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Visceral hypersensitivity in irritable bowel syndrome: evidence for involvement of serotonin metabolism--a preliminary study.
Keszthelyi, D, Troost, FJ, Jonkers, DM, van Eijk, HM, Dekker, J, Buurman, WA, Masclee, AA
Neurogastroenterology and motility. 2015;(8):1127-37
Abstract
BACKGROUND Altered serotonergic (5-HT) metabolism and visceral perception have been associated with the pathogenesis of irritable bowel syndrome (IBS). Aim of this preliminary study was to assess the effect of the direct precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on systemic 5-HT metabolites and visceral perception and to assess potential differential responses between IBS and controls. METHODS 15 IBS patients and 15 healthy volunteers participated in this randomized double-blind placebo controlled study. Visceroperception was measured by rectal barostat. The 100 mg 5-HTP or placebo was ingested orally. Serotonergic metabolites were assessed in platelet poor plasma. KEY RESULTS 5-HTP induces rectal allodynia in a significant number of healthy controls; IBS patients exhibit lowered pain thresholds in both placebo and 5-HTP conditions. 5-HTP induces rectal hyperalgesia in hypersensitive but not in non-hypersensitive IBS patients. Administration of 5-HTP significantly increased plasma 5-HTP levels (p < 0.001), did not affect 5-HT levels (p > 0.05), while levels of the main metabolite of 5-HT, 5-hydroxyindoleacetic acid, increased significantly (p < 0.05) in both groups. The magnitude of these changes observed in 5-HT metabolites was significantly greater in IBS patients. CONCLUSIONS & INFERENCES Oral administration of 5-HTP induced significant alterations in systemic 5-HT metabolites that were accompanied by increased visceroperception of pain in controls and hypersensitive IBS patients. Changes in 5-HT metabolism appear to be important factors involved in visceral hypersensitivity as the 5-HTP-induced pro-nociceptive response was observed in all hypersensitive IBS patients and to a lesser magnitude in a significant number of healthy controls but in none of the non-hypersensitive IBS patients.
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Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.
Keszthelyi, D, Troost, FJ, Jonkers, DM, van Eijk, HM, Lindsey, PJ, Dekker, J, Buurman, WA, Masclee, AA
Alimentary pharmacology & therapeutics. 2014;(4):392-402
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Abstract
BACKGROUND Alterations in serotonergic (5-HT) metabolism and/or intestinal integrity have been associated with irritable bowel syndrome (IBS). AIMS To assess the effects of the precursor of 5-HT, 5-hydroxytryptophan (5-HTP), on mucosal 5-HT availability and intestinal integrity, and to assess potential differences between healthy controls and IBS patients. METHODS Fifteen IBS patients and 15 healthy volunteers participated in this randomised double-blind placebo-controlled study. Intestinal integrity was assessed by dual-sugar test and by determining the mucosal expression of tight junction proteins after ingestion of an oral bolus of 100 mg 5-HTP or placebo. Mucosal serotonergic metabolism was assessed in duodenal biopsy samples. RESULTS 5-HTP administration significantly increased mucosal levels of 5-HIAA, the main metabolite of 5-HT, in both healthy controls (7.1 ± 1.7 vs. 2.5 ± 0.7 pmol/mg, 5-HTP vs. placebo, P = 0.02) and IBS patients (20.0 ± 4.8 vs. 8.1 ± 1.3 pmol/mg, 5-HTP vs. placebo, P = 0.02), with the latter group showing a significantly larger increase. Lactulose/L-rhamnose ratios were significantly lower after administration of 5-HTP (P < 0.05) in healthy controls and were accompanied by redistribution of zonula occludens-1 (ZO-1), pointing to reinforcement of the barrier. In IBS, expression of the tight junction proteins was significantly lower compared to healthy controls, and 5-HTP resulted in a further decrease in occludin expression. CONCLUSIONS Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.
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Clinical features and pharmacotherapy of childhood monoamine neurotransmitter disorders.
Ng, J, Heales, SJ, Kurian, MA
Paediatric drugs. 2014;(4):275-91
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Abstract
Childhood neurotransmitter disorders are increasingly recognised as an expanding group of inherited neurometabolic syndromes. They are caused by disturbance in synthesis, metabolism, and homeostasis of the monoamine neurotransmitters, including the catecholamines (dopamine, norepinephrine, and epinephrine) and serotonin. Disturbances in monoamine neurotransmission will lead to neurological symptoms that often overlap with clinical features of other childhood neurological disorders (such as hypoxic ischaemic encephalopathy, cerebral palsy, other movement disorders, and paroxysmal conditions); consequently, neurotransmitter disorders are frequently misdiagnosed. The diagnosis of neurotransmitter disorders is made through detailed clinical assessment, analysis of cerebrospinal fluid neurotransmitters, and further supportive diagnostic investigations. Early and accurate diagnosis of neurotransmitter disorders is important, as many are amenable to therapeutic intervention. The principles of treatment for monoamine neurotransmitter disorders are mainly directly derived from understanding these metabolic pathways. In disorders characterized by enzyme deficiency, we aim to increase monoamine substrate availability, boost enzyme co-factor levels, reduce monoamine breakdown, and replace depleted levels of monoamines with pharmacological analogs as clinically indicated. Most monoamine neurotransmitter disorders lead to reduced levels of central dopamine and/or serotonin. Complete amelioration of motor symptoms is achievable in some disorders, such as Segawa's syndrome, and, in other conditions, significant improvement in quality of life can be attained with pharmacotherapy. In this review, we provide an overview of the clinical features and current treatment strategies for childhood monoamine neurotransmitter disorders.
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Increased serum free tryptophan in patients with diarrhea-predominant irritable bowel syndrome.
Christmas, DM, Badawy, AA, Hince, D, Davies, SJ, Probert, C, Creed, T, Smithson, J, Afzal, M, Nutt, DJ, Potokar, JP
Nutrition research (New York, N.Y.). 2010;(10):678-88
Abstract
Irregularities of serotonin function in irritable bowel syndrome (IBS) may be due to changes in the metabolism of the serotonin precursor l-tryptophan. Dietary alteration of tryptophan intake may impact upon the mood and bowel symptoms of IBS. We hypothesized that diarrhea-predominant irritable bowel syndrome (d-IBS) patients would exhibit an increase in plasma tryptophan due to alterations in tryptophan metabolism. We also hypothesized that a diet low in tryptophan would reverse this change and reduce symptoms. Thirteen patients with d-IBS had fasting serum free and total tryptophan, large neutral amino acids, and 6 kynurenine metabolites measured before and after 2 weeks of a strict dairy-free diet. Baseline tryptophan parameters were compared with an age- and sex-matched control group. Changes in the specific tryptophan parameters before and after dairy-free diet were correlated with symptoms of IBS and mood. Compared with the control group, d-IBS patients at baseline exhibited significantly higher free serum tryptophan (10.5 ± 4.35 vs 4.75 ± 2.43 μmol/L [means ± standard deviation], P = .006) and significantly lower tryptophan dioxygenase and total tryptophan oxidation as measured by the kynurenine to free tryptophan and total kynurenines to free tryptophan ratios (23.37 ± 10.12 vs 55.33 ± 16.02, P < .001 and 49.34 ± 17.84 vs 258.46 ± 98.67, P < .001, respectively). Dairy-free diet did not modulate metabolites of the kynurenine pathway or symptoms. Tryptophan metabolism along the kynurenine pathway is inhibited in d-IBS, and a dairy-free diet does not alter this. Our findings are consistent with possible enhanced serotonin activity in d-IBS.
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Effects of doxazosin and amlodipine on mean platelet volume and serum serotonin level in patients with metabolic syndrome: a randomised, controlled study.
Demirtunc, R, Duman, D, Basar, M
Clinical drug investigation. 2007;(6):435-41
Abstract
BACKGROUND AND OBJECTIVE In addition to reducing blood pressure, antihypertensive drugs should modify other atherosclerotic risk factors. One such risk factor is the prothrombotic state, which is characterised mainly by increased fibrinogen and plasminogen activator inhibitor-1 levels and abnormalities in platelet function. Platelet activity and aggregation potential can be estimated by measuring mean platelet volume (MPV). Serotonin plays a role in vasospasm and increased platelet aggregation capacity, and has been shown to increase MPV in vitro. However, serotonin levels and MPV have not been studied in the metabolic syndrome. We evaluated mean platelet volume (MPV) in patients with the metabolic syndrome, and compared the effects of doxazosin and amlodipine on MPV and serum serotonin level in patients with this condition. METHODS Thirty-eight patients who met the Adult Treatment Panel III criteria for the metabolic syndrome and 20 healthy controls were included in the study. Patients were randomised into two groups to receive doxazosin 4 mg/day (n=20) or amlodipine 10 mg/day (n=18). Patients' MPV, serum serotonin, insulin, insulin sensitivity, fasting blood glucose and lipid profiles were measured at baseline and after 8 weeks. RESULTS Patients with the metabolic syndrome had a significantly higher MPV compared with the control group. MPV was significantly decreased in the doxazosin-treated group (from 6.9 +/- 1.0 fL at baseline to 6.1 +/- 1.1 fL after treatment; p=0.02) but not in the amlodipine-treated group (6.8 +/- 0.9 fL at baseline vs 6.9 +/- 1.0 fL after treatment; p=0.9). Fasting blood glucose and total cholesterol were also significantly decreased compared with baseline in the doxazosin group. In the amlodipine group, there was a significant increase in serum serotonin levels and a decrease in serum insulin and improved insulin sensitivity. CONCLUSION In patients with the metabolic syndrome, doxazosin treatment not only decreases platelet activity, as measured by a change in MPV, but also improves metabolic abnormalities. Amlodipine also has beneficial effects in patients with the metabolic syndrome but has no effect on MPV.