Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients

Wolfe, Steven G.; Chey, William Y.; Washington, Mary Kay; Harding, Jacqueline; Heath, Amy; McSorley, David; Dukes, George E.; Hunt, Christine M.

doi:10.1016/s0002-9270(00)02419-9

Cited by 8 publications

(7 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…70 These agents, however, including alosetron and cilansetron, have fallen short of licensing approval because of dose-limiting adverse effects that include severe constipation and ischemic colitis. In particular, as well as reducing visceral pain in patients with IBS, 71 alosetron also decreases activity in various limbic structures in response to colorectal distension, which may in part explain its analgesic efficacy. This is noteworthy, because abnormal activity in higher brain, midbrain, and brainstem circuits that sort and merge the sensory, contextual, and emotional components of pain may potentially explain some diffuse pain states, including IBS and fibromyalgia syndrome (FMS), a disorder associated with tenderness and pain in all quadrants of the body.…”

Section: -Ht Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

View full text Add to dashboard Cite

Summary:The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent ␣ 2 -adrenoceptor-mediated inhibitory system and 5-HT 3 (and likely also 5-HT 2 ) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control. Key Words: 5-HT receptors, 5-HT, serotonin, noradrenaline, RVM, rostral ventromedial medulla, opioidinduced hyperalgesia, neuropathy, fibromyalgia. PAIN, COMORBIDITIES, AND MONOAMINESPain and mood share certain neurological pathways in the CNS and have overlapping neurochemical bases, in particular their modulation by monoamine systems. This provides the substrate through which pain can influence mood, giving rise to comorbidities or secondary symptoms such as anxiety and depression, 1,2 and by the same continuum allows mood to exacerbate pain; indeed, patients with depression often present with symptoms that include medically unexplained pain, with the mean prevalence of such occurrence cited as 65%.1,3 Emotional facets of nociception play a significant role in the pain experience, with fear largely driving adaptive behaviors that enable avoidance of actual or impending harm. This therefore subserves the key function of pain, to protect the integrity and survival of an organism. Moreover, the role of emotions and state of mind in pain partly underlie the variable relationship between the intensity of damaging stimuli and perceived pain, such that at any given time and for any given nociceptive stimulus, painful response can be influenced by emotional state (the psychological context in which the stimulus is received), emotional trait (the psychological characteristics of the recipient), and cognitive set (attention and vigilance, for example).Depression is associated with abnormalities in the monoaminergic ...

show abstract

Section: -Ht Function In Different Pain Statesmentioning

confidence: 99%

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

2009

View full text Add to dashboard Cite

show abstract

“…Women made up approximately 84% of the overall clinical trial population 66–78. The diagnosis of IBS in these investigations was based on Rome I66–69,71,72,74,76 or Rome II70,73,75,77,78 criteria. Three of the more recent studies included women with nonconstipated IBS, IBS-D, or severe IBS-D,73,75,77,78 reflecting patient populations that are more consistent with the use of alosetron in the clinical practice setting 79…”

Section: Resultsmentioning

confidence: 99%

Targeted therapies for diarrhea-predominant irritable bowel syndrome

Olden¹

2012

CEG

View full text Add to dashboard Cite

Irritable bowel syndrome (IBS) causes gastrointestinal symptoms such as abdominal pain, bloating, and bowel pattern abnormalities, which compromise patients’ daily functioning. Common therapies address one or two IBS symptoms, while others offer wider symptom control, presumably by targeting pathophysiologic mechanisms of IBS. The aim of this targeted literature review was to capture clinical trial reports of agents receiving the highest recommendation (Grade 1) for treatment of IBS from the 2009 American College of Gastroenterology IBS Task Force, with an emphasis on diarrhea-predominant IBS. Literature searches in PubMed captured articles detailing randomized placebo-controlled trials in IBS/diarrhea-predominant IBS for agents receiving Grade I (strong) 2009 American College of Gastroenterology IBS Task Force recommendations: tricyclic antidepressants, nonabsorbable antibiotics, and the 5-HT3 receptor antagonist alosetron. Studies specific for constipation-predominant IBS were excluded. Tricyclic antidepressants appear to improve global IBS symptoms but have variable effects on abdominal pain and uncertain tolerability; effects on stool consistency, frequency, and urgency were not adequately assessed. Nonabsorbable antibiotics show positive effects on global symptoms, abdominal pain, bloating, and stool consistency but may be most efficacious in patients with altered intestinal microbiota. Alosetron improves global symptoms and abdominal pain and normalizes bowel irregularities, including stool frequency, consistency, and fecal urgency. Both the nonabsorbable antibiotic rifaximin and the 5-HT3 receptor antagonist alosetron improve quality of life. Targeted therapies provide more complete relief of IBS symptoms than conventional agents. Familiarization with the quantity and quality of evidence of effectiveness can facilitate more individualized treatment plans for patients with this heterogeneous disorder.

show abstract

“…This compound had an anti-diarrhoeal effect and was indicated for diarrhoea-predominant IBS 28 ; it soon became apparent that constipation was a real problem, no doubt a consequence of its administration to patients who described 'diarrhoea' but who were not, in reality, so afflicted. 29 It is to be hoped that the new Rome criteria, based on stool consistency, may lead the way to more pathophysiologically appropriate therapies.…”

Section: Getting the Words Right And The Right Wordsmentioning

confidence: 99%

The language of medicine: words as servants and scoundrels

Quigley

Shanahan

2009

Clinical Medicine

View full text Add to dashboard Cite

-Progress in complex disorders requires clear thinking facilitated by clear language. Clinicians and scientists occasionally become captive to inaccurate language or meaningless terminology and this generates lazy thinking and impedes progress. Has this happened in the case of the functional gastrointestinal disorders (FGIDs), in general, and irritable bowel syndrome (IBS), in particular? FGIDs and, especially IBS, are common illnesses and an important burden on healthcare resources but, in general, have suffered from a lack of progress in the development of safe and effective treatment. Among FGIDs, IBS may be the best defined but significant lapses of accuracy in terminology persist. Among other FGIDs, the situation is more serious; imprecision and lack of consistency in terminology continue to mar progress. This article reviews the chequered history of terminology in this area and concludes that removing the obfuscation generated by poor usage of language should be the first step towards understanding the pathogenesis and improving the management of these, and similar, disorders. KEY WORDS: functional dyspepsia, functional gastrointestinal disorders, inflammation, irritable bowel syndromeThe perils of phraseology Understanding complex disorders requires attention to detail and the precise expression of research questions. Nevertheless, clinicians frequently use terms that they actually do not understand or assume they understand but have never actually questioned. Mere repetition of an incorrect concept or inappropriate term seems sufficient to result in its widespread acceptance as dogma and received wisdom, especially if, in the words of Schopenhauer, one 'constantly repeats it with an air of great solemnity' . Thomas Paine encapsulated the dangers of such unquestioned repetition: 'A long habit of not thinking a thing wrong, gives it a superficial appearance of being right'. For example, in a study of physicians' practices and approaches to the surveillance of colonic dysplasia in ulcerative colitis, it was found that the majority of gastroenterologists did not understand the meaning of the word 'dysplasia' , even though they used it on a daily basis. 1 While such deficits adversely affect decision making at an individual level, a more global problem is the corruption of medical language to a degree that may confound thinking on clinical guidelines and even healthcare policy. As one moves from disorders which have a clearly defined molecular and/or pathological basis towards those where a precise pathophysiology remains elusive, imprecision in terminology becomes more prevalent. The functional gastrointestinal disorders (FGIDs), and irritable bowel syndrome (IBS) in particular, represent an important illustrative example. Irritable bowel syndromeWith an estimated community prevalence of 10-15%, IBS can certainly be regarded as a common disorder. 2 IBS is chronic and has a significant impact on quality of life. It affects young people in a productive phase of life, is a cause of work absenteeism and...

show abstract

Tolerability and safety of alosetron during long-term administration in female and male irritable bowel syndrome patients

Abstract: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Cited by 8 publications

References 0 publications

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Preclinical and Early Clinical Investigations Related to Monoaminergic Pain Modulation

Targeted therapies for diarrhea-predominant irritable bowel syndrome

The language of medicine: words as servants and scoundrels

Contact Info

Product

Resources

About