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Biomedical subjects

William L Hasler

Publications and source records attributed to William L Hasler.

At least 19 recordsLinked to original sources
PubMed2006

Modulation of intestinal gas dynamics in healthy human volunteers by the 5-HT receptor agonist tegaserod.

OBJECTIVES: Bloating in irritable bowel syndrome (IBS) may result from impaired intestinal gas transit and is reduced by the 5-HT4 agonist tegaserod. Abnormal serotonergic function underlies many IBS symptoms, but the role of 5-HT4 pathways in regulating gas dynamics under healthy conditions is unexplored. We hypothesized that 5-HT4 activation by tegaserod stimulates gas transit in healthy individuals. METHODS: Sixteen normal volunteers underwent jejunal perfusion of gas mixtures (88% N2, 5.5% O2, 6.5% CO2) at 11.2 mL/min x 3 h under control conditions and 3 h after oral tegaserod 6 mg on separate days. Gas collected from an intrarectal catheter was quantified using a barostat. RESULTS: Under control conditions, gas evacuation after a lag period (1,959 +/- 428 s) was predominantly pulsatile with expulsion of 1,984 +/- 90 mL. A mean of 29 +/- 2 boluses with volumes of 72 +/- 5 mL were expelled. In 10 subjects with physiologic degrees of gas retention in control studies (248 +/- 73 mL), tegaserod increased expulsion from 1,768 +/- 73 to 1,973 +/- 37 mL and decreased retention to 43 +/- 37 mL (p < 0.05). Total volumes expelled as boluses were greater after tegaserod (1,708 +/- 73 vs 1,846 +/- 59 mL, p < 0.05) from increased bolus numbers in four subjects and increased bolus volumes in seven. Nonpulsatile continuous flow tended to increase with tegaserod (43 +/- 7 vs 126 +/- 43 mL, p= 0.10). Tegaserod did not increase evacuation in individuals without physiologic gas retention. CONCLUSIONS: The 5-HT4 agonist tegaserod promotes evacuation of jejunally perfused gas mixtures in healthy humans. These findings provide the foundation for future investigations into use of 5-HT4 agonists in conditions of pathologic gas retention.

Administration, Oral↗
PubMed2006

Nutrient modulation of intestinal gas dynamics in healthy humans: dependence on caloric content and meal consistency.

The actions of nutrients on gut transit of liquids and solids have been extensively studied, but the effects of meal ingestion on intestinal gas flow are unexplored. We hypothesized that meals of varying caloric content and consistency modulate gas transit to different degrees. Nine healthy volunteers underwent jejunal perfusion of physiological gas mixtures at 12 ml.min(-1).3 h, with ingestion of nothing (control), water (240 ml), 240-kcal liquid meals, and 240-kcal solid meals at the end of the second hour in separate studies. Gas was quantified from an intrarectal catheter. After an initial lag phase, gas evacuation approached steady state by the end of the fasting period. Solid and liquid caloric meals increased total gas volumes evacuated from 5-40 min after ingestion vs. control studies (P < 0.05). These increases resulted from increased numbers of bolus gas evacuations (P < 0.05), whereas bolus volumes, pressures, and flow rates were similar for all test conditions. Solid and liquid caloric meals elicited similar effects on bolus gas dynamic parameters, whereas water did not affect these measures vs. control (NS, not significant). Both caloric meals and the noncaloric liquid meal increased continuous gas flow, which represented <2% of total gas expulsion. In conclusion, caloric meals promote bolus gas transit in healthy humans, whereas noncaloric liquids have no effect. Solids stimulate early postprandial gas dynamics to the same extent as liquid meals of similar caloric content. Thus modulatory effects of meals on intestinal gas transit depend on their caloric content but not their consistency.

Adaptation, Physiological↗
PubMed2004

Selective reversal of hyperglycemia-evoked gastric myoelectric dysrhythmias by nitrergic stimulation in healthy humans.

Acute hyperglycemia disrupts gastric myoelectric rhythm in healthy humans. Defective nitrergic function is a factor in animal models of diabetic gastropathy. We tested participation of nitrergic pathways in hyperglycemia-evoked myoelectric dysrhythmias and compared their role in preventing dysrhythmic actions of experimental motion sickness. Twelve healthy volunteers underwent electrogastrography (EGG) with and without intravenous 20% dextrose to produce plasma glucoses of 250 mg/dl. EGG continued for 2 h after oral nitroglycerin (9 mg) or the cyclic GMP-specific phosphodiesterase inhibitor sildenafil (100 mg). In separate studies, 12 volunteers underwent circular vection (60 degrees /s) without and 90 min after nitroglycerin (9 mg) or sildenafil (100 mg) with concurrent EGG. Hyperglycemia decreased recording time in normal rhythm, increased tachygastria more than 3-fold, and decreased power of the dominant frequency (P < 0.05). Nitroglycerin and sildenafil reversed effects of hyperglycemia, improving normal rhythm, decreasing tachygastria (both P < 0.05), and blunting power decreases. Neither agent affected EGG rhythm during euglycemia. Vection decreased time in normal rhythm and increased tachygastria (P < 0.05). However, nitroglycerin and sildenafil did not reverse dysrhythmic effects of vection (P = N.S.). In conclusion, administration of a nitric oxide (NO) donor or an inhibitor of cyclic GMP-selective phosphodiesterase reverses the dysrhythmic effects of hyperglycemia on gastric myoelectric activity in healthy humans. These agents have no effect on dysrhythmias during motion sickness. These findings are consistent with selective impairment of nitrergic function in this model of diabetic gastropathy and suggest that NO donors and other agents that increase NO activity may be useful for treating diabetic dysrhythmias.

Adult↗
PubMed2004

Safety profile of tegaserod, a 5-HT4 receptor agonist, for the treatment of irritable bowel syndrome.

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts. In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod.

Drug Interactions↗
PubMed2003

Ginger reduces hyperglycemia-evoked gastric dysrhythmias in healthy humans: possible role of endogenous prostaglandins.

Acute hyperglycemia evokes gastric slow wave dysrhythmias via endogenous prostaglandin generation. Ginger exhibits slow wave antiarrhythmic effects in other models, but its actions on hyperglycemia-evoked gastric dysrhythmias are unexplored. We hypothesized that ginger prevents disruption of slow wave rhythm by acute hyperglycemia via inhibition of prostaglandin production but not its actions. Twenty-two healthy humans underwent fasting electrogastrography during hyperglycemic clamping to 250 to 290 mg/dl after double-blind placebo or ginger root (1 g). Responses were compared with the prostaglandin E1 analog misoprostol (400 microg). Dominant frequencies (DF) and the percentage of recording times in the bradygastric [0.5-2 cycles/min (cpm)], normal (2-4 cpm), and tachygastric (4-9 cpm) frequency ranges were analyzed. After placebo, hyperglycemia reduced normal 2 to 4 cpm activity from 94.4 +/- 2.6 to 66.0 +/- 10.4%, increased the DF from 2.96 +/- 0.04 to 4.09 +/- 0.45 cpm, and increased tachygastria from 2.0 +/- 1.4 to 29.3 +/- 10.7% (P < 0.05). Hyperglycemia effects on normal activity (77.3 +/- 8.3%), DF (3.46 +/- 0.37 cpm), and tachygastria (15.6 +/- 8.6%) were significantly reduced by ginger (P < 0.05). Misoprostol evoked decreases in normal activity from 95.4 +/- 2.0 to 81.7 +/- 3.0% and increases in tachygastria from 3.1 +/- 1.6 to 11.2 +/- 2.4% (P < 0.05). However, ginger did not correct these abnormalities versus placebo (P = N.S.). In conclusion, acute hyperglycemia evokes gastric slow wave dysrhythmias that are prevented by ginger root. Conversely, the compound has no effect on dysrhythmias elicited by a prostaglandin E(1) analog, indicating that ginger likely acts to blunt production of prostaglandins rather than inhibiting their action. These findings suggest novel mechanisms for the traditional Chinese herbal remedy ginger.

Adult↗
PubMed2003

The irritable bowel syndrome during pregnancy.

The irritable bowel syndrome (IBS) is characterized by altered bowel habits and abdominal discomfort in the absence of organic disease. No markers exist for IBS, and the definition of IBS is based on the presence of specific symptoms. The Rome II criteria for defining IBS include abdominal pain or discomfort for 12 weeks or longer, which need not be continuous, over the past 12 months plus two of the following: (1) relief of discomfort with defecation; (2) association of discomfort with altered stool frequency; and (3) association of discomfort with altered stool form. Nine percent to 22% of the population report symptoms consistent with IBS. IBS is the most prevalent digestive disease, representing 12% of visits to primary care physicians and 28% of referrals to gastroenterologists.

Antidepressive Agents↗
PubMed2003

Pharmacotherapy for intestinal motor and sensory disorders.

Motor disorders of the gastrointestinal tract are characterized by definable impairments of gut contractile function. Other conditions exhibit specific disturbances of visceral afferent and efferent activity, which may underlie selected symptom complexes. Medications in several classes have been developed to treat these disorders of gastrointestinal function. Prokinetic agents are effective therapies for ailments with reduced motor function, whereas antispasmodic drugs reduce symptoms in conditions with exaggerated pressure wave activity. Recently, medications designed to blunt transmission in visceral sensory pathways have been proposed for use in the functional bowel disorders. Finally, some patients may benefit from initiation of nonspecific therapies, which have no appreciable effect on gut motor or sensory function.

Antidepressive Agents↗