Zelnorm ( Tegaserod ) may offer new approach in the treatment of upper gastrointestinal ( GI ) disorders, such as dyspepsia, gastroesophageal reflux disease ( GERD ) and functional heartburn.
Zelnorm, also known in some countries as Zelmac, is the first in a novel class of drugs that act as an agonist at 5HT4 ( serotonin type 4 ) receptors.
Zelnorm mimics the natural effects of serotonin by activating 5HT4 receptors, which normalizes impaired motility in the GI tract, inhibits visceral sensitivity and stimulates intestinal secretion.
Zelnorm is currently approved for the treatment of women with Irritable Bowel Syndrome with constipation (IBS-C) and for patients less than 65 years of age with Chronic Idiopathic Constipation.
" These results are promising, suggesting that in addition to its proven pro-motility benefits, Tegaserod may also improve the body's sensory responses during digestion, working to normalize functions throughout the GI tract," said Philip Miner, Oklahoma Foundation for Digestive Research. " Results of this nature deepen our understanding of the impact various disorders can have on how the GI tract works and how Zelnorm may help to restore its normal function. "
Zelnorm and dyspepsia study
Dyspepsia is a digestive condition that affects approximately one in four Americans. It is characterized by impaired gut function, accompanied by abdominal pain or discomfort, often associated with a meal.
In some patients, the inability of the stomach to properly accommodate ( expand to hold food ) or impaired gastric compliance ( the elasticity of the stomach wall ) may play an important role in causing the symptoms of dyspepsia.
Two studies in patients with dyspepsia found Zelnorm was able to increase meal-induced gastric accommodation and postprandial gastric compliance.
These data suggest Zelnorm affects a sensory pathway in the stomach of these patients that triggers its expansion, allowing it to accommodate a meal.
The first study examined 30 Helicobacter pylori negative dyspepsia patients ( seven males, mean age 42 +/- 2 years ).
Twenty-two of these patients ( 73 percent ) had normal gastric emptying and eight ( 27 percent ) had delayed gastric emptying ( t1/2 octanoic acid breath test >109 min, which is a measurement of how much time it takes for half the food to leave the stomach; up to 108 minutes is normal ).
Patients underwent a gastric barostat ( balloon ) study on two separate occasions, two weeks apart, after five days of pretreatment with placebo or Zelnorm 6 mg b.i.d. in a double-blind randomized fashion. After introduction of the barostat bag, graded pressure distensions ( 2 mmHg increments/2 min ) were performed to determine gastric compliance ( the elasticity of the stomach walls ) and the stomach wall's sensitivity to distension.
In dyspepsia patients with normal gastric emptying ( which represent the majority of dyspepsia patients in clinical practice ), Zelnorm 6 mg b.i.d. increased meal-induced gastric accommodation. These findings suggest a therapeutic potential for Zelnorm in dyspepsia patients with impaired accommodation and normal emptying.
In the second study, 16 patients with dyspepsia ( nine women, mean age 32.6 years ) and 12 healthy volunteers ( eight women, mean age 24.6 years ) were studied on two separate occasions, each after a seven day treatment period with either placebo or Zelnorm 6 mg b.i.d. using a double-blind, randomized, cross-over design.
Treatment periods were separated by seven to 14 days.
At the end of each treatment period a gastric barostat (balloon) study was performed. The fasting period was examined, as well as the administration of a 10 percent intraduodenal lipid infusion ( infusion rate 1 ml/min ), and pain sensation thresholds were studied along with proximal gastric compliance ( elasticity) by ramp distension at 2 mmHg increments up to a bag volume of 1000 ml. This was recorded during a 30-minute period to simulate and quantify meal-induced stomach relaxation and the severity of dyspeptic symptoms during gastric volume measurements.
Zelnorm was shown to enhance the postprandial gastric compliance of the stomach in dyspepsia patients and the ability to accommodate in healthy controls. Thus, the improvement of the stomach's motor function with a simulated meal suggests a therapeutic role for Zelnorm in dyspepsia patients.
Zelnorm and GERD studies
In gastroesophageal reflux disease, or GERD, sensations occur when the lower esophagus does not close properly and stomach contents leak back, or reflux, into the esophagus.
Persistent heartburn is the most frequent symptom of GERD, which affects approximately 20 percent of the U.S. population on a weekly basis.
Researchers in the GERD study found that Zelnorm significantly enhanced the secretion of salivary protective factors, especially increasing buffering capacity of the esophagus, which protects the esophageal lining from acid.
In addition, data showed Zelnorm enhanced esophageal release of epidermal growth factor.
Administration of Zelnorm was shown to augment production of potential esophago-protective factors, which could potentially lead to therapeutic benefit in patients with GERD.
The first GERD study was conducted in a double-blind, placebo-controlled, cross-over design with 38 GERD patients ( 26 female and 12 male ) from 23 to 61 years of age, with an average age of 41.
Saliva samples were collected basally, during mastication and during the esophageal phase ( after placement of a specially designed esophageal catheter ) to initial sodium chloride followed by hydrochloric acid/pepsin and final sodium chloride, to mimic gastroesophageal reflux.
In salivary samples, the volume and the content of salivary buffers, protein, mucin, EGF, TGF alpha, and PGE2 were measured using standard methods.
Collected data were analyzed using SPSS statistical software.
Salivary flow rates during administration of Zelnorm increased significantly over corresponding values recorded during placebo, both in basal conditions ( by 23 percent; P=0.003 ) and during stimulation with mastication ( by 15 percent; P<0.001 ).
The rate of secretion of salivary bicarbonate and non-bicarbonate buffers also increased significantly in basal conditions ( by 44 percent; P<0.001 and by 28 percent; P<0.01, respectively ) and during mastication ( by 19 percent; P=0.047 and by 15 percent; P=0.05, respectively ).
Salivary EGF increased by 38 percent in basal conditions ( P=0.064 ) and significantly ( by 47 percent; P=0.016 ) during mastication, whereas PGE2 and TGF alpha increased significantly in basal conditions ( by 35 percent; P=0.024 and by 47 percent; P=0.009, respectively ).
A second double-blind, placebo-controlled, cross-over design study was conducted with 32 GERD patients ( 21 female and 11 male ), from 23 to 61 years of age, with an average age of 41.
The esophageal secretion from submucosal mucous glands was collected, using the specially designed esophageal perfusion catheter, during mucosal exposure to initial NaCl followed by HCl/pepsin and final NaCl to mimic the natural gastroesophageal reflux scenario.
In collected samples their volume and the content of bicarbonate and non-bicarbonate buffers, protein, mucin, EGF, TGF alpha, and PGE2 were measured using commercial assays.
Collected data were statistically analyzed using SPSS statistical software.
Esophageal perfusate volumes were similar during administration of Zelnorm or placebo except in basal conditions ( 6.68 +/-0.06 vs. 6.53 +/-0.05 ml/min; P=0.021 ).
The rate of EGF secretion in basal conditions ( perfusion with initial NaCl ) during administration of Zelnorm was 13 percent higher than after placebo therapy ( 440 +/-129 vs. 390 +/-81 pg/min, NS ).
However, after the mucosal exposure to HCl/pepsin and subsequent final perfusion with NaCl, the rate of esophageal EGF secretion in patients receiving Zelnorm was significantly higher ( 46 percent ) than after placebo ( 408 +/-94 vs. 281 +/-88 pg/min, P=0.02 ). The increase in the rate of secretion of remaining investigated parameters varied between 2.1 percent and 24.6 percent, but did not reach statistical significance.
Zelnorm and functional heartburn study
Functional heartburn is characterized by the sensation of burning typically associated with heartburn, however, patients do not exhibit evidence of acid reflux.
As many patients experiencing functional heartburn do not respond to traditional heartburn treatments, research has suggested that this sensation may be caused by mechanistic function in the esophagus.
In the functional heartburn study, treatment with Zelnorm reduced a range of dysmotility-related upper GI symptoms, including epigastric discomfort, regurgitation, dysphagia ( pain while swallowing ), early satiety ( a sense of fullness while eating ), post-meal bloating, heartburn/acid reflux and chest pain.
Researchers indicated that these results showed promise for Zelnorm in the treatment of a number of GI conditions and called for additional studies of Zelnorm in functional heartburn and functional dyspepsia.
The functional heartburn study consisted of 42 patients ( 15 males and 27 females, from 20 to 68 years of age ) with functional heartburn.
Patients were randomly assigned to Zelnorm 6 mg b.i.d. and placebo for 14 consecutive days, in a crossover design, separated by a seven-to-10-day washout.
Patients completed a multi-symptom questionnaire, which evaluated nine prominent upper GI symptoms at baseline prior to all study procedures, and after completion of each treatment regimen. Symptoms assessed included epigastric pain, epigastric discomfort, heartburn/acid reflux, regurgitation, chest pain, dysphagia, early satiety, post-meal bloating, and nausea.
Symptom occurrence was compared using McNemar tests. Frequency, severity and distress were compared by randomized block analysis, P<0.05.
When compared to baseline, the following symptom parameters were significantly improved by Zelnorm but not by placebo: occurrence of epigastric discomfort, regurgitation, dysphagia, early satiety and post-meal bloating ( all P<0.05 ); frequency of epigastric discomfort, heartburn/acid reflux, and chest pain ( all P<0.05 ); severity of epigastric discomfort ( P<0.05 ); and distress from epigastric discomfort ( P<0.05 ). Distress from regurgitation was the only symptom significantly improved by placebo and not by Zelnorm when compared to baseline score ( P<0.05 ).
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In IBS-C clinical trials, Zelnorm was generally well tolerated. The only adverse events reported notably more often with Zelnorm than with placebo were diarrhea ( 9 percent vs. 4 percent ) and headache ( 15 percent vs. 12 percent ).
The majority of patients reporting diarrhea had a single episode and in most cases, diarrhea occurred in the first week of treatment. Typically, it resolved with continued therapy.
Serious consequences of diarrhea, including hypovolemia, hypotension and syncope, have been reported in the clinical studies ( 0.04 percent ) and during marketed use of Zelnorm.
In some cases, these complications have required hospitalization for rehydration.
Ischemic colitis and other forms of intestinal ischemia have been reported in patients receiving Zelnorm during marketed use of the drug. A causal relationship between Zelnorm and these events has not been established.
Source: Digestive Disease Week ( DDW ), 2005
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