(63) Continuation-in-part of application No. 1 1/372,857, filed on Mar. 10, 2006, said application No. 1 1/372, 857 is a continuation-in-part of application No. 10/827,689, filed on Apr. 19, 2004, which is a continu ation of application No. 10/354.483, filed on Jan. 30, 2003, now Pat. No. 6,793,936, which is a continuation in-part of application No. 10/331,754, filed on Dec. 30, 2002, now Pat. No. 6,902,742, which is a continuation of application No. 09/850.425, filed on May 7, 2001, now Pat. No. 6,730,325, which is a continuation of application No. 09/566,636, filed on May 8, 2000, now Pat. No. 6,228,398, which is a continuation of appli cation No. PCT/US99/25632, filed on Nov. 1, 1999.

Purpose: Pindolol is a synthetic beta-adrenergic receptor blocking agent with intrinsic sympathomimetic activity which exists as a racemic mixture of the R and S enantiomers. The R and S enantiomers of pindolol differ in both their pharmacokinetics and pharmacodynamics. The beta-adrenoceptor blocking effects of pindolol are largely confined to the S enantiomer, while the intrinsic sympathomimetic activity is shared equally by the R and S enantiomers. In addition, 5HT1a antagonism is a property of s-pindolol. Given these properties and our current understanding of IBS, our aim was to evaluate the efficacy of s-pindolol in IBS. Methods: Following a 8–14 day run-in period, eligible patients were randomly allocated to s-pindolol 2.5 mg t.i.d or placebo t.i.d. for four weeks. Patients receiving s-pindolol then had dose adjusted to 5 mg t.i.d for a further four weeks and to 7.5 mg t.i.d for the final four weeks, if tolerated. Three primary endpoints: Difference in the percentage of responders between AGI-001 and placebo based on 1. patient's global impression and 2. relief of abdominal pain/discomfort; 3. use of rescue medication (paracetamol). Numerous secondary endpoints were also assessed. The pre-defined statistical analysis was a one-sided analysis based on the hypothesis that s-pindolol is better than placebo. Results: There was no difference between treatments in terms of the number of patients who felt better on at least 50% of study days (one-sided P= 0.30). Logistic regression analysis yielded an odds ratio for AGI-001 relative to placebo: 0.73 (95% C.I. 0.24–2.20). The proportion of days of adequate relief of abdominal discomfort/pain did not differ between treatments (one-sided P= 0.34); odds ratio for AGI-001 relative to placebo: 0.77 (95% C.I. 0.25–2.42). Use of paracetamol was sparse and similar in both groups (one-sided P= 0.11). There were significant s-pindolol related improvements compared to baseline in the secondary endpoints of global severity of illness, abdominal pain, bloating/distention and straining at the highest dose visit (week 12). The incidence of adverse events was similar in s-pindolol- and placebo-treated groups. Conclusion: In this IBS study we have failed to reveal a significant benefit for s-pindolol at the doses administered in terms of global relief of IBS symptoms, relief of abdominal pain, or use of rescue medication.

Purpose: IBS is a common and clinically challenging gastrointestinal disorder for which few therapies of proven value are available for clinical use. Since the r-enantiomer of verapamil (r-verapamil) has been found to have a unique combination of activity not involving 5HT3 or 5HT4 and has been shown to have highly selective activity on the gastrointestinal tract compared to the cardiovascular system, the aim of this study was to assess the efficacy and safety of r-verapamil in the treatment of IBS. Methods: 129 male or female patients who fulfilled Rome II criteria for non-constipation predominant IBS were randomised to placebo (N = 64) or to r-verapamil (N = 65). R-verapamil was administered in an ascending dose schedule from 20, 40, to 80 mg t.i.d. across all r-verapamil treated patients. Dose escalation occurred at 4-week intervals; the entire treatment period was 12 weeks. The primary efficacy variables were the responder rates for patient global impression and relief of abdominal pain/discomfort which in turn were defined as feeling better on at least 50% of the entire 42 study days. The pre-defined statistical analysis was a one-sided analysis based on the hypothesis that r-verapamil is better than placebo. Results: 14 patients discontinued prematurely, 6 in the r-verapamil and 8 in the placebo group. Analysis of the intention-to-treat (ITT) population for the primary efficacy variables revealed significantly higher responder rates for r-verapamil for both the patient global impression (56.9% vs 37.5%, one-sided P= 0.0057) and abdominal pain/discomfort (56.9% vs 43.8%, one-sided P= 0.05). Significant benefits for r-verapamil were also evident for several secondary endpoints: composite GI symptom scale, bloating, stool frequency, urgency, Bristol stool scale and quality of life, as measured by the IBS-QOL. Adverse events were experienced by 17 patients in the r-verapamil and 8 in the placebo group. No severe AEs were recorded with the AE profile being very similar to the reported AE profile for racemic verapamil. Only 4 patients reduced their dose because of an AE. Conclusion: R-verapamil appears to be effective and well tolerated in the management of patients with non-constipation predominant irritable bowel syndrome given the significant response seen in the two primary and numerous secondary endpoints.

L'invention concerne des methodes et des formulations servant a traiter une maladie intestinale inflammatoire. Les methodes et les formulations comprennent, entre autres, des methodes et des formulations permettant d'administrer au niveau de regions affectees de l'intestin, a savoir, l'intestin distal, des concentrations efficaces d'acide 4-aminosalicylique et/ou d'acide 5-aminosalicylique, ainsi que des sels acceptables pharmaceutiquement et des promedicaments associes. Les methodes et les formulations comprennent des elements a liberation modifiee, ce qui permet d'administrer des medicaments au niveau de la region affectee ou desiree. Des maladies et des troubles pouvant etre traites par les methodes et les formulations de cette invention englobent la maladie de Crohn et la colite ulcereuse.