Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans.

BACKGROUND: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

The effects of camicinal, a novel motilin agonist, on gastro-esophageal function in healthy humans-a randomized placebo controlled trial.

BACKGROUND: A proportion of patients with foregut dysmotility fail to respond to standard interventions. Motilin agonists may be beneficial in this group. We aimed to determine the effect of camicinal, a novel motilin agonist, on gastrointestinal physiology in healthy volunteers. METHODS: Healthy male subjects were randomly assigned to receive a single dose of 125 mg camicinal or placebo in a double-blind cross-over design. Esophageal function and reflux indices were assessed using high-resolution manometry (pre and 1.5-h post dose) and 24-h ambulatory multichannel intraluminal impedance/pH. After a standardized meal, subjects ingested a wireless motility capsule from which compartmental transit times and motility indices were derived. Subjects were restudied with the alternate intervention after 7 days. KEY RESULTS: The study subjects (12 male, mean age 47.4 years, range 22-55) tolerated the drug well, except one who exhibited mild abdominal pain on both placebo and camicinal. In comparison to placebo, gastric emptying time (GET) was accelerated following camicinal (-115.4 min, 95% confidence interval -194.4, -36.4, p = 0.009). No effect was demonstrable on esophageal function, small bowel, colonic, or whole bowel transit times and motility indices. With camicinal, as part of a post hoc analysis, there was a trend association between the percentage reduction in GET and total number of acidic reflux events (r = 0.56, p = 0.09). CONCLUSIONS & INFERENCES: Camicinal decreases GET and was generally well-tolerated. In health, the direct effects of camicinal are on accelerating GET with a potential secondary benefit of reducing reflux events, which warrant further exploration in patient cohorts.

Drugs acting at 5-HT4 , D2 , motilin, and ghrelin receptors differ markedly in how they affect neuromuscular functions in human isolated stomach.

BACKGROUND: Progress in identifying safer, effective drugs to increase gastric emptying is impeded by failed clinical trials. One potential reason for failure is lack of translation from animal models to the human condition. To make progress, the actions of existing drugs and new therapeutic candidates need to be understood in human isolated stomach. METHODS: Neuromuscular activities were evoked in human gastric antrum circular muscle by electrical field stimulation (EFS), defined phenotypically using pharmacological tools. KEY RESULTS: EFS evoked cholinergically mediated contractions, attenuated by simultaneous nitrergic activation. The 5-HT4 receptor agonist/D2 antagonist metoclopramide and the selective 5-HT4 agonist prucalopride, facilitated contractions in the absence (respectively, Emax 95 ± 29% and 42 ± 9%, n = 3-6 each concentration) and presence (139 ± 38%, 55 ± 13%, n = 3-5) of the NO synthase inhibitor L-NAME, without affecting submaximal contractions to carbachol; the 5-HT4 antagonist SB204070 prevented facilitation by metoclopramide 100 µM (respectively, -5 (range -26 to 34) and 167 (12-1327)% in presence and absence; n = 5-6). The selective motilin receptor agonist camicinal provided considerably greater facilitation (478 (12-2080)% at 30 µM, n = 8). Domperidone (0.001-100 µM; n = 3-6) and acylated or des-acylated ghrelin (1-300 nM; n = 2-4) had no consistent activity, even with protease inhibitors. CONCLUSIONS & INFERENCES: 5-HT4 receptor agonists show different efficacies. Motilin receptor activation has greater potential to increase gastric emptying, whereas ghrelin and D2 receptor antagonism have no direct activity. Drugs stimulating human gastric motility directly can act regardless of disease mechanisms, whereas drugs without direct activity but an ability to block nausea/vomiting may be effective only if these symptoms exist.

Regional- and agonist-dependent facilitation of human neurogastrointestinal functions by motilin receptor agonists.

BACKGROUND AND PURPOSE: Delayed gastric emptying is poorly managed. Motilin agonists are potential treatments but inadequate understanding into how enteric nerve functions are stimulated compromises drug/dose selection. Resolution is hampered by extreme species dependency so methods were developed to study human gastrointestinal neuromuscular activities and the neurobiology of motilin. EXPERIMENTAL APPROACH: Protocols to study neuromuscular activities were developed for different regions of human stomach and intestine (71 patients) using circular muscle preparations and electrical field stimulation (EFS) of intrinsic nerves. Other tissues were fixed for immunohistochemistry. KEY RESULTS: EFS evoked contractions and/or relaxations via cholinergic and nitrergic neurons, with additional tachykinergic activity in colon; these were consistent after 154 min (longer if stored overnight). Motilin 1-300 nM and the selective motilin agonist GSK962040 0.1-30 µM acted pre-junctionally to strongly facilitate cholinergic contractions of the antrum (E(max) ≈ 1000% for motilin), with smaller increases in fundus, duodenum and ileum; high concentrations increased baseline muscle tension in fundus and small intestine. There were minimal effects in the colon. In the antrum, cholinergic facilitation by motilin faded irregularly, even with peptidase inhibitors, whereas facilitation by GSK962040 was long lasting. Motilin receptor immunoreactivity was identified in muscle and myenteric plexus predominantly in the upper gut, co-expressed with choline acetyltransferase in neurons. CONCLUSIONS AND IMPLICATIONS: Motilin and GSK962040 strongly facilitated cholinergic activity in the antrum, with lower activity in fundus and small intestine only. Facilitation by motilin was short lived, consistent with participation in migrating motor complexes. Long-lasting facilitation by GSK962040 suggests different receptor interactions and potential for clinical evaluation.

GSK962040: a small molecule motilin receptor agonist which increases gastrointestinal motility in conscious dogs.

BACKGROUND: GSK962040, a small molecule motilin receptor agonist, was identified to address the need for a safe, efficacious gastric prokinetic agent. However, as laboratory rodents lack a functional motilin system, studies in vivo have been limited to a single dose, which increased defecation in rabbits. Motilin agonists do not usually increase human colonic motility, so gastric prokinetic activity needs to be demonstrated. METHODS: The effect of intravenous GSK962040 on gastro-duodenal motility was assessed in fasted dogs implanted with strain gauges. Activity was correlated with blood plasma concentrations of GSK962040 (measured by HPLC-MS/MS) and potency of GSK962040 at the dog recombinant receptor [using a Fluorometric Imaging Plate Reader (Molecular Devices, Wokingham, UK) after expression in HEK293 cells]. KEY RESULTS: GSK962040 activated the dog motilin receptor (pEC(50) 5.79; intrinsic activity 0.72, compared with [Nle(13) ]-motilin). In vivo, GSK962040 induced phasic contractions, the duration of which was dose-related (48 and 173 min for 3 and 6 mg kg(-1) ), driven by mean plasma concentrations >1.14 µmol L(-1) . After the effects of GSK962040 faded, migrating motor complex (MMC) activity returned. Migrating motor complex restoration was unaffected by 3 mg kg(-1) GSK962040 but at 6 mg kg(-1) , MMCs returned 253 min after dosing, compared with 101 min after saline (n=5 each). CONCLUSIONS & INFERENCES: The results are consistent with lower potency for agonists at the dog motilin receptor, compared with humans. They also define the doses of GSK962040 which stimulate gastric motility. Correlation of in vivo and in vitro data in the same species, together with plasma concentrations, guides further studies and translation to other species.

The Patient Health Questionnaire 12 Somatic Symptom scale as a predictor of symptom severity and consulting behaviour in patients with irritable bowel syndrome and symptomatic diverticular disease.

BACKGROUND: Anxiety, depression and nongastrointestinal symptoms are often prominent in irritable bowel syndrome (IBS), but their relative value in patient management has not been quantitatively assessed. We modified the Patient Health Questionnaire 15 (PHQ-15) by excluding three gastrointestinal items to create the PHQ-12 Somatic Symptom (PHQ-12 SS) scale. AIMS: To compare the value of the PHQ-12 SS scale with the Hospital Anxiety and Depression (HAD) scale in predicting symptoms and patient behaviour in IBS and diverticular disease. METHODS: We compared 151 healthy volunteers (HV), 319 IBS patients and 296 patients with diverticular disease (DD), 113 asymptomatic [ASYMPDD] and 173 symptomatic DD (SYMPDD). RESULTS: Patient Health Questionnaire 12 SS scores for IBS and SYMPDD were significantly higher than HV. Receiver-operator curves showed a PHQ-12 SS >6, gave a sensitivity for IBS of 66.4% with a specificity of 94.7% and a positive likelihood ratio (PLR) = 13.2, significantly better than that associated with an HAD anxiety score >7, PLR = 3.0 and depression score >7 PLR = 6.5. PHQ-12 SS correlated strongly with IBS severity scale and GP visits in both IBS and DD. CONCLUSION: The PHQ-12 SS scale is a useful clinical tool which correlates with patient behaviour in both IBS and symptomatic DD.

Effect of the NK(3) receptor antagonist, talnetant, on rectal sensory function and compliance in healthy humans.

Visceral hypersensitivity is important in the pathophysiology of irritable bowel syndrome and thus a target for modulation in drug development. Neurokinin (NK) receptors, including NK(3) receptors, are expressed in the motor and sensory systems of the digestive tract. The aim of this study was to compare the effects of two different doses (25 and 100 mg) of the NK(3) receptor antagonist, talnetant (SB223412) with placebo on rectal sensory function and compliance in healthy volunteers studied at two centres. Rectal barostat tests were performed on 102 healthy volunteers, randomized to receive either oral talnetant 25 or 100 mg or placebo over 14-17 days. Studies were performed on three occasions: day 1 immediately prior to 1st dose, day 1 4 h postdose, and after 14- to17-day therapy. Compliance, and pressure thresholds for first sensation, urgency, discomfort and pain were measured using ascending method of limits, and sensory intensity ratings for gas, urgency, discomfort and pain determined during four random phasic distensions (12, 24, 36 and 48 mmHg). Talnetant had no effect on rectal compliance, sensory thresholds or intensity ratings compared with placebo. In general, the results obtained at the two centres differed minimally, with intensity scores at one centre consistently somewhat lower. At the doses tested, talnetant has no effect on rectal compliance or distension-induced rectal sensation in healthy participants.

Association between a functional polymorphism in the serotonin transporter gene and diarrhoea predominant irritable bowel syndrome in women.

BACKGROUND AND AIMS: Serotonin (5-hydroxtryptamine, 5-HT) is an important factor in gut function, playing key roles in intestinal peristalsis and secretion, and in sensory signalling in the brain-gut axis. Removal from its sites of action is mediated by a specific protein called the serotonin reuptake transporter (SERT or 5-HTT). Polymorphisms in the promoter region of the SERT gene have effects on transcriptional activity, resulting in altered 5-HT reuptake efficiency. It has been speculated that such functional polymorphisms may underlie disturbance in gut function in individuals suffering with disorders such as irritable bowel syndrome (IBS). The aim of this study was to assess the potential association between SERT polymorphisms and the diarrhoea predominant IBS (dIBS) phenotype. SUBJECTS: A total of 194 North American Caucasian female dIBS patients and 448 female Caucasian controls were subjected to genotyping. METHODS: Leucocyte DNA of all subjects was analysed by polymerase chain reaction based technologies for nine SERT polymorphisms, including the insertion/deletion polymorphism in the promoter (SERT-P) and the variable tandem repeat in intron 2. Statistical analysis was performed to assess association of any SERT polymorphism allele with the dIBS phenotype. RESULTS: A strong genotypic association was observed between the SERT-P deletion/deletion genotype and the dIBS phenotype (p = 3.07x10(-5); n = 194). None of the other polymorphisms analysed was significantly associated with the presence of disease. CONCLUSIONS: Significant association was observed between dIBS and the SERT-P deletion/deletion genotype, suggesting that the serotonin transporter is a potential candidate gene for dIBS in women.

A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder seen in primary care practice. The symptoms of IBS, including abdominal pain, discomfort, and abnormal bowel function, may be modulated by activity of the serotonin type 3 receptor (5-HT(3)). The efficacy and tolerability of the 5-HT(3) receptor antagonist alosetron hydrochloride in nonconstipated female patients with IBS were evaluated in a double-blind, randomized, placebo-controlled trial. METHODS: Patients received either 1 mg of alosetron hydrochloride (n = 309) or placebo (n = 317) twice daily for 12 weeks, followed by a 4-week posttreatment period. Adequate relief of IBS pain and discomfort was the primary end point. Secondary end points included improvements in urgency, stool frequency, stool consistency, incomplete evacuation, and bloating. RESULTS: Seventy-one percent of patients were classified as having diarrhea-predominant IBS. Forty-three percent of alosetron-treated patients with diarrhea-predominant IBS reported adequate relief for all 3 months compared with 26% of placebo-treated patients (P<.001; percentage point difference = 17; 95% confidence interval, 8.0-25.4). Improvement with alosetron compared with placebo was observed by the end of the fourth week of treatment and persisted throughout the remainder of treatment. Alosetron significantly decreased urgency and stool frequency and caused firmer stools within 1 week of starting treatment. Effects were sustained throughout treatment and symptoms returned following treatment cessation. No significant improvement in the percentage of days with sense of incomplete evacuation or bloating was observed compared with placebo during the first month of treatment. Constipation was the most commonly reported adverse event. CONCLUSION: Alosetron hydrochloride, 1 mg twice daily for 12 weeks, is effective in relieving pain and some bowel-related symptoms in diarrhea-predominant female patients with IBS.

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

OBJECTIVES: Alosetron (Lotronex) is a new therapeutic agent for irritable bowel syndrome (IBS) in women with diarrhea-predominant IBS. This multicenter randomized, double-blind, placebo-controlled study assessed the safety and tolerability of alosetron during long-term (< or = 12 months) treatment. METHODS: A total of 859 subjects (637 female and 222 male) with IBS were enrolled from 130 sites in the United States and were randomized 3:1 to receive 1 mg alosetron or placebo b.i.d. for 48 wk; of the subjects, 649 (76%) were randomized to the alosetron group and 212 (24%) to the placebo group. Of the original group, 850 subjects received at least one dose of alosetron (n = 640) or placebo (n = 210). RESULTS: In all, 59% of the subjects completed the study. Safety data were similar in treatment groups and within age, sex, racial origin, and hormone use. Adverse events were reported by 83% (530/640) and 76% (159/210) of subjects in the alosetron and placebo groups, respectively, (p < 0.05) and were similar with the exception of constipation; 32% of subjects receiving alosetron reported constipation, compared to 5% in the placebo group (p < 0.001). Most reports (72%) of constipation were of mild or moderate severity, and 66% of subjects with constipation had single episode of 8 days median duration. Constipation occurred a median of 13 days after initiating treatment and resolved spontaneously, with laxative, or after a brief interruption of therapy. Of the subjects, 4% (11/210) in the alosetron and 5% (28/ 640) in the placebo group experienced serious adverse events. Two deaths occurred in subjects with pre-existing cardiovascular risk factors; neither death was attributed to the study drug. CONCLUSIONS: Alosetron 1 mg b.i.d. for 12 months was well tolerated. Constipation is the most frequent adverse event, with a higher incidence of transient constipation in alosetron-treated patients, typically occurring in the first month of treatment.

Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder with symptoms of abdominal pain, discomfort, and altered bowel function. Antagonists of the type 3 serotonin receptor (5-HT3) have shown promising results in the relief of IBS-associated symptoms. We aimed to confirm these findings by doing a randomised, placebo-controlled trial. METHODS: We studied 647 female IBS patients with diarrhoea-predominant or alternating bowel patterns (diarrhoea and constipation). 324 patients were assigned 1 mg alosetron and 323 placebo orally twice daily for 12 weeks, followed by a 4-week post-treatment period. Adequate relief of abdominal pain and discomfort was the primary endpoint; secondary endpoints included improvements in urgency, stool frequency, and stool consistency. Analysis was by intention to treat. FINDINGS: 79 (24%) of patients in the alosetron group and 53 (16%) in the placebo group dropped out. The difference in the drop-out rate between groups was mainly due to a greater occurrence of constipation in the alosetron group. A greater proportion of alosetron-treated patients than placebo-treated patients (133 [41%] vs 94 [29%], respectively) reported adequate relief for all 3 months of treatment (difference 12% [4.7-19.2]). Alosetron also significantly decreased urgency and stool frequency, and increased stool firmness. Constipation occurred in 30% and 3% of patients in the alosetron and placebo groups, respectively. INTERPRETATION: Alosetron was well tolerated and clinically effective in alleviating pain and bowel-related symptoms in this population of women with IBS.

Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist.

BACKGROUND: No currently available treatment provides consistent relief of irritable bowel syndrome. Colonic sensory and motor function are modulated partly through 5HT3-receptors. AIM: To evaluate effects of the 5HT3-receptor antagonist, alosetron, in irritable bowel syndrome. METHODS: Randomized, double-blind, placebo-controlled, dose-ranging (1, 2, 4, 8 mg b.d. alosetron), 12-week trial in 370 patients with diarrhoea-predominant or alternating constipation and diarrhoea irritable bowel syndrome. Weekly measurement of adequate relief was the key end-point; other irritable bowel syndrome symptoms were collected daily using an electronic phone system. RESULTS: Alosetron (1 mg or 2 mg b.d.) significantly (P < 0.05 vs. placebo) increased the proportion of females, but not males, reporting adequate relief. Stool consistency, frequency and percentage days with urgency improved over placebo (P < 0.05) within the first month with all doses of alosetron, and persisted throughout the trial with all doses in female patients. With 1 mg b.d. alosetron, females had improved stool consistency and urgency within the first week, and adequate relief and improved stool frequency within the first 2 weeks. There was no consistent improvement in bowel function among male patients. CONCLUSION: In female irritable bowel syndrome patients with predominant diarrhoea or alternating constipation and diarrhoea, alosetron is effective in treatment of abdominal pain and discomfort and bowel-related symptoms.

Adequate relief as an endpoint in clinical trials in irritable bowel syndrome.

Irritable bowel syndrome is characterized by recurrent abdominal pain and altered bowel function. In designing studies to evaluate new treatments for this disease, however, it is difficult to select appropriate endpoints to reflect improvement in the range of symptoms of the syndrome. In the present study we evaluated the parameter of adequate relief of abdominal pain and discomfort, as perceived by the patients, as a key endpoint for efficacy in the treatment of patients with irritable bowel syndrome. Abdominal pain and bowel function data were collected daily from 370 patients with the disease during treatment with placebo or a novel potent 5HT3 receptor antagonist. Once every 7 days adequate relief of pain and discomfort was assessed. Quality-of-life data were collected using self-administered questionnaires. The endpoint of adequate relief was significantly (P < 0.05) correlated with improvement in pain severity scores, percentage of pain-free days, percentage of days with urgency, improvement in stool frequency and consistency, and quality-of-life parameters. Adequate relief of pain and discomfort is significantly correlated with changes in multiple parameters associated with irritable bowel syndrome and can be used as an endpoint for assessing response to therapy in these patients.

Pharmacokinetics of amiloride after inhalation and oral administration in adolescents and adults with cystic fibrosis.

STUDY OBJECTIVE: To compare the pharmacokinetics and systemic exposure of nebulized and oral amiloride in adolescents and adults with mild to moderate cystic fibrosis (CF). DESIGN: Open-label, randomized, two-way crossover, single-dose pharmacokinetic study. SETTING: University hospital clinical research unit. PATIENTS: Nine adolescents and 10 adults with mild to moderate CF (forced expiratory volume in 1 sec > or = 50% predicted, Brasfield score > or = 15). INTERVENTIONS: Patients received amiloride solution orally (10 mg of amiloride 1-mg/ml solution) and by inhalation [4.5 ml amiloride of 1-mg/ml solution in 12% saline (approximately 3.8 mmol/L) by DeVilbiss 646 nebulizer] during two study phases separated by a 7- to 28-day washout period. Serial blood and urine samples were collected for 48 and 72 hours, respectively. MEASUREMENTS AND MAIN RESULTS: After oral dosing, the mean +/- SD maximum peak concentration (Cmax) was 20.6 +/- 10.0 ng/ml at 3.2 +/- 1.2 hours in adults and 21.7 +/- 4.88 at 2.9 +/- 0.6 hours in the adolescents. Mean area under the concentration-time curve (AUC) from time zero to infinity hours was 275 +/- 115 and 254 +/- 60 ng.hr/ml in the adult and adolescent groups; half-life was 16.0 +/- 0.7 and 13.4 +/- 1.4 hours, respectively. After nebulization, 14 of 19 subjects exhibited two concentration peaks (Cmax1 and Cmax2) with mean values of 1.57 +/- 1.67 ng/ml at 0.5 +/- 0.2 hours and 1.37 +/- 1.21 ng/ml at 4.0 +/- 1.0 hours for adults, and 1.49 +/- 0.99 ng/ml at 0.5 +/- 0.1 hours and 1.52 +/- 0.81 ng/ml at 3.3 +/- 0.5 hours for adolescents. Estimated mean +/- SD dose nebulized was 1.91 +/- 0.66 and 2.28 +/- 0.30 mg in the adult and adolescent groups, respectively. Mean +/- SD AUC from time zero to the last measurable plasma amiloride concentration after inhalation was 14.4 +/- 17.6 and 15.4 +/- 10.1 ng.hr/ml in the adults and adolescents. No significant adverse events occurred during the study. Pharmacokinetic parameters were not statistically different between the adolescent and adult groups by route of administration. However significant differences in peak amiloride concentration, AUC, and urinary amiloride excretion were evident when comparing oral versus inhalation administration within each group. CONCLUSIONS: Mean amiloride plasma concentration peaks and AUC after inhalation were significantly lower than after oral dosing. In addition, the second amiloride plasma concentration peak may be due to oral ingestion of the nebulized amiloride, whereas the earlier Cmax1 after inhalation may be due to pulmonary absorption of amiloride. These results suggest that single-dose amiloride inhalation in patients with mild to moderate CF results in minimal systemic exposure compared with oral dosing, and that drug disposition is similar in adolescents and adults with CF.

Use of a novel electronic data collection system in multicenter studies of irritable bowel syndrome.

BACKGROUND: The reliability of symptom data collected during efficacy studies in irritable bowel syndrome (IBS) is paramount to the proper assessment of potential therapeutic agents. Historically, data have been collected on paper diary cards, which patients were requested to fill out at a specified interval. However, with paper diary cards it is not possible to determine whether the cards are filled out as required, or at random times. To circumvent this problem, a novel electronic data collection system that ensures the reliability and security of data entry was used. METHODS: Data were collected from 640 patients during the 2-week screening and 12-week treatment phases of two multicentre trials of IBS. The electronic data collection system used was based upon a touchtone telephone system. RESULTS: The electronic data collection system had a potential 8135 up-time hours during the study. An up-time of 8040 h and down-time of 95 h was observed. This corresponds to an up-time of approximately 99%. Patient compliance for data entry in the two studies was 81% and 83%, respectively. On a single random day during their daily telephone call, patients were asked questions to assess satisfaction with the system. On aggregate, 79% of patients were satisfied or very satisfied with the system, only 10% were dissatisfied or very dissatisfied. CONCLUSION: A unique electronic data collection system was tested for use in clinical studies in IBS. This system provided 100% reliability as to the date of data entry, and data were not subject to modification once entered. This methodology represents a marked advancement in clinical studies of IBS.

Disposition of didanosine in HIV-seropositive patients with normal renal function or chronic renal failure: influence of hemodialysis and continuous ambulatory peritoneal dialysis.

OBJECTIVE: To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic kidney failure. METHODS: Three groups of patients with human immunodeficiency virus (HIV) infection were studied: group I, six men with normal kidney function (creatinine clearance > 90 ml/min/1.73 m2); group II, six men with chronic renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD); and group III, four men and two women with chronic renal failure receiving hemodialysis three times a week. A 300 mg dose of didanosine was administered orally and intravenously according to a two-period randomized crossover design. Patients in group III were studied between hemodialysis sessions during the crossover periods. In addition, patients in group III were studied in a third period after administration of a 300 mg oral dose of didanosine 4 hours before hemodialysis. RESULTS: After intravenous administration in group I, the mean (+/-SD) total clearance (CLT) was 13.0 +/- 1.6 ml/min/kg and the elimination half-life (t 1/2) was 1.56 +/- 0.43 hour. In groups II and III, the CLT decreased significantly to 3.4 +/- 1.2 and 3.2 +/- 1.2 ml/min/kg, respectively, whereas the t1/2 increased to 3.60 +/- 0.82 hours and 3.11 +/- 0.88 hours, respectively. The absolute bioavailability of didanosine in groups I, II, and III was 42% +/- 12%, 52% +/- 6%, and 38% +/- 11%, respectively, and did not differ significantly. CAPD had little effect on the removal of didanosine, whereas approximately 30% of the drug present in the body at the start of dialysis was eliminated by an average 3-hour dialysis session. CONCLUSION: The clearance of didanosine is impaired in patients with chronic renal failure. To compensate, the dose and schedule of administration should be adjusted. It is recommended that one-fourth of the total daily dose of didanosine be administered once a day in this patient population.

Pharmacokinetics of ondansetron in patients with hepatic insufficiency.

Ondansetron is primarily eliminated via hepatic metabolism; thus, liver disease may affect its clearance. The pharmacokinetics of ondansetron in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age- and gender-matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron. This was an open-label study in which 8 mg ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of ondansetron was lower among patients with hepatic impairment that control subjects. After a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first-pass effect in patients with liver disease resulting in a higher AUC0-infinity. A correlation existed between clearance of ondansetron and decreased antipyrine clearance; a smaller correlation existed between ondansetron clearance and indocyanine green clearance. Mean percent of ondansetron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to ondansetron. A reduction in the clearance of ondansetron is associated with increasing degrees of hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of > 9) should have their daily dose of ondansetron limited to 8 mg (or 0.15 mg/kg).

Comparison of quantitative methods to assess hepatic function: Pugh's classification, indocyanine green, antipyrine, and dextromethorphan.

STUDY OBJECTIVES: To compare three quantitative metabolic markers used to assess hepatic function, indocyanine green (ICG), a high-extraction marker; antipyrine, a low-extraction marker; and dextromethorphan, a P-450IID6 marker, with the clinically used Pugh's classification. DESIGN: Comparison of 12 healthy controls with 12 age- and sex-matched patients with different degrees of liver disease. SETTING: Research center in a university-affiliated teaching hospital. PATIENTS: The 12 patients had different degrees of liver disease: 4 mild (Pugh's score 6 or 7); 4 moderate (Pugh's score 8 or 9); and 4 severe (Pugh's score > or = 10). Each level had an equal number of men and women subjects. MEASUREMENTS AND MAIN RESULTS: Clearance of ICG detected mild alterations in hepatic function as efficiently as it did for moderate and severe impairment, but it lacked the specificity to distinguish among the classification groups. In contrast, antipyrine was effective in identifying moderate and severe hepatic impairment; however, its clearance was not reduced in mild liver disease. Pugh's classification appears to be a clinically useful method of assessing the global degree of hepatic impairment in patients with chronic disease, and there was a significant correlation between it and antipyrine clearance (r = 0.67, p = 0.0003) and ICG clearance (r = 0.86, p = 0.0001). Four of eight patients with a Pugh's score greater than 8 had a dextromethorphan metabolic ratio expression reflective of a poor metabolizer phenotype based on 0- to 4-hour urine collection, but only two of those eight patients were classified as poor metabolizers based on 4- to 12-hour urine collection. These percentages of poor metabolizers are substantially higher than for historical controls (8.5-10.4%) and most likely reflect a decrease in the P-450IID6 functional ability with progression of liver disease. However, due to small sample size and lack of knowledge of the patients' genotypes, these data are only suggestive. CONCLUSION: Pugh's classification appears to be a reliable indicator of the degree of chronic liver disease and could be employed as a drug development research classification tool; however, it does not replace quantitative metabolic markers, especially isozyme-specific markers.

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.