed an impressive deep black pigmentation of the whole colon mucosa which could be verified by histopathology as a widespread lipofuscin granulation. In addition, various adenomas but no colorectal carcinoma could be detected. The term melanosis coli describes a brown or black pigmentation of the colonic mucosa. Induction of melanosis coli by anthraquinone laxatives and their derivatives can be regarded as verified. The question if melanosis coli predisposes for colorectal neoplasia is discussed controversially. Based on the current literature, an association of melanosis coli between colorectal adenomas, but not colorectal carcinomas, is under discussion but the mechanisms to effect the development of colorectal neoplasia are not completely understood. Considering our case and the current scientific backround, we conclude that due to pharmaceutical side effects of anthraquinone derivatives such as electrolytic shift and water loss in addition to the risk of developing melanosis coli, anthraquinone laxatives should not be used for long-term therapy of constipation.

ABSTRACTIntermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to “regeneration,” “implant,” and “distraction osteogenesis” were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.