Amy Schonfeld

NEW YORK – Targeted inhibition of tyrosine kinases with the use of imatinib mesylate is one of the most promising new areas of therapy for scleroderma, according to Dr. Jonathan Kay, who gave a “Year in Review” update on scleroderma therapy at the meeting.

“We know that imatinib mesylate reduces bone marrow fibrosis in patients with chronic myelogenous leukemia, the disease for which it is indicated and FDA [Food and Drug Administration] approved,” said Dr. Kay, who is director of clinical research in the rheumatology division at the University of Massachusetts, Worcester. “It also strongly inhibits transcription and translation of extracellular matrix proteins by dermal fibroblasts.”

Dr. Kay described the results of a study published online (Ann. Rheum. Dis. 2011;70:1003-9).

In this phase IIa, open-label, single-arm clinical trial, 30 patients with diffuse cutaneous systemic sclerosis (dcSSc) were treated with imatinib 400 mg daily and monitored monthly, making it the largest prospective trial of imatinib in dcSSC reported to date. Twenty-four patients completed a year of imatinib therapy. Patients were stratified according to disease duration, with 20 in the early-disease group (time of onset of first symptom less than 4 years) and 10 in the later-disease group (time of onset of first symptom 4–10 years).

To assess cutaneous symptoms, the investigators used the modified Rodnan skin score (MRSS), a standard outcome measure of skin disease in systemic sclerosis, which is calculated by summation of skin tethering scores at 17 different body sites. Over the 12-month treatment, the MRSS decreased by 22.4%. Significant changes were noted within 6 months of treatment. Similar improvements were noted regardless of the stage of the disease.

Blinded dermatopathologic analysis showed that the median skin thickness decreased significantly with treatment. Before treatment, the skin specimens exhibited changes characteristic of scleroderma, including thick and hyalinized collagen bundles with decreased interstitial spaces. After treatment, 7 of 10 specimens showed a qualitative decrease in the thickness of collagen bundles and an increase in interstitial spaces. Significant increases in the number of hair follicles and eccrine glands were also noted. Dermatopathologic changes correlated with MRSS scores.

Lung function, as assessed by forced vital capacity, improved significantly over the course of the year. When patients were divided into those in whom interstitial lung disease (ILD) was present or absent, significant improvements were observed only in those without ILD (mean increase 10.7%) compared to those with ILD (mean increase 2.1%).

Treatment with imatinib also led to improvements in patient-reported and physician-reported quality of life measures, such as the visual analog scale (VAS) global, VAS shortness of breath, VAS pain, mental component of Short Form-36 Health Survey, and physician global assessment.

Eighty percent of the patients were able to complete the trial, although 83% required a dose adjustment. The median imatinib dose taken was 300 mg daily. A total of 171 adverse events were reported possibly, probably, or definitely related to imatinib, and 97.6% were grade 1 or 2. The most common side effects were edema (80%), nausea (73%), and myalgia (67%), but these were felt to be manageable and tolerable. There were 24 serious adverse events.

One patient with severe ILD and pulmonary artery hypertension died, but this was not believed to be medication related. One patient was repeatedly hospitalized for hemorrhagic cystitis, which was thought to be due to a preexisting condition. While cardiac toxicity is a general concern with imatinib treatment, two patients developed cardiac issues that were not thought to be imatinib related.

Dr. Kay pointed out that because this was an open-label study, the findings cannot be definitively attributed to effects of the medication. “Results have been promising with the use of tyrosine kinase inhibitors to treat fibrosing conditions such as nephrogenic systemic fibrosis and scleroderma, but we need randomized, double-blind controlled trials,” he said.

Dr. Kay has demonstrated a rapid response to imatinib in two patients with nephrogenic systemic fibrosis, a disabling condition cause by gadolinium that is characterized by rapidly progressing fibrosis (Arthritis Rheum. 2008;58:2543-8). He suggested that imatinib may work best for conditions that are predominantly proliferative rather than inflammatory.

Dr. Kay also reviewed other notable recent publications on scleroderma and fibrosis. Bosentan is a dual endothelin receptor antagonist, which is FDA-approved for the treatment of pulmonary arterial hypertension. A randomized controlled trial (RCT) on the use of bosentan for scleroderma indicated that the agent may be a useful adjunct for the treatment of scleroderma digital ulcers (Ann. Rheum. Dis. 2011;70:32-8).

The study showed that bosentan reduced the occurrence of new digital ulcers but had no effect on digital ulcer healing. Data from another study (Arthritis Rheum. 2010;62:2101-8) do not support bosentan as therapy for interstitial lung disease due to scleroderma.

An RCT published online evaluated methotrexate in a group of 85 children with active juvenile localized scleroderma, and found it to be effective and well tolerated (Arthritis Rheum. 2011 [doi:10.1002/art.30264]).

Over a 12-month period, infrared thermography of target lesions showed significant benefits from methotrexate treatment, beginning at 9 months. The proportion of patients without disease flare was significantly higher among those treated with methotrexate, but the number of patients with new lesions did not differ between the two groups. Many of the side effects were attributed to concomitant corticosteroids, which were withdrawn after 3 months.

Dr. Kay also described the results of a 1-year RCT of rituximab in 14 scleroderma patients (Rheumatology 2010;49:271-80). Eight patients received rituximab according to the lymphoma regimen (2 cycles of rituximab 375 mg/m

Dr. Kay is a consultant to Array BioPharma, Bristol-Myers Squibb, Centocor Ortho-Biotech Inc., Eisai Research Institute, Genentech, Johnson & Johnson, Mallinckrodt, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, and UCB. He receives research funding from Roche and Sanofi-Aventis.

In one study of 30 patients, treatment with imatinib led to improvements in several quality of life measures.

Source DR. KAY

NEW YORK – Targeted inhibition of tyrosine kinases with the use of imatinib mesylate is one of the most promising new areas of therapy for scleroderma, according to Dr. Jonathan Kay, who gave a “Year in Review” update on scleroderma therapy at the meeting.

“We know that imatinib mesylate reduces bone marrow fibrosis in patients with chronic myelogenous leukemia, the disease for which it is indicated and FDA [Food and Drug Administration] approved,” said Dr. Kay, who is director of clinical research in the rheumatology division at the University of Massachusetts, Worcester. “It also strongly inhibits transcription and translation of extracellular matrix proteins by dermal fibroblasts.”

Dr. Kay described the results of a study published online (Ann. Rheum. Dis. 2011;70:1003-9).

In this phase IIa, open-label, single-arm clinical trial, 30 patients with diffuse cutaneous systemic sclerosis (dcSSc) were treated with imatinib 400 mg daily and monitored monthly, making it the largest prospective trial of imatinib in dcSSC reported to date. Twenty-four patients completed a year of imatinib therapy. Patients were stratified according to disease duration, with 20 in the early-disease group (time of onset of first symptom less than 4 years) and 10 in the later-disease group (time of onset of first symptom 4–10 years).

To assess cutaneous symptoms, the investigators used the modified Rodnan skin score (MRSS), a standard outcome measure of skin disease in systemic sclerosis, which is calculated by summation of skin tethering scores at 17 different body sites. Over the 12-month treatment, the MRSS decreased by 22.4%. Significant changes were noted within 6 months of treatment. Similar improvements were noted regardless of the stage of the disease.

Blinded dermatopathologic analysis showed that the median skin thickness decreased significantly with treatment. Before treatment, the skin specimens exhibited changes characteristic of scleroderma, including thick and hyalinized collagen bundles with decreased interstitial spaces. After treatment, 7 of 10 specimens showed a qualitative decrease in the thickness of collagen bundles and an increase in interstitial spaces. Significant increases in the number of hair follicles and eccrine glands were also noted. Dermatopathologic changes correlated with MRSS scores.

Lung function, as assessed by forced vital capacity, improved significantly over the course of the year. When patients were divided into those in whom interstitial lung disease (ILD) was present or absent, significant improvements were observed only in those without ILD (mean increase 10.7%) compared to those with ILD (mean increase 2.1%).

Treatment with imatinib also led to improvements in patient-reported and physician-reported quality of life measures, such as the visual analog scale (VAS) global, VAS shortness of breath, VAS pain, mental component of Short Form-36 Health Survey, and physician global assessment.

Eighty percent of the patients were able to complete the trial, although 83% required a dose adjustment. The median imatinib dose taken was 300 mg daily. A total of 171 adverse events were reported possibly, probably, or definitely related to imatinib, and 97.6% were grade 1 or 2. The most common side effects were edema (80%), nausea (73%), and myalgia (67%), but these were felt to be manageable and tolerable. There were 24 serious adverse events.

One patient with severe ILD and pulmonary artery hypertension died, but this was not believed to be medication related. One patient was repeatedly hospitalized for hemorrhagic cystitis, which was thought to be due to a preexisting condition. While cardiac toxicity is a general concern with imatinib treatment, two patients developed cardiac issues that were not thought to be imatinib related.

Dr. Kay pointed out that because this was an open-label study, the findings cannot be definitively attributed to effects of the medication. “Results have been promising with the use of tyrosine kinase inhibitors to treat fibrosing conditions such as nephrogenic systemic fibrosis and scleroderma, but we need randomized, double-blind controlled trials,” he said.

Dr. Kay has demonstrated a rapid response to imatinib in two patients with nephrogenic systemic fibrosis, a disabling condition cause by gadolinium that is characterized by rapidly progressing fibrosis (Arthritis Rheum. 2008;58:2543-8). He suggested that imatinib may work best for conditions that are predominantly proliferative rather than inflammatory.

Dr. Kay also reviewed other notable recent publications on scleroderma and fibrosis. Bosentan is a dual endothelin receptor antagonist, which is FDA-approved for the treatment of pulmonary arterial hypertension. A randomized controlled trial (RCT) on the use of bosentan for scleroderma indicated that the agent may be a useful adjunct for the treatment of scleroderma digital ulcers (Ann. Rheum. Dis. 2011;70:32-8).

The study showed that bosentan reduced the occurrence of new digital ulcers but had no effect on digital ulcer healing. Data from another study (Arthritis Rheum. 2010;62:2101-8) do not support bosentan as therapy for interstitial lung disease due to scleroderma.

An RCT published online evaluated methotrexate in a group of 85 children with active juvenile localized scleroderma, and found it to be effective and well tolerated (Arthritis Rheum. 2011 [doi:10.1002/art.30264]).

Over a 12-month period, infrared thermography of target lesions showed significant benefits from methotrexate treatment, beginning at 9 months. The proportion of patients without disease flare was significantly higher among those treated with methotrexate, but the number of patients with new lesions did not differ between the two groups. Many of the side effects were attributed to concomitant corticosteroids, which were withdrawn after 3 months.

Dr. Kay also described the results of a 1-year RCT of rituximab in 14 scleroderma patients (Rheumatology 2010;49:271-80). Eight patients received rituximab according to the lymphoma regimen (2 cycles of rituximab 375 mg/m

Dr. Kay is a consultant to Array BioPharma, Bristol-Myers Squibb, Centocor Ortho-Biotech Inc., Eisai Research Institute, Genentech, Johnson & Johnson, Mallinckrodt, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, and UCB. He receives research funding from Roche and Sanofi-Aventis.

In one study of 30 patients, treatment with imatinib led to improvements in several quality of life measures.

Source DR. KAY

NEW YORK – Targeted inhibition of tyrosine kinases with the use of imatinib mesylate is one of the most promising new areas of therapy for scleroderma, according to Dr. Jonathan Kay, who gave a “Year in Review” update on scleroderma therapy at the meeting.

“We know that imatinib mesylate reduces bone marrow fibrosis in patients with chronic myelogenous leukemia, the disease for which it is indicated and FDA [Food and Drug Administration] approved,” said Dr. Kay, who is director of clinical research in the rheumatology division at the University of Massachusetts, Worcester. “It also strongly inhibits transcription and translation of extracellular matrix proteins by dermal fibroblasts.”

Dr. Kay described the results of a study published online (Ann. Rheum. Dis. 2011;70:1003-9).

In this phase IIa, open-label, single-arm clinical trial, 30 patients with diffuse cutaneous systemic sclerosis (dcSSc) were treated with imatinib 400 mg daily and monitored monthly, making it the largest prospective trial of imatinib in dcSSC reported to date. Twenty-four patients completed a year of imatinib therapy. Patients were stratified according to disease duration, with 20 in the early-disease group (time of onset of first symptom less than 4 years) and 10 in the later-disease group (time of onset of first symptom 4–10 years).

To assess cutaneous symptoms, the investigators used the modified Rodnan skin score (MRSS), a standard outcome measure of skin disease in systemic sclerosis, which is calculated by summation of skin tethering scores at 17 different body sites. Over the 12-month treatment, the MRSS decreased by 22.4%. Significant changes were noted within 6 months of treatment. Similar improvements were noted regardless of the stage of the disease.

Blinded dermatopathologic analysis showed that the median skin thickness decreased significantly with treatment. Before treatment, the skin specimens exhibited changes characteristic of scleroderma, including thick and hyalinized collagen bundles with decreased interstitial spaces. After treatment, 7 of 10 specimens showed a qualitative decrease in the thickness of collagen bundles and an increase in interstitial spaces. Significant increases in the number of hair follicles and eccrine glands were also noted. Dermatopathologic changes correlated with MRSS scores.

Lung function, as assessed by forced vital capacity, improved significantly over the course of the year. When patients were divided into those in whom interstitial lung disease (ILD) was present or absent, significant improvements were observed only in those without ILD (mean increase 10.7%) compared to those with ILD (mean increase 2.1%).

Treatment with imatinib also led to improvements in patient-reported and physician-reported quality of life measures, such as the visual analog scale (VAS) global, VAS shortness of breath, VAS pain, mental component of Short Form-36 Health Survey, and physician global assessment.

Eighty percent of the patients were able to complete the trial, although 83% required a dose adjustment. The median imatinib dose taken was 300 mg daily. A total of 171 adverse events were reported possibly, probably, or definitely related to imatinib, and 97.6% were grade 1 or 2. The most common side effects were edema (80%), nausea (73%), and myalgia (67%), but these were felt to be manageable and tolerable. There were 24 serious adverse events.

One patient with severe ILD and pulmonary artery hypertension died, but this was not believed to be medication related. One patient was repeatedly hospitalized for hemorrhagic cystitis, which was thought to be due to a preexisting condition. While cardiac toxicity is a general concern with imatinib treatment, two patients developed cardiac issues that were not thought to be imatinib related.

Dr. Kay pointed out that because this was an open-label study, the findings cannot be definitively attributed to effects of the medication. “Results have been promising with the use of tyrosine kinase inhibitors to treat fibrosing conditions such as nephrogenic systemic fibrosis and scleroderma, but we need randomized, double-blind controlled trials,” he said.

Dr. Kay has demonstrated a rapid response to imatinib in two patients with nephrogenic systemic fibrosis, a disabling condition cause by gadolinium that is characterized by rapidly progressing fibrosis (Arthritis Rheum. 2008;58:2543-8). He suggested that imatinib may work best for conditions that are predominantly proliferative rather than inflammatory.

Dr. Kay also reviewed other notable recent publications on scleroderma and fibrosis. Bosentan is a dual endothelin receptor antagonist, which is FDA-approved for the treatment of pulmonary arterial hypertension. A randomized controlled trial (RCT) on the use of bosentan for scleroderma indicated that the agent may be a useful adjunct for the treatment of scleroderma digital ulcers (Ann. Rheum. Dis. 2011;70:32-8).

The study showed that bosentan reduced the occurrence of new digital ulcers but had no effect on digital ulcer healing. Data from another study (Arthritis Rheum. 2010;62:2101-8) do not support bosentan as therapy for interstitial lung disease due to scleroderma.

An RCT published online evaluated methotrexate in a group of 85 children with active juvenile localized scleroderma, and found it to be effective and well tolerated (Arthritis Rheum. 2011 [doi:10.1002/art.30264]).

Over a 12-month period, infrared thermography of target lesions showed significant benefits from methotrexate treatment, beginning at 9 months. The proportion of patients without disease flare was significantly higher among those treated with methotrexate, but the number of patients with new lesions did not differ between the two groups. Many of the side effects were attributed to concomitant corticosteroids, which were withdrawn after 3 months.

Dr. Kay also described the results of a 1-year RCT of rituximab in 14 scleroderma patients (Rheumatology 2010;49:271-80). Eight patients received rituximab according to the lymphoma regimen (2 cycles of rituximab 375 mg/m

Dr. Kay is a consultant to Array BioPharma, Bristol-Myers Squibb, Centocor Ortho-Biotech Inc., Eisai Research Institute, Genentech, Johnson & Johnson, Mallinckrodt, Novo Nordisk, Pfizer, Roche, Sanofi-Aventis, and UCB. He receives research funding from Roche and Sanofi-Aventis.

In one study of 30 patients, treatment with imatinib led to improvements in several quality of life measures.

Source DR. KAY

Major Finding: LX1031 is a novel, orally administered serotonin synthesis inhibitor that produced a statistically significant improvement in IBS symptoms over a 4-week period in patients with nonconstipating IBS. There was a significant correlation between percent reduction in urinary 5-HIAA and global response, with the best responders to high-dose LX1031 showing at least a 15% reduction in 5-HIAA.

Data Source: A randomized, double-blind, placebo-controlled trial of 134 patients.

Disclosures: Lexicon Pharmaceuticals Inc. supported the study.

BOSTON – LX1031, a novel, orally administered serotonin synthesis inhibitor, significantly improved overall irritable bowel syndrome symptoms in patients with nonconstipating IBS during a 4-week treatment period.

LX1031 is an investigational agent. The global response and improvement in stool form were significantly correlated with serotonergic inhibition, as indicated by the reduction of urinary levels of the serotonin metabolite 5-HIAA. Symptom improvement was greatest for those receiving high-dose LX1031 who had at least a 15% reduction in 5-HIAA levels, according to Dr. Joel P. Freiman, who presented the findings at the meeting.

“LX1031 acts locally on enterochromaffin cells in the GI tract to inhibit tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin,” explained Dr. Freiman, senior medical director of drug safety for Lexicon Pharmaceuticals Inc., manufacturer of LX1031.

“Reducing enteric 5-HT production via inhibition of TPH represents a mechanistically novel approach to the management of IBS symptoms,” he said.

In a randomized, double-blind, placebo-controlled trial, patients with nonconstipating IBS were treated with low-dose LX1031 (250 mg q.i.d., 44 patients), high-dose LX1031 (1,000 mg q.i.d., 43 patients), or placebo (47 patients) for 28 days. The average age of participants was 48 years, and 84% were female.

At the 1,000-mg dose, patients reported “adequate relief from pain and discomfort” within 2 weeks at significantly greater levels than those reported by patients who received placebo, and this benefit was sustained through the fourth week of treatment (P = .046).

After 4 weeks of treatment, the urinary 5-HIAA level was reduced 31.4%, compared with those receiving placebo. The percentage change in urinary 5-HIAA over the 4-week treatment period was significantly correlated with the global response.

To further explore the link between response to LX1031 and serotonin inhibition, the researchers conducted a post hoc subset analysis on data from 24 patients who had received high-dose LX1031. The investigators used a 15% reduction from baseline in urinary 5-HIAA levels as the cut-off and found that 15 patients had a greater than 15% reduction while 9 patients had a smaller than 15% reduction.

The investigators also found that 73% of those in the greater than 15% reduction group reported adequate symptom relief (the high-responder group), compared with 11% of those who had a less than 15% reduction (the low-responder group).

The high responders reported significantly better scores regarding stool consistency and global improvement and trends toward better outcomes regarding measures such as pain, urgency, and bloating than did the low responders.

“Urinary 5-HIAA levels may be a biomarker that will serve as a potential guide to IBS therapy,” Dr. Freiman commented.

He added that studies are planned to prospectively determine whether measuring changes in urinary 5-HIAA can predict which patients will respond best to LX1031.

Regarding safety and tolerability, most adverse events were mild, self-limited, and equally distributed among all the groups, Dr. Freiman said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

The most common adverse events were nausea, diarrhea, vomiting, and headache. There was one serious adverse event, supraventricular tachycardia, that was thought to be unrelated to the study medication. Thirteen patients discontinued the medication, and of those, seven discontinued because of adverse events (one in the placebo group, four in the low-dose group, and two in the high-dose group).

Major Finding: LX1031 is a novel, orally administered serotonin synthesis inhibitor that produced a statistically significant improvement in IBS symptoms over a 4-week period in patients with nonconstipating IBS. There was a significant correlation between percent reduction in urinary 5-HIAA and global response, with the best responders to high-dose LX1031 showing at least a 15% reduction in 5-HIAA.

Data Source: A randomized, double-blind, placebo-controlled trial of 134 patients.

Disclosures: Lexicon Pharmaceuticals Inc. supported the study.

BOSTON – LX1031, a novel, orally administered serotonin synthesis inhibitor, significantly improved overall irritable bowel syndrome symptoms in patients with nonconstipating IBS during a 4-week treatment period.

LX1031 is an investigational agent. The global response and improvement in stool form were significantly correlated with serotonergic inhibition, as indicated by the reduction of urinary levels of the serotonin metabolite 5-HIAA. Symptom improvement was greatest for those receiving high-dose LX1031 who had at least a 15% reduction in 5-HIAA levels, according to Dr. Joel P. Freiman, who presented the findings at the meeting.

“LX1031 acts locally on enterochromaffin cells in the GI tract to inhibit tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin,” explained Dr. Freiman, senior medical director of drug safety for Lexicon Pharmaceuticals Inc., manufacturer of LX1031.

“Reducing enteric 5-HT production via inhibition of TPH represents a mechanistically novel approach to the management of IBS symptoms,” he said.

In a randomized, double-blind, placebo-controlled trial, patients with nonconstipating IBS were treated with low-dose LX1031 (250 mg q.i.d., 44 patients), high-dose LX1031 (1,000 mg q.i.d., 43 patients), or placebo (47 patients) for 28 days. The average age of participants was 48 years, and 84% were female.

At the 1,000-mg dose, patients reported “adequate relief from pain and discomfort” within 2 weeks at significantly greater levels than those reported by patients who received placebo, and this benefit was sustained through the fourth week of treatment (P = .046).

After 4 weeks of treatment, the urinary 5-HIAA level was reduced 31.4%, compared with those receiving placebo. The percentage change in urinary 5-HIAA over the 4-week treatment period was significantly correlated with the global response.

To further explore the link between response to LX1031 and serotonin inhibition, the researchers conducted a post hoc subset analysis on data from 24 patients who had received high-dose LX1031. The investigators used a 15% reduction from baseline in urinary 5-HIAA levels as the cut-off and found that 15 patients had a greater than 15% reduction while 9 patients had a smaller than 15% reduction.

The investigators also found that 73% of those in the greater than 15% reduction group reported adequate symptom relief (the high-responder group), compared with 11% of those who had a less than 15% reduction (the low-responder group).

The high responders reported significantly better scores regarding stool consistency and global improvement and trends toward better outcomes regarding measures such as pain, urgency, and bloating than did the low responders.

“Urinary 5-HIAA levels may be a biomarker that will serve as a potential guide to IBS therapy,” Dr. Freiman commented.

He added that studies are planned to prospectively determine whether measuring changes in urinary 5-HIAA can predict which patients will respond best to LX1031.

Regarding safety and tolerability, most adverse events were mild, self-limited, and equally distributed among all the groups, Dr. Freiman said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

The most common adverse events were nausea, diarrhea, vomiting, and headache. There was one serious adverse event, supraventricular tachycardia, that was thought to be unrelated to the study medication. Thirteen patients discontinued the medication, and of those, seven discontinued because of adverse events (one in the placebo group, four in the low-dose group, and two in the high-dose group).

Major Finding: LX1031 is a novel, orally administered serotonin synthesis inhibitor that produced a statistically significant improvement in IBS symptoms over a 4-week period in patients with nonconstipating IBS. There was a significant correlation between percent reduction in urinary 5-HIAA and global response, with the best responders to high-dose LX1031 showing at least a 15% reduction in 5-HIAA.

Data Source: A randomized, double-blind, placebo-controlled trial of 134 patients.

Disclosures: Lexicon Pharmaceuticals Inc. supported the study.

BOSTON – LX1031, a novel, orally administered serotonin synthesis inhibitor, significantly improved overall irritable bowel syndrome symptoms in patients with nonconstipating IBS during a 4-week treatment period.

LX1031 is an investigational agent. The global response and improvement in stool form were significantly correlated with serotonergic inhibition, as indicated by the reduction of urinary levels of the serotonin metabolite 5-HIAA. Symptom improvement was greatest for those receiving high-dose LX1031 who had at least a 15% reduction in 5-HIAA levels, according to Dr. Joel P. Freiman, who presented the findings at the meeting.

“LX1031 acts locally on enterochromaffin cells in the GI tract to inhibit tryptophan hydroxylase, the rate-limiting enzyme in the synthesis of serotonin,” explained Dr. Freiman, senior medical director of drug safety for Lexicon Pharmaceuticals Inc., manufacturer of LX1031.

“Reducing enteric 5-HT production via inhibition of TPH represents a mechanistically novel approach to the management of IBS symptoms,” he said.

In a randomized, double-blind, placebo-controlled trial, patients with nonconstipating IBS were treated with low-dose LX1031 (250 mg q.i.d., 44 patients), high-dose LX1031 (1,000 mg q.i.d., 43 patients), or placebo (47 patients) for 28 days. The average age of participants was 48 years, and 84% were female.

At the 1,000-mg dose, patients reported “adequate relief from pain and discomfort” within 2 weeks at significantly greater levels than those reported by patients who received placebo, and this benefit was sustained through the fourth week of treatment (P = .046).

After 4 weeks of treatment, the urinary 5-HIAA level was reduced 31.4%, compared with those receiving placebo. The percentage change in urinary 5-HIAA over the 4-week treatment period was significantly correlated with the global response.

To further explore the link between response to LX1031 and serotonin inhibition, the researchers conducted a post hoc subset analysis on data from 24 patients who had received high-dose LX1031. The investigators used a 15% reduction from baseline in urinary 5-HIAA levels as the cut-off and found that 15 patients had a greater than 15% reduction while 9 patients had a smaller than 15% reduction.

The investigators also found that 73% of those in the greater than 15% reduction group reported adequate symptom relief (the high-responder group), compared with 11% of those who had a less than 15% reduction (the low-responder group).

The high responders reported significantly better scores regarding stool consistency and global improvement and trends toward better outcomes regarding measures such as pain, urgency, and bloating than did the low responders.

“Urinary 5-HIAA levels may be a biomarker that will serve as a potential guide to IBS therapy,” Dr. Freiman commented.

He added that studies are planned to prospectively determine whether measuring changes in urinary 5-HIAA can predict which patients will respond best to LX1031.

Regarding safety and tolerability, most adverse events were mild, self-limited, and equally distributed among all the groups, Dr. Freiman said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

The most common adverse events were nausea, diarrhea, vomiting, and headache. There was one serious adverse event, supraventricular tachycardia, that was thought to be unrelated to the study medication. Thirteen patients discontinued the medication, and of those, seven discontinued because of adverse events (one in the placebo group, four in the low-dose group, and two in the high-dose group).

Major Finding: In women with constipation-predominant IBS (IBS-C), genetic variations in bile acid regulatory genes may determine the therapeutic response to the drug sodium chenodeoxycholate.

Data Source: Two double-blind, randomized studies of chenodeoxycholate 500 mg and 1,000 mg in 36 female IBS-C patients and 60 healthy volunteers.

Disclosures: No disclosures were reported.

BOSTON – The therapeutic response of a patient with constipation-predominant irritable bowel syndrome to sodium chenodeoxycholate may reflect particular variations in genes that control bile acid homeostasis, according to Dr. Banny S. Wong.

“Common single-nucleotide polymorphisms in genes regulating the feedback inhibition of bile acid synthesis, specifically the FGF19-mediated feedback pathway, affect chenodeoxycholate-mediated acceleration of colonic transit in IBS-C [constipation-predominant irritable bowel syndrome], and perhaps less so in health,” Dr. Wong said at the meeting, hosted by the American Neurogastroenterology and Motility Society.

In this study, 15 single-nucleotide polymorphisms (SNPs) from seven genes (SHP, ASBT, Klotho-beta, FGFR4, OST-alpha, OST-beta, and CYP7A1) were analyzed. The chosen genes are thought to play critical roles in bile acid synthesis, ileal absorption, and hepatic uptake. Genomic DNA was isolated from blood using standard methods.

Genotyping was carried out in 36 female IBS-C patients and 60 healthy volunteers who were enrolled in two double-blind, randomized, placebo-controlled trials. Chenodeoxycholate was administered in a pH-sensitive methacrylate coating to maximize delivery to the colon. Participants received either placebo, low-dose chenodeoxycholate (500 mg), or high-dose chenodeoxycholate (1,000 mg) for 4 consecutive days, after which colonic transit was assessed by using a validated scintigraphic method.

Chenodeoxycholate is currently not FDA approved for the treatment of IBS-C, reported Dr. Wong of the Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) program at the Mayo Medical School, Rochester, Minn.

“We found interesting results for genetic variations in two genes, FGFR4 and Klotho-beta, both of which are crucial in allowing the hormone FGF19, secreted by the enterocytes in the ileum, to signal the liver and its hepatocytes to shut off further bile acid production,” said Dr. Wong.

For the FGFR4 SNP rs376618, participants with the TT genotype showed significantly accelerated transit, compared with placebo, in response to both doses of chenodeoxycholate, while only the high dose produced a significant response in those with the TC/CC genotype. Analysis of the Klotho-beta SNP rs17618244 by the GG or GA/AA genotypes showed that the drug accelerated transit only for those with the GG subtype receiving high-dose chenodeoxycholate.

Further analysis focused on chenodeoxycholate's effect on ascending colonic emptying time (a surrogate for colonic transit), taking into consideration both the Klotho-beta rs17618244 genotype and the clinical phenotype (healthy or IBS-C). In this case, differential pharmacogenetic effects were observed only for IBS-C patients with the GG genotype, whose colonic transit was significantly accelerated with both doses of the drug. Therapeutic responses to either dose of chenodeoxycholate were not seen in healthy volunteers, no matter what their rs17618244 genotype, nor in IBS-C patients with the GA/AA genotypes.

In previous studies, chenodeoxycholate accelerated colonic transit, increased stool frequency, and loosened stool consistency in both healthy volunteers and patients with IBS-C. “Our studies strongly support the theory that bile acids are natural laxatives and that derangements of bile acid homeostasis, including those predisposed by certain genetic variants, may play a significant role in constipating or diarrheal disorders such as IBS,” said Dr. Wong.

The current results suggest that screening IBS-C patients for common polymorphisms in the FGFR4 and Klotho-beta genes may help preselect the subset of patients who will achieve the best clinical response to chenodeoxycholate pharmacotherapy.

Major Finding: In women with constipation-predominant IBS (IBS-C), genetic variations in bile acid regulatory genes may determine the therapeutic response to the drug sodium chenodeoxycholate.

Data Source: Two double-blind, randomized studies of chenodeoxycholate 500 mg and 1,000 mg in 36 female IBS-C patients and 60 healthy volunteers.

Disclosures: No disclosures were reported.

BOSTON – The therapeutic response of a patient with constipation-predominant irritable bowel syndrome to sodium chenodeoxycholate may reflect particular variations in genes that control bile acid homeostasis, according to Dr. Banny S. Wong.

“Common single-nucleotide polymorphisms in genes regulating the feedback inhibition of bile acid synthesis, specifically the FGF19-mediated feedback pathway, affect chenodeoxycholate-mediated acceleration of colonic transit in IBS-C [constipation-predominant irritable bowel syndrome], and perhaps less so in health,” Dr. Wong said at the meeting, hosted by the American Neurogastroenterology and Motility Society.

In this study, 15 single-nucleotide polymorphisms (SNPs) from seven genes (SHP, ASBT, Klotho-beta, FGFR4, OST-alpha, OST-beta, and CYP7A1) were analyzed. The chosen genes are thought to play critical roles in bile acid synthesis, ileal absorption, and hepatic uptake. Genomic DNA was isolated from blood using standard methods.

Genotyping was carried out in 36 female IBS-C patients and 60 healthy volunteers who were enrolled in two double-blind, randomized, placebo-controlled trials. Chenodeoxycholate was administered in a pH-sensitive methacrylate coating to maximize delivery to the colon. Participants received either placebo, low-dose chenodeoxycholate (500 mg), or high-dose chenodeoxycholate (1,000 mg) for 4 consecutive days, after which colonic transit was assessed by using a validated scintigraphic method.

Chenodeoxycholate is currently not FDA approved for the treatment of IBS-C, reported Dr. Wong of the Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) program at the Mayo Medical School, Rochester, Minn.

“We found interesting results for genetic variations in two genes, FGFR4 and Klotho-beta, both of which are crucial in allowing the hormone FGF19, secreted by the enterocytes in the ileum, to signal the liver and its hepatocytes to shut off further bile acid production,” said Dr. Wong.

For the FGFR4 SNP rs376618, participants with the TT genotype showed significantly accelerated transit, compared with placebo, in response to both doses of chenodeoxycholate, while only the high dose produced a significant response in those with the TC/CC genotype. Analysis of the Klotho-beta SNP rs17618244 by the GG or GA/AA genotypes showed that the drug accelerated transit only for those with the GG subtype receiving high-dose chenodeoxycholate.

Further analysis focused on chenodeoxycholate's effect on ascending colonic emptying time (a surrogate for colonic transit), taking into consideration both the Klotho-beta rs17618244 genotype and the clinical phenotype (healthy or IBS-C). In this case, differential pharmacogenetic effects were observed only for IBS-C patients with the GG genotype, whose colonic transit was significantly accelerated with both doses of the drug. Therapeutic responses to either dose of chenodeoxycholate were not seen in healthy volunteers, no matter what their rs17618244 genotype, nor in IBS-C patients with the GA/AA genotypes.

In previous studies, chenodeoxycholate accelerated colonic transit, increased stool frequency, and loosened stool consistency in both healthy volunteers and patients with IBS-C. “Our studies strongly support the theory that bile acids are natural laxatives and that derangements of bile acid homeostasis, including those predisposed by certain genetic variants, may play a significant role in constipating or diarrheal disorders such as IBS,” said Dr. Wong.

The current results suggest that screening IBS-C patients for common polymorphisms in the FGFR4 and Klotho-beta genes may help preselect the subset of patients who will achieve the best clinical response to chenodeoxycholate pharmacotherapy.

Major Finding: In women with constipation-predominant IBS (IBS-C), genetic variations in bile acid regulatory genes may determine the therapeutic response to the drug sodium chenodeoxycholate.

Data Source: Two double-blind, randomized studies of chenodeoxycholate 500 mg and 1,000 mg in 36 female IBS-C patients and 60 healthy volunteers.

Disclosures: No disclosures were reported.

BOSTON – The therapeutic response of a patient with constipation-predominant irritable bowel syndrome to sodium chenodeoxycholate may reflect particular variations in genes that control bile acid homeostasis, according to Dr. Banny S. Wong.

“Common single-nucleotide polymorphisms in genes regulating the feedback inhibition of bile acid synthesis, specifically the FGF19-mediated feedback pathway, affect chenodeoxycholate-mediated acceleration of colonic transit in IBS-C [constipation-predominant irritable bowel syndrome], and perhaps less so in health,” Dr. Wong said at the meeting, hosted by the American Neurogastroenterology and Motility Society.

In this study, 15 single-nucleotide polymorphisms (SNPs) from seven genes (SHP, ASBT, Klotho-beta, FGFR4, OST-alpha, OST-beta, and CYP7A1) were analyzed. The chosen genes are thought to play critical roles in bile acid synthesis, ileal absorption, and hepatic uptake. Genomic DNA was isolated from blood using standard methods.

Genotyping was carried out in 36 female IBS-C patients and 60 healthy volunteers who were enrolled in two double-blind, randomized, placebo-controlled trials. Chenodeoxycholate was administered in a pH-sensitive methacrylate coating to maximize delivery to the colon. Participants received either placebo, low-dose chenodeoxycholate (500 mg), or high-dose chenodeoxycholate (1,000 mg) for 4 consecutive days, after which colonic transit was assessed by using a validated scintigraphic method.

Chenodeoxycholate is currently not FDA approved for the treatment of IBS-C, reported Dr. Wong of the Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) program at the Mayo Medical School, Rochester, Minn.

“We found interesting results for genetic variations in two genes, FGFR4 and Klotho-beta, both of which are crucial in allowing the hormone FGF19, secreted by the enterocytes in the ileum, to signal the liver and its hepatocytes to shut off further bile acid production,” said Dr. Wong.

For the FGFR4 SNP rs376618, participants with the TT genotype showed significantly accelerated transit, compared with placebo, in response to both doses of chenodeoxycholate, while only the high dose produced a significant response in those with the TC/CC genotype. Analysis of the Klotho-beta SNP rs17618244 by the GG or GA/AA genotypes showed that the drug accelerated transit only for those with the GG subtype receiving high-dose chenodeoxycholate.

Further analysis focused on chenodeoxycholate's effect on ascending colonic emptying time (a surrogate for colonic transit), taking into consideration both the Klotho-beta rs17618244 genotype and the clinical phenotype (healthy or IBS-C). In this case, differential pharmacogenetic effects were observed only for IBS-C patients with the GG genotype, whose colonic transit was significantly accelerated with both doses of the drug. Therapeutic responses to either dose of chenodeoxycholate were not seen in healthy volunteers, no matter what their rs17618244 genotype, nor in IBS-C patients with the GA/AA genotypes.

In previous studies, chenodeoxycholate accelerated colonic transit, increased stool frequency, and loosened stool consistency in both healthy volunteers and patients with IBS-C. “Our studies strongly support the theory that bile acids are natural laxatives and that derangements of bile acid homeostasis, including those predisposed by certain genetic variants, may play a significant role in constipating or diarrheal disorders such as IBS,” said Dr. Wong.

The current results suggest that screening IBS-C patients for common polymorphisms in the FGFR4 and Klotho-beta genes may help preselect the subset of patients who will achieve the best clinical response to chenodeoxycholate pharmacotherapy.

Major Finding: Thirty percent of 189 patients with a history of Salmonella or Campylobacter gastrointestinal infections claimed to be symptomatic for as long as 10 years after the initial infection.

Data Source: A survey of 189 individuals with a history of Salmonella or Campylobacter infection.

Disclosures: Research support was received from Zentrum für Ernaehrungsmedizin (Center of Nutritional Medicine), an interuniversity institute. Dr. Enck had no disclosures.

BOSTON – Thirty percent of individuals with a history of Salmonella or Campylobacter infections reported ongoing postinfectious symptoms as long as 10 years after the initial infectious event, according to Paul Enck, Ph.D., who presented the results in a poster at the meeting.

“These patients represent a clinically important population with high somatization, anxiety, and depression scores,” said Dr. Enck, director of research in the department of psychosomatic medicine, University Hospital Tübingen (Germany).

Surveys were sent to 576 people who had come to University Hospital Tübingen between 2000 and mid-2009 and had documented Salmonella or Campylobacter gastrointestinal infection. A total of 189 (36%) responded to the brief survey, which asked about current GI symptoms and whether respondents would be willing to participate in a further investigation of their infection history and consequences.

Of the 189 survey respondents, 56 people (30%) indicated that they were still symptomatic (end of 2009). The 56 patients included 6 patients originally infected in 2000, 5 patients infected in 2001, and 2 infected in 2002.

The average age of the respondents at the time of infection was 39.8 years, and at the time of the survey it was 43.1 years. Thirty-two patients had a history of Salmonella, and 24 had a history of Campylobacter, Dr. Enck said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

Symptomatic individuals were then sent a second, more extensive questionnaire that focused on postinfectious irritable bowel syndrome (PI-IBS). This survey was developed and validated by the European Society of Neurogastroenterology and Motility, and is available online at www.postinfectious-ibs.eu

Ninety-one percent (51 patients) responded to the second survey. The majority of the sample (69%, or 35 patients) met criteria for PI-IBS, which includes the presence of two or more symptoms such as sudden-onset fever, diarrhea, vomiting, or bloody stools. Overall, 84% (43/51) were symptomatic during the preceding 9 months. Almost one-third (16) met Rome IBS criteria, but only 7 (14%) had met Rome IBS criteria before the infection.

No link was observed between having IBS symptoms before infection and developing PI-IBS. Neither age nor gender predicted development of PI-IBS, and no association was found between the initial bacterial strain and the risk of developing PI-IBS.

Those respondents with PI-IBS reported significantly more depression (P = .05), and had higher somatization scores than did those without PI-IBS (mean 10.6 ± 3.9 vs. 8.3 ± 3.9, not a significant difference).

“It needs to be shown whether and which individual premorbid and postinfectious clinical factors may explain symptom persistence, and whether long-term development of postinfectious symptoms may be prevented by early postinfection interventions,” noted Dr. Enck.

Major Finding: Thirty percent of 189 patients with a history of Salmonella or Campylobacter gastrointestinal infections claimed to be symptomatic for as long as 10 years after the initial infection.

Data Source: A survey of 189 individuals with a history of Salmonella or Campylobacter infection.

Disclosures: Research support was received from Zentrum für Ernaehrungsmedizin (Center of Nutritional Medicine), an interuniversity institute. Dr. Enck had no disclosures.

BOSTON – Thirty percent of individuals with a history of Salmonella or Campylobacter infections reported ongoing postinfectious symptoms as long as 10 years after the initial infectious event, according to Paul Enck, Ph.D., who presented the results in a poster at the meeting.

“These patients represent a clinically important population with high somatization, anxiety, and depression scores,” said Dr. Enck, director of research in the department of psychosomatic medicine, University Hospital Tübingen (Germany).

Surveys were sent to 576 people who had come to University Hospital Tübingen between 2000 and mid-2009 and had documented Salmonella or Campylobacter gastrointestinal infection. A total of 189 (36%) responded to the brief survey, which asked about current GI symptoms and whether respondents would be willing to participate in a further investigation of their infection history and consequences.

Of the 189 survey respondents, 56 people (30%) indicated that they were still symptomatic (end of 2009). The 56 patients included 6 patients originally infected in 2000, 5 patients infected in 2001, and 2 infected in 2002.

The average age of the respondents at the time of infection was 39.8 years, and at the time of the survey it was 43.1 years. Thirty-two patients had a history of Salmonella, and 24 had a history of Campylobacter, Dr. Enck said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

Symptomatic individuals were then sent a second, more extensive questionnaire that focused on postinfectious irritable bowel syndrome (PI-IBS). This survey was developed and validated by the European Society of Neurogastroenterology and Motility, and is available online at www.postinfectious-ibs.eu

Ninety-one percent (51 patients) responded to the second survey. The majority of the sample (69%, or 35 patients) met criteria for PI-IBS, which includes the presence of two or more symptoms such as sudden-onset fever, diarrhea, vomiting, or bloody stools. Overall, 84% (43/51) were symptomatic during the preceding 9 months. Almost one-third (16) met Rome IBS criteria, but only 7 (14%) had met Rome IBS criteria before the infection.

No link was observed between having IBS symptoms before infection and developing PI-IBS. Neither age nor gender predicted development of PI-IBS, and no association was found between the initial bacterial strain and the risk of developing PI-IBS.

Those respondents with PI-IBS reported significantly more depression (P = .05), and had higher somatization scores than did those without PI-IBS (mean 10.6 ± 3.9 vs. 8.3 ± 3.9, not a significant difference).

“It needs to be shown whether and which individual premorbid and postinfectious clinical factors may explain symptom persistence, and whether long-term development of postinfectious symptoms may be prevented by early postinfection interventions,” noted Dr. Enck.

Major Finding: Thirty percent of 189 patients with a history of Salmonella or Campylobacter gastrointestinal infections claimed to be symptomatic for as long as 10 years after the initial infection.

Data Source: A survey of 189 individuals with a history of Salmonella or Campylobacter infection.

Disclosures: Research support was received from Zentrum für Ernaehrungsmedizin (Center of Nutritional Medicine), an interuniversity institute. Dr. Enck had no disclosures.

BOSTON – Thirty percent of individuals with a history of Salmonella or Campylobacter infections reported ongoing postinfectious symptoms as long as 10 years after the initial infectious event, according to Paul Enck, Ph.D., who presented the results in a poster at the meeting.

“These patients represent a clinically important population with high somatization, anxiety, and depression scores,” said Dr. Enck, director of research in the department of psychosomatic medicine, University Hospital Tübingen (Germany).

Surveys were sent to 576 people who had come to University Hospital Tübingen between 2000 and mid-2009 and had documented Salmonella or Campylobacter gastrointestinal infection. A total of 189 (36%) responded to the brief survey, which asked about current GI symptoms and whether respondents would be willing to participate in a further investigation of their infection history and consequences.

Of the 189 survey respondents, 56 people (30%) indicated that they were still symptomatic (end of 2009). The 56 patients included 6 patients originally infected in 2000, 5 patients infected in 2001, and 2 infected in 2002.

The average age of the respondents at the time of infection was 39.8 years, and at the time of the survey it was 43.1 years. Thirty-two patients had a history of Salmonella, and 24 had a history of Campylobacter, Dr. Enck said at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

Symptomatic individuals were then sent a second, more extensive questionnaire that focused on postinfectious irritable bowel syndrome (PI-IBS). This survey was developed and validated by the European Society of Neurogastroenterology and Motility, and is available online at www.postinfectious-ibs.eu

Ninety-one percent (51 patients) responded to the second survey. The majority of the sample (69%, or 35 patients) met criteria for PI-IBS, which includes the presence of two or more symptoms such as sudden-onset fever, diarrhea, vomiting, or bloody stools. Overall, 84% (43/51) were symptomatic during the preceding 9 months. Almost one-third (16) met Rome IBS criteria, but only 7 (14%) had met Rome IBS criteria before the infection.

No link was observed between having IBS symptoms before infection and developing PI-IBS. Neither age nor gender predicted development of PI-IBS, and no association was found between the initial bacterial strain and the risk of developing PI-IBS.

Those respondents with PI-IBS reported significantly more depression (P = .05), and had higher somatization scores than did those without PI-IBS (mean 10.6 ± 3.9 vs. 8.3 ± 3.9, not a significant difference).

“It needs to be shown whether and which individual premorbid and postinfectious clinical factors may explain symptom persistence, and whether long-term development of postinfectious symptoms may be prevented by early postinfection interventions,” noted Dr. Enck.

Major Finding: Of 51 patients who underwent endoscopically assisted water perfusion esophageal manometry, 46 tolerated the procedure, and the results had a direct impact on clinical management for 32 of 36 (89%) who had follow-up data.

Data Source: A retrospective analysis of the records of 51 patients who underwent EAM.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can't tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. Many, however, were able to tolerate endoscopically assisted water perfusion esophageal manometry (EAM) with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller of Massachusetts General Hospital, Boston.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via a retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using two puffs of lidocaine spray followed by a standard intravenous minimally conscious protocol. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients, in whom standard manometry was not appropriate, were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), Dr. Staller said.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified.

Major Finding: Of 51 patients who underwent endoscopically assisted water perfusion esophageal manometry, 46 tolerated the procedure, and the results had a direct impact on clinical management for 32 of 36 (89%) who had follow-up data.

Data Source: A retrospective analysis of the records of 51 patients who underwent EAM.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can't tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. Many, however, were able to tolerate endoscopically assisted water perfusion esophageal manometry (EAM) with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller of Massachusetts General Hospital, Boston.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via a retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using two puffs of lidocaine spray followed by a standard intravenous minimally conscious protocol. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients, in whom standard manometry was not appropriate, were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), Dr. Staller said.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified.

Major Finding: Of 51 patients who underwent endoscopically assisted water perfusion esophageal manometry, 46 tolerated the procedure, and the results had a direct impact on clinical management for 32 of 36 (89%) who had follow-up data.

Data Source: A retrospective analysis of the records of 51 patients who underwent EAM.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can't tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. Many, however, were able to tolerate endoscopically assisted water perfusion esophageal manometry (EAM) with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller of Massachusetts General Hospital, Boston.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via a retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using two puffs of lidocaine spray followed by a standard intravenous minimally conscious protocol. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients, in whom standard manometry was not appropriate, were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), Dr. Staller said.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified.

Major Finding: Linaclotide improved bowel and abdominal symptoms linked toachronic constipation in two phase III trial. There was no rebound effect during a 4-week randomized withdrawal period.

Data Source: Two randomized, placebo-controlled trials of 642 and 630 patients.

Disclosures: Dr. Lembo and Dr. Johnston have financial ties with Ironwood Pharmaceuticals Inc., which funded the trial. All other authors are employees of Ironwood or Forest Research Laboratories.

BOSTON — The results of two 12-week, randomized, placebo-controlled phase III trials of linaclotide showed that the drug produced significant improvement in key end points related to chronic constipation.

Quality of life self-assessments also showed a favorable response, according to Dr. Anthony J. Lembo, who reported the results of both studies in a poster presentation.

At the same meeting, which was hosted by the American Neurogastroenterology and Motility Society, Dr. Jeffrey M. Johnston reported in an oral presentation the results of the 4-week randomized withdrawal period that followed one of the studies. The findings showed that no rebound effects were seen after linaclotide cessation.

Linaclotide is a minimally absorbed, 14-amino-acid peptide, guanylate cyclase-C agonist, said Dr. Lembo, a gastroenterologist at Beth Israel Deaconess Medical Center, Boston.

It is produced by Ironwood Pharmaceuticals Inc., which supported the studies. Dr. Johnston is the chief medical officer at Ironwood Pharmaceuticals.

Two phase III trials were conducted, one with an intent-to-treat (ITT) population of 642 patients (Trial 303) and the other with an ITT population of 630 (Trial 01). The average age was 48 years, and approximately 12% of the participants were older than 65 years. About 90% of the subjects were female.

Subjects met Rome II criteria for chronic constipation, including fewer than three complete spontaneous bowel movements (CSBMs) per week, six or fewer spontaneous bowel movements per week (SBMs), or one or fewer SBMs on the Bristol Stool Form Scale (BSFS). At baseline, subjects reported 0.3 CSBMs per week and about 2 SBMs per week.

Subjects were treated with either 133 mcg or 266 mcg linaclotide or placebo. The linaclotide groups showed significant improvement compared with placebo on the primary efficacy end point, which was the percentage of patients who had an increase of at least one spontaneous bowel movement over baseline for at least 9 of the 12 treatment weeks.

In the first trial, 39.2% of those receiving low-dose linaclotide and 37.0% of those receiving high-dose linaclotide had an increase of one or more CSBMs per week for 9 of 12 weeks compared with their baseline rate; these rates were significantly greater than the 11% rate observed in the placebo group (P less than .0001).

Similar rates were seen in the second trial (31.0% low dose, 40.1% high dose, 13% placebo).

Patients also reported improvements in other bowel and abdominal symptoms associated with chronic constipation, such as the weekly rate of CSBMs, weekly rates of SBMs, better stool consistency, less severity of straining, less bloating, less abdominal discomfort, and less constipation severity.

For example, the weekly CSBM rate rose to 2 times per week, compared with 0.5 times per week in the placebo group (P less than .0001). In both trials at both doses tested, patients taking linaclotide reported better quality of life as measured on the 4-point Patient Assessment of Constipation—Quality of Life (PAC-QOL) questionnaire.

Eighty-four percent of enrollees in each trial completed treatment. Analysis of pooled safety results from both trials showed that 7% of those receiving the low dose and 7% of those receiving the high dose of linaclotide discontinued due to adverse events, compared with 4% of those receiving placebo.

One patient who had received low-dose linaclotide died as a result of a fentanyl patch overdose unrelated to the study drug. Diarrhea was the most common adverse event reported by those receiving linaclotide, and 4% of linaclotide-treated patients discontinued due to diarrhea.

During the 4-week randomized withdrawal period, those who were treated with linaclotide during the treatment period were rerandomized to either placebo or the linaclotide dose they had received. Those who had received placebo during the treatment period received high-dose linaclotide during the withdrawal period, explained Dr. Johnston. In total, 538 patients participated in the withdrawal phase.

The investigators found that those who had first received placebo and then received the study drug in the withdrawal phase showed improvements in their constipation symptoms similar to those of the patients who had previously been treated with linaclotide.

Those who had received active treatment but were switched to placebo showed regression toward more constipation symptoms, similar to those of the patients who had previously received placebo. No rebound effect was seen after cessation of linaclotide.

Sustained improvement was seen in those treated with linaclotide during both the treatment and withdrawal periods.

Major Finding: Linaclotide improved bowel and abdominal symptoms linked toachronic constipation in two phase III trial. There was no rebound effect during a 4-week randomized withdrawal period.

Data Source: Two randomized, placebo-controlled trials of 642 and 630 patients.

Disclosures: Dr. Lembo and Dr. Johnston have financial ties with Ironwood Pharmaceuticals Inc., which funded the trial. All other authors are employees of Ironwood or Forest Research Laboratories.

BOSTON — The results of two 12-week, randomized, placebo-controlled phase III trials of linaclotide showed that the drug produced significant improvement in key end points related to chronic constipation.

Quality of life self-assessments also showed a favorable response, according to Dr. Anthony J. Lembo, who reported the results of both studies in a poster presentation.

At the same meeting, which was hosted by the American Neurogastroenterology and Motility Society, Dr. Jeffrey M. Johnston reported in an oral presentation the results of the 4-week randomized withdrawal period that followed one of the studies. The findings showed that no rebound effects were seen after linaclotide cessation.

Linaclotide is a minimally absorbed, 14-amino-acid peptide, guanylate cyclase-C agonist, said Dr. Lembo, a gastroenterologist at Beth Israel Deaconess Medical Center, Boston.

It is produced by Ironwood Pharmaceuticals Inc., which supported the studies. Dr. Johnston is the chief medical officer at Ironwood Pharmaceuticals.

Two phase III trials were conducted, one with an intent-to-treat (ITT) population of 642 patients (Trial 303) and the other with an ITT population of 630 (Trial 01). The average age was 48 years, and approximately 12% of the participants were older than 65 years. About 90% of the subjects were female.

Subjects met Rome II criteria for chronic constipation, including fewer than three complete spontaneous bowel movements (CSBMs) per week, six or fewer spontaneous bowel movements per week (SBMs), or one or fewer SBMs on the Bristol Stool Form Scale (BSFS). At baseline, subjects reported 0.3 CSBMs per week and about 2 SBMs per week.

Subjects were treated with either 133 mcg or 266 mcg linaclotide or placebo. The linaclotide groups showed significant improvement compared with placebo on the primary efficacy end point, which was the percentage of patients who had an increase of at least one spontaneous bowel movement over baseline for at least 9 of the 12 treatment weeks.

In the first trial, 39.2% of those receiving low-dose linaclotide and 37.0% of those receiving high-dose linaclotide had an increase of one or more CSBMs per week for 9 of 12 weeks compared with their baseline rate; these rates were significantly greater than the 11% rate observed in the placebo group (P less than .0001).

Similar rates were seen in the second trial (31.0% low dose, 40.1% high dose, 13% placebo).

Patients also reported improvements in other bowel and abdominal symptoms associated with chronic constipation, such as the weekly rate of CSBMs, weekly rates of SBMs, better stool consistency, less severity of straining, less bloating, less abdominal discomfort, and less constipation severity.

For example, the weekly CSBM rate rose to 2 times per week, compared with 0.5 times per week in the placebo group (P less than .0001). In both trials at both doses tested, patients taking linaclotide reported better quality of life as measured on the 4-point Patient Assessment of Constipation—Quality of Life (PAC-QOL) questionnaire.

Eighty-four percent of enrollees in each trial completed treatment. Analysis of pooled safety results from both trials showed that 7% of those receiving the low dose and 7% of those receiving the high dose of linaclotide discontinued due to adverse events, compared with 4% of those receiving placebo.

One patient who had received low-dose linaclotide died as a result of a fentanyl patch overdose unrelated to the study drug. Diarrhea was the most common adverse event reported by those receiving linaclotide, and 4% of linaclotide-treated patients discontinued due to diarrhea.

During the 4-week randomized withdrawal period, those who were treated with linaclotide during the treatment period were rerandomized to either placebo or the linaclotide dose they had received. Those who had received placebo during the treatment period received high-dose linaclotide during the withdrawal period, explained Dr. Johnston. In total, 538 patients participated in the withdrawal phase.

The investigators found that those who had first received placebo and then received the study drug in the withdrawal phase showed improvements in their constipation symptoms similar to those of the patients who had previously been treated with linaclotide.

Those who had received active treatment but were switched to placebo showed regression toward more constipation symptoms, similar to those of the patients who had previously received placebo. No rebound effect was seen after cessation of linaclotide.

Sustained improvement was seen in those treated with linaclotide during both the treatment and withdrawal periods.

Major Finding: Linaclotide improved bowel and abdominal symptoms linked toachronic constipation in two phase III trial. There was no rebound effect during a 4-week randomized withdrawal period.

Data Source: Two randomized, placebo-controlled trials of 642 and 630 patients.

Disclosures: Dr. Lembo and Dr. Johnston have financial ties with Ironwood Pharmaceuticals Inc., which funded the trial. All other authors are employees of Ironwood or Forest Research Laboratories.

BOSTON — The results of two 12-week, randomized, placebo-controlled phase III trials of linaclotide showed that the drug produced significant improvement in key end points related to chronic constipation.

Quality of life self-assessments also showed a favorable response, according to Dr. Anthony J. Lembo, who reported the results of both studies in a poster presentation.

At the same meeting, which was hosted by the American Neurogastroenterology and Motility Society, Dr. Jeffrey M. Johnston reported in an oral presentation the results of the 4-week randomized withdrawal period that followed one of the studies. The findings showed that no rebound effects were seen after linaclotide cessation.

Linaclotide is a minimally absorbed, 14-amino-acid peptide, guanylate cyclase-C agonist, said Dr. Lembo, a gastroenterologist at Beth Israel Deaconess Medical Center, Boston.

It is produced by Ironwood Pharmaceuticals Inc., which supported the studies. Dr. Johnston is the chief medical officer at Ironwood Pharmaceuticals.

Two phase III trials were conducted, one with an intent-to-treat (ITT) population of 642 patients (Trial 303) and the other with an ITT population of 630 (Trial 01). The average age was 48 years, and approximately 12% of the participants were older than 65 years. About 90% of the subjects were female.

Subjects met Rome II criteria for chronic constipation, including fewer than three complete spontaneous bowel movements (CSBMs) per week, six or fewer spontaneous bowel movements per week (SBMs), or one or fewer SBMs on the Bristol Stool Form Scale (BSFS). At baseline, subjects reported 0.3 CSBMs per week and about 2 SBMs per week.

Subjects were treated with either 133 mcg or 266 mcg linaclotide or placebo. The linaclotide groups showed significant improvement compared with placebo on the primary efficacy end point, which was the percentage of patients who had an increase of at least one spontaneous bowel movement over baseline for at least 9 of the 12 treatment weeks.

In the first trial, 39.2% of those receiving low-dose linaclotide and 37.0% of those receiving high-dose linaclotide had an increase of one or more CSBMs per week for 9 of 12 weeks compared with their baseline rate; these rates were significantly greater than the 11% rate observed in the placebo group (P less than .0001).

Similar rates were seen in the second trial (31.0% low dose, 40.1% high dose, 13% placebo).

Patients also reported improvements in other bowel and abdominal symptoms associated with chronic constipation, such as the weekly rate of CSBMs, weekly rates of SBMs, better stool consistency, less severity of straining, less bloating, less abdominal discomfort, and less constipation severity.

For example, the weekly CSBM rate rose to 2 times per week, compared with 0.5 times per week in the placebo group (P less than .0001). In both trials at both doses tested, patients taking linaclotide reported better quality of life as measured on the 4-point Patient Assessment of Constipation—Quality of Life (PAC-QOL) questionnaire.

Eighty-four percent of enrollees in each trial completed treatment. Analysis of pooled safety results from both trials showed that 7% of those receiving the low dose and 7% of those receiving the high dose of linaclotide discontinued due to adverse events, compared with 4% of those receiving placebo.

One patient who had received low-dose linaclotide died as a result of a fentanyl patch overdose unrelated to the study drug. Diarrhea was the most common adverse event reported by those receiving linaclotide, and 4% of linaclotide-treated patients discontinued due to diarrhea.

During the 4-week randomized withdrawal period, those who were treated with linaclotide during the treatment period were rerandomized to either placebo or the linaclotide dose they had received. Those who had received placebo during the treatment period received high-dose linaclotide during the withdrawal period, explained Dr. Johnston. In total, 538 patients participated in the withdrawal phase.

The investigators found that those who had first received placebo and then received the study drug in the withdrawal phase showed improvements in their constipation symptoms similar to those of the patients who had previously been treated with linaclotide.

Those who had received active treatment but were switched to placebo showed regression toward more constipation symptoms, similar to those of the patients who had previously received placebo. No rebound effect was seen after cessation of linaclotide.

Sustained improvement was seen in those treated with linaclotide during both the treatment and withdrawal periods.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Patients who can’t tolerate standard esophageal manometry may be able to undergo an alternative procedure known as endoscopically assisted water perfusion esophageal manometry, with results that are useful in guiding clinical management.

Between 2007 and 2009, 88 (2.7%) of 3,304 patients who were sent for assessment of a motility disorder using standard esophageal manometry failed the procedure. However, many of these patients were able to tolerate an alternative procedure – endoscopically assisted water perfusion esophageal manometry (EAM) – with minimal sedation, reported Dr. Rita Brun and Dr. Kyle Staller, who presented the study results at Neurogastroenterology and Motility 2010.

According to the researchers, patients may be unable to tolerate standard manometry for different reasons. In the group of 88 patients who were identified via retrospective analysis, 87.5% could not tolerate intranasal intubation and 12.5% had anatomical obstacles, such as large hiatal hernias, esophageal diverticula, or prior nasal surgery.

But EAM appears to offer an effective alternative. “To our knowledge, this technique has not been reported previously,” said Dr. Brun, a gastroenterologist associated with Massachusetts General Hospital in Boston. “EAM with minimal sedation is a safe, reliable, and feasible technique providing objective diagnostic information. EAM is geared toward an especially challenging patient population, in whom no other way to assess esophageal motility is feasible yet quantified manometric information for clinical management is required. EAM can provide a needed solution in cases of problematic catheter placement, where evaluation of esophageal motility is a necessity.”

For EAM, patients are minimally sedated, using 2 puffs of lidocaine spray followed by a standard intravenous minimally conscious sedation protocol using primarily midazolam and fentanyl. A standard upper endoscopy is performed. The guide wire is inserted via the working channel of the scope, and the scope is then pulled out, leaving the wire in the stomach. A water perfusion manometry catheter is introduced over the wire, and standard water perfusion manometry is carried out. The mean time from beginning of sedation until withdrawal of the manometry probe was 42 minutes, with the procedure itself lasting about 31 minutes.

To assess the clinical value of EAM, Dr. Staller of Massachusetts General Hospital performed a retrospective analysis of the medical records of all adult patients who had undergone EAM between 2007 and 2009. In all, 41 of the 88 patients who had failed transnasal standard manometry went on to EAM. An additional 10 patients – in whom standard manometry was not appropriate because they had Zenker diverticulum, severe achalasia, or neurologic disease – were sent directly to EAM. Of these 51 patients (37 females; mean age, 60 years; age range, 24-88 years), 5 were excluded because they could not complete EAM, which yielded 46 patient records for clinical analysis.

Of the 46 patients, 10 patients were lost to follow-up. Among the 36 remaining patients, EAM had a direct influence on clinical management for 88.9% (32 patients) and had no meaningful impact for 11.1% (4 patients), according to Dr. Staller.

For instance, 27.8% (10) underwent EAM as part of a preoperative work-up for antireflux surgery. Of those, three did not undergo surgery based on the study results, whereas the other seven proceeded to surgery.

Overall, 12 patients (33.3%) were diagnosed with achalasia as a result of EAM and were treated for that condition with Botox, dilatation, or myotomy (4, 3, and 5 patients, respectively). Achalasia was ruled out in one patient, which prevented an invasive intervention.

Another 12 patients had their medications changed because of the EAM findings. In some cases, a promotility agent was added or an acid-suppression regimen was modified. Some patients had more than one change in their management.

Disclosures: The research was supported in part by a grant from the International Foundation of Functional Gastrointestinal Disorders. No other disclosures were reported.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.

BOSTON – Daily infusion of an investigational drug known as TZP-101, a ghrelin agonist, for a period of 4 days decreased vomiting in a small group of patients with severe diabetic gastroparesis, reported Dr. John M. Wo, who presented the findings at Neurogastroenterology and Motility 2010.

“The most important symptoms to address in acutely severe gastroparesis are nausea, vomiting, and retching,” explained Dr. Wo, director of the swallowing and motility center at the University of Louisville (Ky.). “In severe cases, diabetic-associated gastroparesis is associated with dehydration, malnutrition, and weight loss, and can cause frequent hospitalizations and [emergency department] admissions.” Vomiting is considered by regulatory agencies to be the key variable to measure treatment success in this population, he said.

Dr. Wo studied 20 patients with severe diabetic gastroparesis. The average age was 41 years, 70% had type 1 diabetes, and half of the group was female. During a 4-day run-in period, these patients vomited daily and had mean scores of 3.88 out of 5 on the Gastroparesis Cardinal Symptom Index (GCSI).

Following hospital admission, 12 of the 20 patients were randomized to receive TZP-101 and 8 received placebo as an intravenous 30-minute infusion daily for 4 days. Patients were treated with one of six different TZP-101 doses, said Dr. Wo at the meeting, which was hosted by the American Neurogastroenterology and Motility Society.

During the 4 treatment days, the severity of vomiting decreased in those who were treated with TZP-101 (all doses combined), with a mean decrease of 1.23 points on the GCSI, compared with patients receiving placebo (P = .021). The severity of vomiting decreased as the trial progressed. Those who received TZP-101 had more vomiting-free days, compared with those receiving placebo (2.9 vs. 1.5), but this difference did not reach statistical significance (P = .059).

Trends in improvement in the severity of nausea and retching were seen in patients who were treated with TZP-101, but these differences also did not reach statistical significance (P = .052 and .087, respectively).

One surprising finding, noted Dr. Wo, was that the suppression of vomiting was sustained, at least when assessed 30 days after the initial treatment period. This was unexpected because the half life of TZP-101 is 20 hours.

Patients in both the TZP-101 and placebo groups showed improvement in nausea, vomiting, and retching upon admission to the hospital, even before treatment. Dr. Wo attributes these improvements to better supportive care, including fluid stabilization, management of blood pressure, and better diabetic control. Unlike patients in the placebo group, patients who received TZP-101 improved steadily over the 4-day treatment period.

TZP-101 is a small molecule that does not cross the blood-brain barrier, Dr. Wo said. It is a 28–amino acid peptide that is potent, reversible, and selective, with a small propensity for tolerance to develop. In healthy volunteers, it has a prokinetic effect, and Dr. Wo said that it may act via ghrelin receptors in the stomach, but its mechanism of action has not yet been determined.

Disclosures: Research support was provided by Tranzyme Inc., but the company did not provide any salary support.