Pharmacokinetic considerations for drugs that treat diarrhea-predominant irritable bowel syndrome: what's new?

INTRODUCTION: Irritable bowel syndrome (IBS), which presents a significant healthcare and socioeconomic burden, is one of the main issues in the field of therapy. Hence, it is imperative to tackle this matter by evaluating the safety and efficacy of the available treatments and determining the ideal approach for each patient. AREAS COVERED: We reviewed the pharmacokinetics and safety of pharmacologic interventions administered in diarrhea-predominant IBS (IBS-D) patients. PubMed, Google Scholar and the USFDA databases were searched up to November 2023 to include all updated information on eluxadoline, alosetron, and rifaximin. EXPERT OPINION: The most effective way to treat IBS-D is to focus on managing the most common symptoms. However, healthcare providers face a challenge when it comes to identifying the right treatment for each patient, and the root cause of this is the diversity of IBS-D population. Studies have shown that there are differences in how men and women metabolize drugs, which may lead to gender-specific adverse reactions. Women tend to have higher drug concentrations in their bloodstream and take longer to eliminate them. Therefore, healthcare providers may need to reduce the dosage for female patients. Integrating IBS care into sustainable development efforts can indirectly contribute to achieving SDGs and promote health and well-being for all.

Drugs of the future for diarrhea-predominant irritable bowel syndrome: an overview of current investigational drugs.

INTRODUCTION: Irritable bowel syndrome (IBS) has a significant impact on society and quality of life. Current treatments are ineffective, and new investigational drugs are necessary. AREAS COVERED: Numerous potential therapies are developing, targeting different areas such as cannabinoid signaling, opioid receptors, tachykinin (NK2) receptors, ß3-adrenergic receptors, intestinal microbiota, inflammation, and 5HT receptors. Clinical trial evidence has shown that loperamide, eluxadoline, alosetron, ramosetron, bile acid sequestrants, and rifaximin can modulate GI alterations and benefit patients with IBS-D. Among the potential therapies, ibodutant, ibudilast, blautix, BOS-589, solabegron, vibegron, olorinab, ebastine, and ORP-101 have demonstrated possible effects but remain confirmed. EXPERT OPINION: Individuals with IBS-D require cost-effective treatment options that do not impede their productivity or that of their caregivers. This is necessary for consistent healthcare and improved quality of life. Therefore, we should focus on developing new, efficient, and affordable medications for IBS-D. The government, insurers, and society must recognize this need and collaborate to ensure its fulfillment.

Common gastrointestinal drug-drug interactions in geriatrics and the importance of careful planning.

INTRODUCTION: Polypharmacy, which uses multiple medications to treat chronic illnesses, is common among elderly patients. However, it can lead to drug interactions, especially with gastrointestinal (GI) medicines that are extensively used. These drug interactions can have severe consequences and pose a significant challenge to healthcare providers. Therefore, it is crucial to identify the underlying mechanisms of these interactions and develop strategies to minimize medication errors. AREAS COVERED: We analyzed databases on GI illnesses common in older adults, including GERD, peptic ulcer disease, IBS, IBD, constipation, and diarrhea. Our research identified noteworthy drug interactions and utilized major electronic databases such as USFDA, PubMed, Scopus, and Google Scholar until 15 May 202315 May 2023, along with a review of reference lists. EXPERT OPINION: Aging can affect how the body processes drugs, leading to an increased risk of drug interactions. Therefore, healthcare professionals must carefully evaluate a patient's medical history and health condition to design personalized treatment plans.

The pharmacological management of constipation in patients with Parkinson's disease: a much-needed relief.

INTRODUCTION: Constipation is common in patients with Parkinson's disease (PD). Due to the considerable negative outcomes of constipation, significant efforts have been made to prevent and manage chronic constipation in these patients. AREAS COVERED: Herein, the authors review some of the known pathophysiological causes for slow gastrointestinal (GI) transit in PD patients and the different pharmacological options. All relevant clinical and experimental data found through online databases were included. Bulking agents, osmotic and stimulant laxatives, chloride channel activators, ghrelin agonists, 5-HT4 receptor agonists, and probiotics are some of the proposed medicinal agents. of the authors further review the evidence on alpha-synuclein and botulinum neurotoxin in these patients. It should be noted, however, that some of these interventions are required to be further validated. EXPERT OPINION: Reduction of GI transit and dysfunction of the anorectum is obvious in PD, affecting the incidence of constipation and thus, quality of life (QOL). Furthermore, due to an inadequate and delayed absorption of oral anti PD medications, dose adjustments and changes in the route of administration are recommended.

On the use of herbal medicines in management of inflammatory bowel diseases: a systematic review of animal and human studies.

Because of potential adverse events and lack of effectiveness of standard therapies, the use of complementary and alternative medicines (CAM), particularly of herbal therapies, for inflammatory bowel disease (IBD) is increasing. Results from the use of herbal therapies for managing IBD are promising, and no serious adverse events have been reported from them. Herbal therapies show their benefit in managing IBD by different mechanisms such as immune system regulation, antioxidant activity, inhibition of leukotriene B4, inhibition of nuclear factor-kappa B (NF-kappaB), and antiplatelet activity. In this paper, all reported herbal therapies established in animal IBD models or used for managing human IBD are systematically reviewed and their possible mechanisms of action discussed. Conducting clinical trials with high quality and validity (randomized, double blinded, controlled, on a large number of patients) to obtain more conclusive results about the use of herbal therapies in IBD is recommended.

Is there an appropriate strategy for treating co-morbid irritable bowel syndrome and bladder pain syndrome?

INTRODUCTION: Two of the most frequent components of chronic pelvic pain syndrome (CPPS) are irritable bowel syndrome (IBS) and bladder pain syndrome (BPS), characterized by considerable overlapping symptoms and pathophysiology. Currently, its management is challenging meaning there is high the demand for novel efficient therapeutics to aid patient care and to tackle the socioeconomic burden of IBS and BPS. As there are presently no sufficient treatment strategies, identifying the mechanisms that result in their main symptoms is the opportunity for developing appropriate therapies. Areas covered: Herein, the authors explore the potential common treatment strategies for co-morbid IBS and BPS and highlight the absolute need for further research of these deliberating clinical entities. Expert opinion: In the future, the authors summise that the discovery of predictive molecular biomarkers combined with clinical phenotypic categorization will likely allow for more definitive differentiation of patients and thus for better treatment options. Furthermore, it has been suggested that effective IBS treatment strategies would be of great value to co-morbid IBS and BPS therapy.

Methylnaltrexone bromide for the treatment of opioid-induced constipation.

INTRODUCTION: The extensive and alarming use of opioids for pain management in patients with chronic pain receiving palliative care is associated with non-tolerable gastrointestinal (GI) adverse effects. Opioid-induced constipation (OIC) is the most common adverse effect impairing patient quality of life (QOL). In addition, OIC is one of the treatment limiting consequences of opioid analgesics. Management of OIC is becoming a challenge since traditional laxatives have limited efficiency. Peripherally acting mu-opioid receptor antagonists (PAMORA) have been developed for the treatment of OIC with methylnaltrexone bromide being the first approved to treat OIC in adults with advanced illness undergoing palliative care. Areas covered: The authors systematically review the clinical evidence for methylnaltrexone bromide including a review of the pharmacokinetic and pharmacodynamic data along with clinical effectiveness and cost-effectiveness. Though there is a need for further long-term clinical investigation, there is a large body of evidence for both its efficacy and safety in the treatment of OIC. Expert opinion: Methylnaltrexone has both subcutaneous injection and oral dosage forms available in the market. The lack of more evidence in specific populations such as pregnant women, pediatrics and elderly still remains. The global consumption of methylnaltrexone shows a projection of increased use since its approval worldwide in 2008.

Investigational opioid antagonists for treating opioid-induced bowel dysfunction.

INTRODUCTION: Opioids have been highlighted for their role in pain relief among cancer and non-cancer patients. Novel agents have been investigated to reduce opioid-induced constipation (OIC) as the main adverse effect that may lead to treatment discontinuation. Development of peripherally acting mu-opioid receptor antagonists (PAMORA) has resulted in a novel approach to preserve the efficacy of pain control along with less OIC. AREAS COVERED: Clinical evidence for investigational PAMORAs was reviewed and clinical trials on investigational agents to reduce OIC were included. TD-1211 is currently being evaluated in Phase II clinical trial. Oxycodone-naltrexone and ADL-5945 went through Phase III clinical trials, but have been discontinued. EXPERT OPINION: There is a substantial need to develop agents with specific pharmacokinetic properties to meet the needs of patients with underlying diseases. Holding the efficacy of a medicine with the highest selectivity on targeted receptors and the least adverse effects is the main approach in upcoming investigations to improve patients' quality of life (QoL). Novel agents to reduce opioid-induced bowel dysfunction (OIBD) that do not reverse peripherally mediated pain analgesia are of great interest. Direct comparison of available agents in this field is lacking in the literature.

Tumor Necrosis Factor-alpha Antibodies in Fistulizing Crohn's Disease: An Updated Systematic Review and Meta-analysis.

Medical treatment for fistulizing Crohn's disease (FCD) is changing rapidly over the time by the introduction of novel therapeutic medicines, while no global consensus is available. This study aims to accomplish a systematic review and meta-analysis on the efficacy of tumor necrosis factor-alpha antibodies (anti-TNF-α antibodies) versus placebo in FCD. A systematic review of published literature was carried out till December 2016, and a meta-analysis of identified studies was done. Data have been explored from PubMed, Scopus, Cochrane Library Database, and Web of Science. Predefined exclusion criteria for included studies in meta-analysis are based on search methodology and are as follows: Randomized clinical trial about Crohn's disease (CD) patients without fistula, pediatrics CD, randomized clinical trials about pregnant women with FCD, nonhuman studies, randomized clinical trials with surgical therapies interventions, conference abstracts, case reports, and language other than English studies. All randomized placebo-controlled trials were included. To assess risk of bias, Jadad score was applied to evaluate trials' methodological quality. Relative risk (RR) and 95% confidence intervals were computed using Mantel-Haenszel and/or Rothman-Boice (for fixed effects) or Der Simonian-Laird (for random effects) techniques. Nine studies attained defined inclusion criteria. The meta-analysis results showed that anti-TNF-α antibodies are remarkably more effective in comparison to placebo for fistula closure maintenance (RR = 2.36; 95% confidence interval: 1.58-3.55; P < 0.0001) in patients with FCD, whereas anti-TNF-α antibodies were not superior to placebo neither in fistula improvement nor in fistula closure. We concluded that adalimumab and certolizumab pegol are both effective in fistula closure maintenance in adult patients with FCD.

Inflammatory bowel disease therapies discontinued between 2009 and 2014.

INTRODUCTION: New therapeutic approaches are currently under development, which consider the fundamental mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD). The disease is associated with inflamed intestinal and colonic mucosa in response to the dysregulated immune system. AREAS COVERED: The aim of this article is to review drugs that have been designed for the treatment of IBD and discontinued between 2009 and 2014. Herein, nine molecules with different mechanisms of action are under review. Brodalumab, daclizumab, elubrixin and vatelizumab were withdrawn from the Phase II trial due to the lack of efficacy. Abatacept was not significantly superior to the placebo in the rate of remission and its Phase III trials were stopped. CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively. Finally, NU-206 and alkaline phosphatase also ceased in development during Phase I and II tests. EXPERT OPINION: The development in our knowledge and understanding of the pathophysiology of IBD and the identification of key objectives for the future play significant roles in IBD therapeutic development. Furthermore, well-planned clinical trials with concise measures of efficacy and safety are required to better decide whether to extend or terminate the development process. Some anti-inflammatory cytokines such as IL-2, IL-12, IL-17, IL-18, IL-23 and INF-γ could garner more attention in the future.

Effectiveness of probiotics in irritable bowel syndrome: Updated systematic review with meta-analysis.

AIM: To investigate the efficacy of probiotics in irritable bowel syndrome (IBS) patients. METHODS: PubMed, Cochrane library, Scopus, Google Scholar, and Clinicaltrial.gov databases were searched for literature published between September 2007 and December 2013. The applied Mesh terms were "probiotics," "irritable bowel syndrome," and "irritable bowel syndrome treatment." The collected data contained24 clinical trials, of which 15 were eligible for meta-analysis and nine were reviewed systematically. All studies were randomized placebo-controlled trials in patients with IBS that investigated the efficacy of probiotics in IBS improvement. The Jadad score was used to assess the methodological quality of trials. The quality scale ranges from 0 to 5 points, with a score ≤ 2 indicating a low quality report, and a score of ≥ 3 indicating a high quality report. Relative risk (RR), standardized effect size, and 95%CI were calculated using the DerSimonian-Laird method. The Cochran Q test was used to test heterogeneity with P < 0.05. Funnel plots were constructed and Egger's and Begg-Mazumdar tests were performed to assess publication bias. RESULTS: A total of 1793 patients were included in the meta-analysis. The RR of responders to therapies based on abdominal pain score in IBS patients for two included trials comparing probiotics to placebo was 1.96 (95%CI: 1.14-3.36; P = 0.01). RR of responders to therapies based on a global symptom score in IBS patients for two included trials comparing probiotics with placebo was 2.43 (95%CI: 1.13-5.21; P = 0.02). For adequate improvement of general symptoms in IBS patients, the RR of seven included trials (six studies) comparing probiotics with placebo was 2.14 (95%CI: 1.08-4.26; P = 0.03). Distension, bloating, and flatulence were evaluated using an IBS severity scoring system in three trials (two studies) to compare the effect of probiotic therapy in IBS patients with placebo, the standardized effect size of mean differences for probiotics therapy was -2.57 (95%CI: -13.05--7.92). CONCLUSION: Probiotics reduce pain and symptom severity scores. The results demonstrate the beneficial effects of probiotics in IBS patients in comparison with placebo.

Efficacy and tolerability of renzapride in irritable bowel syndrome: a meta-analysis of randomized, controlled clinical trials including 2528 patients.

INTRODUCTION: By targeting different subtypes of 5-hydroxytryptamine (5HT) receptors in the gastrointestinal (GI) tract, several drugs have been introduced for the management of irritable bowel syndrome (IBS). Renzapride is a full agonist for 5HT4 receptor and an antagonist to 5HT2b and 5HT3 receptors which is thought a promising therapeutic agent for constipation predominant IBS (C-IBS) patients due to its accelerating effect on the GI tract. In this meta-analysis, our aim was to evaluate the efficacy and tolerability of renzapride in the management of IBS. MATERIAL AND METHODS: A search was done from 1992 to February 2013 for placebo-controlled trials that investigated the efficacy of renzapride in IBS. RESULTS: Relative risk (RR) for clinical efficacy in IBS patients treated for 5 weeks or less comparing renzapride to placebo was 1.07 (95% CI = 0.89-1.29, p = 0.38). This value for IBS patients treated for more than 5 weeks was 1.04 (95% CI = 0.78-1.239, p = 0.77). The RR for clinical efficacy in IBS patients treated with renzapride (4 mg) for 5 weeks or less and more than 5 weeks in comparison to placebo was 1.2 (95% CI = 0.97-1.48, p = 0.1) and 1.16 (95% CI = 0.98-1.37, p = 0.08), respectively, which were statistically non-significant but clinically important. The analysis of tolerability demonstrated that amongst different reported adverse effects, renzapride caused diarrhea more than placebo (RR = 1.61 with a 95% CI = 1.16-2.24, p = 0.004). The RR for withdrawals from renzapride compared to placebo was 1.58 (95% CI = 1.26-2.07, p = 0.0007). CONCLUSIONS: Renzapride is not superior to placebo in relieving IBS symptoms and causes significant incidences of diarrhea and drop-outs due to adverse effects in treated patients vs. placebo. Thus, this medicine might be a cost burden to patients without providing good effectiveness.

The safety of novel drugs used to treat irritable bowel syndrome.

INTRODUCTION: Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder with a high prevalence. Besides efficacy, the safety of each drugs used to treat GI disorders is an important issue in the drug development process. AREAS COVERED: This article reviews all Phase I to IV clinical trials or case reports with results related to the safety of novel GI drugs. The drugs are currently approved or under evaluation for approval. EXPERT OPINION: Most of the reported adverse events were related to the GI tract with mild-to-moderate severity. Diarrhea was significantly higher versus placebo following use of linaclotide and renzapride, similar to that of constipation with ramosetron. Lubiprostone, linaclotide and rifaximin with low systemic bioavailability have less adverse events and exert more advantageous results. Asimadoline acts peripherally on κ-opioid receptors and is not associated with CNS side effects. As lubiprostone and linaclotide cause dose-dependent adverse events, starting the treatment with the lowest effective doses is advised. Ramosetron is under evaluation for diarrhea-predominant IBS due to its acceptable safety and tolerability, besides its efficacy. Rifaximin, asimadoline and renzapride are still in need of more long-term studies regarding their safety.

Phase II drugs under clinical investigation for the treatment of chronic constipation.

INTRODUCTION: Chronic constipation (CC) is a common gastrointestinal (GI) motility disorder that significantly impairs the quality of life in affected subjects. As almost half of the patients suffering from CC are not satisfied with currently available medicines, there is a need to develop new molecules with better effectiveness and tolerability. AREAS COVERED: The authors include all experimental and clinical trials (up to Phase II) about new investigational drugs for the treatment of CC. The article identifies nine new agents: mitemcinal, TD-8954, YKP10811, itopride, RM-131, KWA-0711, elobixibat, velusetrag, and naronapride. All nine agents have shown prokinetic effects in different stages of the development. The mechanisms of new developing drugs include: the activation of 5-hydroxytryptamine type-4 (5-HT4), ghrelin and motilin receptors, antagonizing dopamine type-2 (D2) receptors, inhibition of ileal bile acid reabsorption and acetylcholine esterase, as well as water absorption from the GI tract. EXPERT OPINION: At this current point in time, new generations of 5-HT4 receptor agonists (velusetrag, noranopride and YKP10811) are hoped to progress, further in the future, due to better efficiency and safety. However, it is not possible to make a concise conclusion at this current time due to a lack of evidence. Further clinical trials with a longer duration and a larger sample size are warranted.

A systematic review of the safety of probiotics.

INTRODUCTION: There is growing evidence on the use of probiotics in various diseases, especially in gastrointestinal (GI) diseases. Although probiotics have been found helpful in many illnesses, they do not always seem to be safe. Through interference with commensal microflora, they can result in opportunistic performances in the host due to bacterimia and fungemia. Since considerable numbers of consumers use probiotic products worldwide, assurance of safety of these products is necessary. AREAS COVERED: This review evaluates all the existing information about the safety of probiotics in humans and animal models up to May 2013. In all eligible published studies in which adverse effects and tolerability of probiotics were investigated and reported, no language limitations were applied. The main key search terms were 'probiotics,' 'safety,' 'side effects,' 'clinical trial' and 'adverse effects.' The vast majority of trials investigated Bifidobacterium (B) and Lactobacillus (L) species. EXPERT OPINION: The main observed adverse effects of probiotics were sepsis, fungemia and GI ischemia. Generally, critically ill patients in intensive care units, critically sick infants, postoperative and hospitalized patients and patients with immune-compromised complexity were the most at-risk populations. While the overwhelming existing evidence suggests that probiotics are safe, complete consideration of risk-benefit ratio before prescribing is recommended.

New biologic therapeutics for ulcerative colitis and Crohn's disease.

INTRODUCTION: Some inflammatory bowel disease (IBD) patients especially those with refractory Crohn's disease (CD) or relapsing ulcerative colitis (UC) do not respond to current therapies. The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements. AREAS COVERED: In 46 included randomized, placebo-controlled clinical trials, the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients. Current investigated drugs include new anti-TNF drugs (adalimumab, certolizumab pegol, etanercept, onercept and golimumab), anti-CD20 (rituximab), T-cell inhibitors (abatacept) and anti-α4 integrins (natalizumab and vedolizumab). Adalimumab, certolizumab, and golimumab showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials. Natalizumab and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients. However, vedolizumab caused less adverse effects than natalizumab. onercept, etanercept, rituximab and abatacept were all well tolerated but were not effective in CD or UC patients. EXPERT OPINION: Anti-TNF drugs, except for onercept and etanercept, and anti-α4 integrins exhibit beneficial therapeutic effects. Although they were all well tolerated, the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed.

Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis.

AIM: To investigate the beneficial effect of the combination of butyrate, Lactobacillus casei, and L-carnitine in a rat colitis model. METHODS: Rats were divided into seven groups. Four groups received oral butyrate, L-carnitine, Lactobacillus casei and the combination of three agents for 10 consecutive days. The remaining groups included negative and positive controls and a sham group. Macroscopic, histopathological examinations, and biomarkers such as tumor necrosis factor-alpha (TNF-α) and interlukin-1ß (IL-1ß), myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), and ferric reduced ability of plasma (FRAP) were determined in the colon. RESULTS: The combination therapy exhibited a significant beneficial effect in alleviation of colitis compared to controls. Overall changes in reduction of TNF-α (114.66 ± 18.26 vs 171.78 ± 9.48 pg/mg protein, P < 0.05), IL-1ß (24.9 ± 1.07 vs 33.06 ± 2.16 pg/mg protein, P < 0.05), TBARS (0.2 ± 0.03 vs 0.49 ± 0.04 µg/mg protein, P < 0.01), MPO (15.32 ± 0.4 vs 27.24 ± 3.84 U/mg protein, P < 0.05), and elevation of FRAP (23.46 ± 1.2 vs 15.02 ± 2.37 µmol/L, P < 0.05) support the preference of the combination therapy in comparison to controls. Although the monotherapies were also effective in improvement of colitis markers, the combination therapy was much better in improvement of colon oxidative stress markers including FRAP, TBARS, and MPO. CONCLUSION: The present combination is a suitable mixture in control of experimental colitis and should be trialed in the clinical setting.

Metabolic and toxicological considerations for the latest drugs used to treat irritable bowel syndrome.

INTRODUCTION: The high prevalence of irritable bowel syndrome (IBS), a chronic gastrointestinal (GI) disorder, its lack of satisfactory effective drugs and its complicated pathophysiology lead to the demand of new therapeutic agents. During a new drug development process, the pharmacokinetic profiling is of a great considerable importance comparable to drug's efficacy. This involves the drug's absorption, distribution, metabolism and excretion, all of which are crucial to its usefulness. In addition, the toxicological profile and possible adverse reactions of the drug should be identified. Also its interactions should be identified at different phases of trials. Several pharmacokinetic studies are carried out to achieve drugs with the best absorption and bioavailability and the least adverse effects and lowest toxicity. AREAS COVERED: To make an update on new clinically introduced drugs for IBS and their dynamics and kinetics data, the present systematic review was accomplished. All relevant bibliographic databases were searched from the year 2003 up to May 2012 to identify all clinical trials that evaluated the potential efficacy of a novel agent in IBS. EXPERT OPINION: Some evaluated drugs, such as ramosetron (5-HT3 antagonist) and pexacerfont (CRF1 receptor antagonist), have shown some benefits in diarrhea-predominant IBS (D-IBS), while, prucalopride and mosapride (5-HT4 agonist) with prokinetic effect were found useful in constipation-predominant IBS (C-IBS). Besides, dexloxiglumide, lubiprostone and linaclotide have shown beneficial effects in C-IBS patients. Melatonin regulates GI tract motility and, asimadoline, gabapentin and pregabalin show reduction of pain threshold and visceral hypersensitivity. Glucagon-like peptide analog, calcium-channel blockers and neurokinin receptor antagonists have shown benefits in pain attacks. More time is required to indicate both efficacy and safety in long-term treatment due to multifactorial pathophysiology, variations in individual responses and insufficient assessment methods, which limit the right decision-making process about the efficacy and tolerability of these new drugs.

Benefit of Aloe vera and Matricaria recutita mixture in rat irritable bowel syndrome: Combination of antioxidant and spasmolytic effects.

OBJECTIVE: To evaluate the beneficial effects of a mixture of Aloe vera (AV) and Matricaria recutita (German chamomile, GC) in an experimental model of irritable bowel syndrome (IBS). METHODS: IBS was induced by a 5-day restraint stress in rats including the groups of control (water), GC (300 mg/kg), loperamide (10 mg/kg), mixed AV and GC (50: 50 at doses of 150, 300 or 450 mg/kg assigned as Mix-150, Mix-300 and Mix-450, respectively) and the sham group which did not receive any restraint stress and was fed with saline. All medications were administered intragastrically by gavage for 7 days, 2 days as pre-treatment followed by 5 days during induction of IBS every day before restraining. RESULTS: The increased tumor necrosis factor alpha (TNF-α), myeloperoxidase (MPO) activity, and lipid peroxidation (LPO) in colonic cells in the control group were significantly decreased in the treatment groups. GC inhibited only small bowel transit while the AV/GC mixture delayed gastric emptying at the doses of 150 and 300 mg/kg. The AV/GC mixture also reduced colonic transit and small bowel transit at the dose of 150 mg/kg. CONCLUSIONS: The severity of stress-induced IBS was diminished by the AV/GC mixture at all doses used but not dose-dependently, via inhibiting colonic MPO activity and improving oxidative stress status. The effect of the mixture was more effective than GC alone. The present results support effectiveness of the AV and GC combination in IBS.

Melatonin, a promising supplement in inflammatory bowel disease: a comprehensive review of evidences.

Inflammation and oxidative process are associated with inflammatory bowel disease (IBD). Regarding anti-inflammatory and antioxidant potentials, melatonin has been found beneficial in several experimental and clinical studies including inflammatory bowel disease (IBD). Our objective in this study is to review and evaluate all non-clinical and clinical studies on the efficacy of melatonin in IBD. All indexing databases were searched for inflammatory bowel disease' and 'melatonin' keywords, without time limit up to May 2011. Three clinical trials and fifteen non-clinical studies are reviewed and analyzed. The majority of these studies indicate that melatonin has a positive impact on IBD with no or negligible side effects. Such results have been mostly explained through free radical scavenging and diminishing inflammation. It is yet crucial to determine the efficacy of melatonin in combination with other established drugs in more clinical trials, not only for further confirmation of its efficacy, but also to investigate its possible side effects in longer durations of therapy.