EP1284732A2 - Methode de traitement de la dyspepsie fonctionnelle - Google Patents

Methode de traitement de la dyspepsie fonctionnelle

Info

Publication number
EP1284732A2
EP1284732A2 EP01935516A EP01935516A EP1284732A2 EP 1284732 A2 EP1284732 A2 EP 1284732A2 EP 01935516 A EP01935516 A EP 01935516A EP 01935516 A EP01935516 A EP 01935516A EP 1284732 A2 EP1284732 A2 EP 1284732A2
Authority
EP
European Patent Office
Prior art keywords
alosetron
treatment
patients
pharmaceutically acceptable
functional dyspepsia
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01935516A
Other languages
German (de)
English (en)
Inventor
Allen Wayne GlaxoSmithKline MANGEL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1284732A2 publication Critical patent/EP1284732A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the invention relates to a new medical use for alosetron, a compound which act as an antagonist of 5-hydroxytryptamine (5-HT) at 5-HT 3 receptors.
  • Alosetron is known to be useful for the treatment of a variety of conditions, including irritable bowel syndrome.
  • PCT Publication No. WO 99/17755 published 15 April 1999, incorporated herein by reference, in particular discloses the use of alosetron and other
  • 5-HT3 receptor antagonists for the treatment of irritable bowel syndrome in females. It has now been discovered that alosetron is useful for the treatment of functional (or "nonulcer") dyspepsia.
  • Functional dyspepsia is a distinct type of dyspepsia.
  • the term "dyspepsia” is defined as the general condition of indigestion and as such encompasses a variety of distinct dyspeptic conditions.
  • There are several recognized types of dyspepsia the most common being acid-related dyspepsia which is associated with excess gastric acidity and may lead to peptic ulcers, gastroesophageal reflux disease (GERD), and other conditions characterized by excess gastric acidity.
  • Functional dyspepsia (FD) is not associated with excess gastric acidity. Rather, the primary pathophysiological causative factor for FD is unclear.
  • FD is a visceral hypersensitivity state characterized by chronic or recurrent upper abdominal symptoms in the absence of any identifiable organic pathology, such as peptic ulceration, gastric cancer, chronic pancreatitis or GERD.
  • identifiable organic pathology such as peptic ulceration, gastric cancer, chronic pancreatitis or GERD.
  • the absence of identifiable organic pathology is established using conventional techniques including endoscopy, radiography, histology, and other techniques known to those skilled in the art.
  • the primary symptoms of FD include upper abdominal pain or discomfort (often aggravated by food or milk or occurring after meals), early satiety (which can lead to weight loss or anorexia), nausea and vomiting, bloating, belching, and post-prandial fullness.
  • FD has been divided into subtypes based upon the predominant symptom(s) observed in the patient.
  • "Ulcer-like” FD is characterized primarily by pain.
  • "Reflux-like” FD is primarily characterized by heartburn that is often alleviated by acid-suppressing agents. It is believed that most cases of reflux-like FD can actually be attributed to GERD, and is not actually FD because the condition can be associated with an organic pathology.
  • “Dysmotility-like” FD is characterized primarily by discomfort, bloating, nausea, vomiting, early satiety, and post-prandial fullness.
  • "Unspecified” FD refers to FD patients having symptoms that do not fit into the above categories. Typically FD patients exhibit symptoms across the various sub-types.
  • Symptoms exhibited by many FD patients have traditionally been erroneously associated with acid-related dyspepsia (i.e., heartburn, reflux of acid, etc.) and as a result antisecretory agents have been evaluated for their applicability in the treatment of FD.
  • Efficacy studies with histamine H-2 receptor antagonists have produced conflicting results; several studies having failed to demonstrate an effect different from placebo.
  • Patients with ulcer-like FD or coexistent symptomatic GERD were the most likely to respond positively to treatment with an H-2 receptor antagonist.
  • the present invention provides a method for treatment of functional dyspepsia comprising administering an effective amount of alosetron or a pharmaceutically acceptable derivative thereof.
  • the present invention provides a method of treatment for functional dyspepsia in females comprising administering an effective amount of alosetron or a pharmaceutically acceptable derivative thereof.
  • the present invention provides a method of treatment for functional dyspepsia in subjects having normal gastric emptying comprising administering an effective amount of alosetron or a pharmaceutically acceptable derivative thereof.
  • the present invention provides the use of alosetron or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of functional dyspepsia.
  • the present invention provides the use of alosetron or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of functional dyspepsia in females.
  • the present invention provides the use of alosetron or a pharmaceutically acceptable derivative thereof in the manufacture of a medicament for the treatment of functional dyspepsia in subjects having normal gastric emptying.
  • pharmaceutically acceptable derivative any pharmaceutically acceptable salt or solvate of alosetron, which upon administration to the recipient is capable of providing (directly or indirectly) alosetron or an active metabolite or residue thereof.
  • Suitable pharmaceutically acceptable salts of alosetron include acid addition salts formed with inorganic or organic acids (for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates, succinates, lactates, glutarates, glutaconates, acetates, tricarballylates, citrates, fumarates and maleates), and solvates (for example hydrates) thereof.
  • inorganic or organic acids for example hydrochlorides, hydrobromides, sulphates, phosphates, benzoates, naphthoates, hydroxynaphthoates, p-toluenesulphonates, methanesulphonates, sulphamates, ascorbates, tartrates, salicylates
  • alosetron is employed in the form of its hydrochloride salt. It is to be understood that reference to treatment includes both treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
  • alosetron or a pharmaceutically acceptable derivative thereof may be formulated in conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • alosetron or a pharmaceutically acceptable derivative thereof may, for example, be formulated for oral, sub-lingual, buccal, parenteral, rectal or intranasal administration, or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose), or in a form suitable for topical administration.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrates (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrates e.g. potato starch or sodium starch glycollate
  • wetting agents
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • parenteral administration the compositions may take the form of injections, conveniently intravenous, intramuscular or subcutaneous injections, for example bolus injections or continuous intravenous infusions.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, optionally with an added preservative.
  • compositions for parenteral administration may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the compositions may be in dry form such as a powder, crystalline or freeze-dried solid for constitution with a suitable vehicle, e.g. sterile pyrogen-free water or isotonic saline before use. They may be presented, for example, in sterile ampoules or vials.
  • compositions may take the form of suppositories or retention enemas.
  • Tablets for sub-lingual administration may be formulated in a conventional manner.
  • intranasal administration or administration by inhalation or insufflation, conventional formulations may be employed.
  • compositions may be liquids, for example solutions, suspensions or emulsions presented in the form of creams or gels.
  • compositions may also be formulated as a depot preparations.
  • Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection.
  • the compositions may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • effective doses for the treatment of FD, the treatment of FD in females, and the treatment of FD in subjects with normal gastric emptying will lie in the range of 0.001 to 500mg, such as 0.01 to 100mg, preferably 0.05 to 50mg, for example 0.5 to 25mg per unit dose, which could be administered in single or divided doses, for example, 1 to 4 times per day.
  • effective doses of alosetron for the treatment of FD, the treatment of FD in females, and the treatment of FD in subjects with normal gastric emptying will lie in the range of 0.01 to 100mg, such as 0.05 to 50mg, preferably 0.1 to 25mg, for example 0.5, 1 , 2 or 4mg of alosetron per unit dose, which could be administered in single or divided doses, for example, 1 to 4 times per day.
  • 0.5 mg of alosetron is administered twice per day.
  • 1 mg of alosetron is administered twice per day.
  • 2 mg of alosetron is adminstered once per day.
  • Three hundred and twenty (320) ambulatory outpatient male and female FD patients at least 18 years of age who have chronic or recurrent abdominal pain or discomfort centered in the upper abdomen were randomised for study comprising twelve (12) weeks of treatment: eighty one (81) were randomised to treatment with placebo BID, seventy seven (77) to 0.5 mg BID alosetron, seventy nine (79) to 1 mg BID alosetron, and eighty three (83) to 2 mg BID alosetron.
  • Study participants included patients who have been diagnosed with FD and patients with symptoms that fulfilled the modified Rome criteria for FD for at least 6 months. Study participants were screened for two weeks prior to the testing phase, to confirm symptoms of sufficient severity for participation in the study.
  • the primary endpoint was adequate relief of FD (upper abdominal) pain or discomfort.
  • Secondary endpoints included 1) changes in daily upper abdominal pain severity ratings, 2) proportion of pain free days, 3) changes in self-ratings of nausea, early satiety, bloating or distension, post-prandial fullness and burping or belching, 4) changes in quality of life (Q0L) SF-36 scores, 5) changes in SCL-90R® scores, and 6) safety and tolerability with respect to the incidence of adverse events and changes in laboratory values.
  • Subjects also responded daily to yes/no questions assessing whether early satiety, postprandial fullness and burping or belching were present.
  • a "completed subject" is one who completed the screening phase, treatment phase and one-week follow-up phase of the study. Subjects who did not complete the three phases of the study were considered prematurely discontinued and were not replaced.
  • the number of subjects per treatment group needed to detect a 20% difference in proportion of patients with adequate relief between alosetron and any dose of alosetron was 64 per group, assuming the proportion with adequate relief in the placebo group was 35%.
  • a target sample size of 70 patients per treatment group was chosen to allow for an approximate 10% dropout rate.
  • ITT Intent-to-Treat
  • LOCF last observation carried forward
  • Secondary efficacy measures included subject self-rating of pain severity, frequency and the FD symptoms of nausea, bloating/distension, burping/belching, early satiety and postprandial fullness.
  • the percentage of pain-free days, days with nausea, bloating/distension, early satiety, post-prandial fullness and burping/belching were calculated at baseline (for the 2 week screening period), and for each week of the treatment and follow-up phases.
  • average severity of pain, nausea and bloating/distension were calculated at baseline and for the same weekly intervals. For each parameter, changes from baseline in treatment groups were compared using a Wilcoxon rank sum test stratified by geographical cluster.
  • Adverse events were coded and group by body system. Adverse events occurring after randomization were summarized separately from adverse events occurring during the screening phase. For each body system and over all body systems, the frequency of subjects reporting at least one adverse event was calculated by treatment group. In addition, the number of subjects reporting at least one drug-related adverse event and the number of subjects reporting serious adverse events were summarized by treatment group. The four treatment groups were compared using a correlation chi-square test; pairwise comparisons were made with Fisher's exact test.
  • alosetron substantially improved abdominal pain and discomfort in FD patients, particularly female FD patients.
  • Alosetron also substantially improved nausea, early satiety and post-prandial fullness in female patients and patients with normal gastric emptying.
  • alosetron is an effective and well-tolerated therapy for the treatment of FD patients.
  • the use of alosetron for the treatment of functional dyspepsia shows unexpected benefits in female patients.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne l'utilisation de l'alosetron dans le traitement de la dyspepsie fonctionnelle.
EP01935516A 2000-05-18 2001-05-15 Methode de traitement de la dyspepsie fonctionnelle Withdrawn EP1284732A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US20530800P 2000-05-18 2000-05-18
US205308P 2000-05-18
PCT/US2001/015633 WO2001087305A2 (fr) 2000-05-18 2001-05-15 Methode de traitement de la dyspepsie fonctionnelle

Publications (1)

Publication Number Publication Date
EP1284732A2 true EP1284732A2 (fr) 2003-02-26

Family

ID=22761668

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01935516A Withdrawn EP1284732A2 (fr) 2000-05-18 2001-05-15 Methode de traitement de la dyspepsie fonctionnelle

Country Status (4)

Country Link
EP (1) EP1284732A2 (fr)
JP (1) JP2003533482A (fr)
AU (1) AU2001261606A1 (fr)
WO (1) WO2001087305A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003237657A1 (en) * 2002-05-24 2003-12-12 Epidauros Biotechnologie Ag Means and methods for improved treatment using "setrones"
US7820690B2 (en) 2004-03-19 2010-10-26 Solvay Pharmaceuticals Gmbh Method of treating or inhibiting a non-digestive tract derived abdominal disorder associated with pain using a 5-HT, receptor antagonist
CA2560279A1 (fr) * 2004-03-19 2005-09-29 Solvay Pharmaceuticals Gmbh Utilisation d'un antagoniste du recepteur 5-ht3 pour la fabrication d'un medicament pour le traitement de troubles abdominaux lies au tube non-digestif et associes a la douleur

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL96486A (en) * 1989-11-28 1995-03-30 Syntex Inc Preparation tricyclic compounds and pharmaceutical preparations containing them
US5189041A (en) * 1990-11-16 1993-02-23 Syntex (U.S.A.) Inc. Tricyclic 5-ht3 receptor antagonists
US5192770A (en) * 1990-12-07 1993-03-09 Syntex (U.S.A.) Inc. Serotonergic alpha-oxoacetamides
US5516782A (en) * 1991-03-07 1996-05-14 G. D. Searle & Co. New meso-azacyclic aromatic acid amides and esters as novel serotonergic agents
GB9721139D0 (en) * 1997-10-07 1997-12-03 Glaxo Group Ltd Medicaments
TWI263496B (en) * 1999-12-10 2006-10-11 Novartis Ag Pharmaceutical combinations and their use in treating gastrointestinal disorders
GB9930077D0 (en) * 1999-12-20 2000-02-09 Glaxo Group Ltd Medicaments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0187305A2 *

Also Published As

Publication number Publication date
WO2001087305A2 (fr) 2001-11-22
AU2001261606A1 (en) 2001-11-26
JP2003533482A (ja) 2003-11-11
WO2001087305A3 (fr) 2002-04-25

Similar Documents

Publication Publication Date Title
Matsueda et al. A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome
Konturek et al. Gastrocytoprotection by colloidal bismuth subcitrate (De-Nol) and sucralfate. Role of endogenous prostaglandins.
KR960016582B1 (ko) 위장장해의 치료 및 예방용 약제학적 조성물
Vergara et al. Helicobacter pylorieradication prevents recurrence from peptic ulcer haemorrhage
Seno et al. Usefulness of famotidine in functional dyspepsia patient treatment: comparison among prokinetic, acid suppression and antianxiety therapies
UA122974C2 (uk) Комбінований лікарський засіб, який містить канагліфлозин і фентермін, для лікування ожиріння й пов'язаних з ожирінням порушень
Adachi et al. Nocturnal gastric acid breakthrough during the administration of rabeprazole and ranitidine in Helicobacter pylori-negative subjects: effects of different regimens
EA036237B1 (ru) Режим приема селективного модулятора рецептора прогестерона (sprm)
EP1284732A2 (fr) Methode de traitement de la dyspepsie fonctionnelle
de Boer et al. Optimal treatment of Helicobacter pylori with ranitidine bismuth citrate (RBC): a randomized comparison between two 7-day triple therapies and a 14-day dual therapy
US20030187017A1 (en) Method for treating functional dyspepsia
EP3558296B1 (fr) Produit à faible dose et méthode de traitement de la diarrhée
WO2022246298A1 (fr) Méthodes de traitement du syndrome de la cystite interstitielle/douleur de la vessie
US20110275667A1 (en) Compositions useful for treating gastroesophageal reflux disease
Avner et al. Comparison of once daily doses of lansoprazole (15, 30, and 60 mg) and placebo in patients with gastric ulcer.
Lam et al. Sucralfate compared with ranitidine in the short-term healing of duodenal ulcers
Arnestad et al. In single doses ranitidine effervescent is more effective than lansoprazole in decreasing gastric acidity
KR20200086285A (ko) 경구 리파마이신 sv 조성물
AU770580B2 (en) Use of prucalopride for the manufacture of a medicament for the treatment of dyspepsia
Stewart et al. Prokinetic effects of erythromycin after antimotion sickness drugs
RU2793319C2 (ru) Композиции рифамицина sv для перорального применения
Eddlestone Drug Therapies Used in Gastrointestinal
Sabbatini et al. Comparative study of mifentidine and ranitidine in the short-term treatment of duodenal ulcer
JP2023173771A (ja) 内服用医薬組成物
Weissberg et al. The value of a special pepsin-pancreatic preparation in the treatment of peptic ulcer and gastric hyperacidity

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021212

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RIN1 Information on inventor provided before grant (corrected)

Inventor name: MANGEL, ALLEN WAYNE

17Q First examination report despatched

Effective date: 20030620

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20051201