WO2000074680A1 - The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder - Google Patents
The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder Download PDFInfo
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- WO2000074680A1 WO2000074680A1 PCT/GB2000/002234 GB0002234W WO0074680A1 WO 2000074680 A1 WO2000074680 A1 WO 2000074680A1 GB 0002234 W GB0002234 W GB 0002234W WO 0074680 A1 WO0074680 A1 WO 0074680A1
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- mph
- treatment
- study
- saline
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- This invention relates to the therapeutic use of d-tbreo-methylphenidate.
- Background of the Invention 5 the literature has indicated that the pharmacological action of d,l- r ⁇ reo-methylphenidate (d,/-MPH; available as Ritalin®) in the treatment of attention- deficit hyperactivity disorder (ADHD) is the property of the d-enantiomer (d-MPH), as no action on the part of the /-enantiomer (/-MPH) has been detected; see Patrick (1987), and Srinivas (1992). It has also been found that, following oral dosing, the /-
- enantiomer is metabolised preferentially such that plasma levels of the d-enantiomer are generally found to be higher than those of the /-enantiomer, and very little /-MPH enters the circulation or becomes available to the brain; seeAoyama eta/, Eur. J. Clin. Pharmacol. 44:79-84 (1993), and Hubbard, J. Pharm. Sci. 78:944-7 (1989).
- Intravenous administration of d,/-MPH has shown similar plasma levels of the
- the present invention is based on new evidence (presented below) that d-MPH may be used to treat non-responders to racemic MPH.
- /-MPH possesses pharmacological activity broadly similar to that of the d-enantiomer and the racemate.
- the two enantiomers and the racemate induced similar stimulant effects in the Irwin Observation Test (see Irwin, Psychopharm. 131:71-8 (1968)), including mainly excitation with signs of hypersensitivity to external stimulation, stereotypies with fore- paw treading, mydriasis and hyperthermia.
- the /-enantiomer was approximately one- eighth as active as the d-enantiomer and one-quarter as active as d,/-MPH and is, therefore, a partial agonist.
- a second piece of evidence is based on a study, in the mouse, that tested the ability of /-MPH to antagonise the effects of d-MPH or d,/-MPH on locomotor activity. It was found that /-MPH dosed subcutaneously at 25 mg/kg followed by d,/-MPH at 5 mg/kg resulted in a reduction in locomotor activity, compared with a control group dosed with saline followed by d,/-MPH.
- the d-MPH that is used in this invention is substantially free of its antipode (/-MPH), e.g. in an enantiomeric excess (ee) of at least 70%, preferably at least 90%, and more preferably at least 95%.
- the d-MPH may be substantially enantiopure. It may be used in the form of any suitable salt, e.g. the hydrochloride.
- the d-MPH may be administered by the same means as is known for racemic methylphenidate, in an immediate, modified or sustained-release formulation, e.g. a coated tablet, or as a liquid. It may be administered in any other conventional formulation, via any suitable route of administration. Conventional dosing parameters may be adopted, i.e. those which are known to or adapted to the practice of those skilled in the art. Examples of suitable compositions are disclosed in WO-A-9703673, the content of which is incorporated herein by reference.
- compositions of the invention may be administered for known purposes e g the treatment of attention-deficient hyperactivity disorder (ADHD, this term is used herein to encompass attention-deficit disorder) in pre-pubertal children, adolescents and in adults, as a stimulant in cancer patients treated with narcotic analgesics, and also for the treatment of depression (e g in AIDS patients), compulsive shopping disorder, narcolepsy and hypersomnia
- ADHD attention-deficient hyperactivity disorder
- the patient may be any that has been identified as a "non-responder" This represents a class of patients that is already known, or patients that can readily be identified by the skilled person See Jonkman et a/, supra Typically, the patient will be adolescent or pre-adolescent The age of the patient may be, for example, from 5 to 15 years However adults may also be suitable for treatment according to this invention
- Study 1 This study was designed to examine the general clinical effects (Irwin test) and anticonvulsant activity of /-MPH and its effects on barbital-induced sleep intestinal transit and gastric function in the rat For the Irwin test, intestinal transit and gastric function, it was compared with the d-enantiomer and the racemate
- caffeine barbital test
- diazepam barbital and PTZ tests
- RO 15-4513 morphine
- intestinal transit test intestinal transit test
- cimetidme gastric acid secretion test
- Barbital and pentylenetetrazole tests 8 16 and 32 mg/kg s c 30 minutes before the test, Intestinal transit and gastric secretion tests 16 mg/kg s c 30 minutes before the test.
- Results showed that the two enantiomers and the racemate induced similar effects in the Irwin observation test, including mainly excitation with signs of hypersensitivity to external stimulation, stereotypies with fore-paw treading, myd ⁇ asis and hyperthermia Clear stimulant effects were observed from 16 mg/kg for the I- enantiomer, from 2 mg/kg for the d-enantiomer and from 4 mg/kg for the racemate /-MPH was not lethal up to 256 mg/kg In contrast, the d-enantiomer and the racemate induced lethality at 64 mg/kg. /-MPH completely antagonised barbital-induced sleep and clearly and dose- dependently antagonised the convulsive effects of pentylenetetrazole It also decreased intestinal transit, gastric fluid volume and gastric acidity
- mice Male male BKW (Bradford bred) mice weighing 34-50 g at the start of the study were used. Mice were housed in groups of 10 in a holding room maintained at
- mice were transported to the experimental room in an enclosed trolley, at least 1 h before testing commenced.
- the experimental room was maintained in red lighting.
- a preliminary dose ranging study using locomotor activity (LMA) assessment apparatus consisted of 15 individual clear plexiglass cages (10 x 24 x 14 cm), each fitted with two photocell units located 2.5 cm above the floor of the cage and 3 cm from the long sides. Interruptions of the light beams were recorded automatically and are presented as total counts/time period.
- a second dose of saline or /-MPH (6.25/kg, s.c.) was administered, and the mice returned to the LMA apparatus.
- a third dose of saline or /-MPH (12.5 mg/kg, s.c.) was administered and LMA was recorded.
- a fourth dose of saline or /-MPH 25 mg/kg, s.c. was administered and LMA was recorded for 30 min
- n 5/treatment group. Data are presented as mean ⁇ sem. * P ⁇ 0.05 (ANOVA followed by Dunnett's t-test): significant increase from the corresponding saline control.
- CPP was assessed in a 3-chambered apparatus (76 x 30 x 30 cm) constructed from Plexiglass
- the outer two chambers measured 30 x 30 x 30 cm, one with a striped wood floor/metal walls and the other with a textured glass floor/striped wood walls This combination of textures and visual clues has been chosen since it ensures that the two chambers are distinct Mice are allocated to the initially preferred and non-preferred chamber using a counterbalanced design
- the smaller central chamber (16 x 30 x 30 cm) consists of a permanently black painted floor with clear walls All three chambers are connected by guillotine doors, which are staggered to prevent visual communication between the chambers
- Naive mice were placed in the central chamber, with the guillotine doors raised, and allowed free access to all three sections of the apparatus for 15 mm on three consecutive days
- the position of the mouse in the apparatus was monitored automatically using a system of photocell beams and the time spent (s) in each of the two outer chambers was recorded, from which the pre-conditioning preference was determined (mean ⁇ sem of the 3 days)
- the time spent in the central chamber reflects the number of transitions between the two outer chambers Conditioning:
- mice received saline or /-MPH (25 mg/kg, s.c.) followed 20 min later by saline, d-MPH (2.5 mg/kg, s.c.) or d,/-MPH (5 mg/kg, s.c).
- Locomotor activity was measured in individual photocell boxes during the subsequent 60 min period as described in detail previously.
- the total number of counts/time period was recorded and the data analysed by one-way analysis of variance with Dunnett's t-test for multiple comparison against a single control.
- mice were exposed to the apparatus on each of three preconditioning test days.
- the initial preference for each mouse was calculated from the time spent (s) in each of the two outer chambers of the apparatus (mean ⁇ sem) From this the mice were allocated to 1 of the 7 treatment groups in a design which was balanced to take account of preferred/non-preferred chambers and order of drug administration.
- mice On each day mice received saline or drug and were exposed to one chamber of the apparatus. A daily record of individual body weights was also maintained. Post-conditioning:
- the GIS is a validated scheme for diagnosing ADHD which is recognised worldwide.
- Relevant references are: Conners CK, Conners' rating scales manual: Conners' teacher rating scale:
- the CGI is an established clinical measure of the severity of the illness, in the form of a score capable of detecting any change following treatment, and hence, providing an assessment of efficacy.
- the CPP data confirm that d-amphetamine and d-MPH produce a preference response in the murine conditioned place preference paradigm although, in contrast to a previous study, d,/-MPH was ineffective at the dose used.
- the lack of effect with d,/-MPH may reflect an inversion of the dose-response curve of this compound, a profile of effect suggested but not confirmed in the earlier study
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE60022033T DE60022033T2 (en) | 1999-06-09 | 2000-06-08 | THERAPEUTIC USE OF D-THREO METHYLPHENIDATE FOR THE TREATMENT OF ATTENTION DEFICIT HYPERACTIVITY DISORDERS |
DK00940504T DK1185268T3 (en) | 1999-06-09 | 2000-06-08 | Therapeutic use of D-threo-methylphenidate for the treatment of attentional hyperactivity disorder |
EP00940504A EP1185268B1 (en) | 1999-06-09 | 2000-06-08 | The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder |
JP2001501216A JP2003501387A (en) | 1999-06-09 | 2000-06-08 | Therapeutic use of D-threo-methylphenidate for the treatment of attention deficit hyperactivity disorder |
AU55432/00A AU766748B2 (en) | 1999-06-09 | 2000-06-08 | The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder |
AT00940504T ATE302006T1 (en) | 1999-06-09 | 2000-06-08 | THERAPEUTIC USE OF D-THREOMETHYLPHENIDATE FOR THE TREATMENT OF ATTENTION DEFICIENCY HYPERACTIVITY DISORDER |
CA002376215A CA2376215A1 (en) | 1999-06-09 | 2000-06-08 | The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9913458.7A GB9913458D0 (en) | 1999-06-09 | 1999-06-09 | The therapeutic use of d-threo-methylphenidate |
GB9913458.7 | 1999-06-09 |
Publications (1)
Publication Number | Publication Date |
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WO2000074680A1 true WO2000074680A1 (en) | 2000-12-14 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/GB2000/002234 WO2000074680A1 (en) | 1999-06-09 | 2000-06-08 | The therapeutic use of d-threo-methylphenidate for the treatment of attention-deficit hyperactivity disorder |
Country Status (9)
Country | Link |
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EP (1) | EP1185268B1 (en) |
JP (1) | JP2003501387A (en) |
AT (1) | ATE302006T1 (en) |
AU (1) | AU766748B2 (en) |
CA (1) | CA2376215A1 (en) |
DE (1) | DE60022033T2 (en) |
ES (1) | ES2243273T3 (en) |
GB (1) | GB9913458D0 (en) |
WO (1) | WO2000074680A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7115631B2 (en) | 1995-12-04 | 2006-10-03 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
US8076485B2 (en) | 2005-01-20 | 2011-12-13 | Institute For Molecular Medicine, Inc. | Methylphenidate derivatives and uses of them |
US8871772B2 (en) | 2008-05-27 | 2014-10-28 | Ampio Pharmaceuticals, Inc. | Therapeutic methods and compounds |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5837284A (en) | 1995-12-04 | 1998-11-17 | Mehta; Atul M. | Delivery of multiple doses of medications |
US6962997B1 (en) | 1997-05-22 | 2005-11-08 | Celgene Corporation | Process and intermediates for resolving piperidyl acetamide steroisomers |
JP6983161B2 (en) | 2015-09-15 | 2021-12-17 | プラクシス・バイオリサーチ・エルエルシー | Fencanfamin prodrug |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997003673A1 (en) * | 1995-07-14 | 1997-02-06 | Medeva Europe Limited | Sustained-release formulation of d-threo-methylphenidate |
WO1997027176A1 (en) * | 1996-01-22 | 1997-07-31 | Medeva Europe Limited | Optical resolution of methylphenidate by 0,0'-bisaroyl tartaric acids |
WO1999003471A1 (en) * | 1997-07-14 | 1999-01-28 | Mehta, Atul, M. | Improved delivery of multiple doses of medications |
WO1999016439A1 (en) * | 1997-09-29 | 1999-04-08 | Celgene Corporation | CHRONIC, BOLUS ADMINISTRATION OF D-threo METHYLPHENIDATE |
US5908850A (en) * | 1995-12-04 | 1999-06-01 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
WO1999030694A2 (en) * | 1997-12-15 | 1999-06-24 | Noven Pharmaceuticals, Inc. | Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
US6025502A (en) * | 1999-03-19 | 2000-02-15 | The Trustees Of The University Of Pennsylvania | Enantopselective synthesis of methyl phenidate |
-
1999
- 1999-06-09 GB GBGB9913458.7A patent/GB9913458D0/en active Pending
-
2000
- 2000-06-08 AT AT00940504T patent/ATE302006T1/en not_active IP Right Cessation
- 2000-06-08 AU AU55432/00A patent/AU766748B2/en not_active Ceased
- 2000-06-08 EP EP00940504A patent/EP1185268B1/en not_active Expired - Lifetime
- 2000-06-08 DE DE60022033T patent/DE60022033T2/en not_active Expired - Fee Related
- 2000-06-08 WO PCT/GB2000/002234 patent/WO2000074680A1/en active IP Right Grant
- 2000-06-08 ES ES00940504T patent/ES2243273T3/en not_active Expired - Lifetime
- 2000-06-08 CA CA002376215A patent/CA2376215A1/en not_active Abandoned
- 2000-06-08 JP JP2001501216A patent/JP2003501387A/en active Pending
Patent Citations (7)
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WO1997003673A1 (en) * | 1995-07-14 | 1997-02-06 | Medeva Europe Limited | Sustained-release formulation of d-threo-methylphenidate |
US5908850A (en) * | 1995-12-04 | 1999-06-01 | Celgene Corporation | Method of treating attention deficit disorders with d-threo methylphenidate |
WO1997027176A1 (en) * | 1996-01-22 | 1997-07-31 | Medeva Europe Limited | Optical resolution of methylphenidate by 0,0'-bisaroyl tartaric acids |
WO1999003471A1 (en) * | 1997-07-14 | 1999-01-28 | Mehta, Atul, M. | Improved delivery of multiple doses of medications |
WO1999016439A1 (en) * | 1997-09-29 | 1999-04-08 | Celgene Corporation | CHRONIC, BOLUS ADMINISTRATION OF D-threo METHYLPHENIDATE |
WO1999030694A2 (en) * | 1997-12-15 | 1999-06-24 | Noven Pharmaceuticals, Inc. | Compositions and methods for treatment of attention deficit disorder and attention deficit/hyperactivity disorder with methylphenidate |
US6025502A (en) * | 1999-03-19 | 2000-02-15 | The Trustees Of The University Of Pennsylvania | Enantopselective synthesis of methyl phenidate |
Non-Patent Citations (2)
Title |
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JONKMAN L M ET AL: "Differences in plasma concentrations of the D- and L-threo methylphenidate enantiomers in responding and non- responding children with attention - deficit-- hyperactivity disorder.", PSYCHIATRY RESEARCH, (1998 MAR 20) 78 (1-2) 115-8., XP000949999 * |
SRINIVAS NUGGEHALLY R; HUBBARD JOHN W; QUINN DECLAN; MIDHA KAMAL K: "Enantioselective pharmacokinetics and pharmacodynamics of racemic-threo-methylphenidate in children with attention deficit hyperactivity disorder.", CLINICAL PHARMACOLOGY & THERAPEUTICS, vol. 52, no. 5, 1992, pages 561 - 568, XP000950002 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7115631B2 (en) | 1995-12-04 | 2006-10-03 | Celgene Corporation | Methods for treatment of cognitive and menopausal disorders with D-threo methylphenidate |
US8076485B2 (en) | 2005-01-20 | 2011-12-13 | Institute For Molecular Medicine, Inc. | Methylphenidate derivatives and uses of them |
US9463187B2 (en) | 2005-01-20 | 2016-10-11 | Ampio Pharmaceuticals, Inc. | Methylphenidate derivatives and uses of them |
US8871772B2 (en) | 2008-05-27 | 2014-10-28 | Ampio Pharmaceuticals, Inc. | Therapeutic methods and compounds |
US9522893B2 (en) | 2008-05-27 | 2016-12-20 | Ampio Pharmaceuticals, Inc. | Therapeutic methods and compounds |
Also Published As
Publication number | Publication date |
---|---|
AU5543200A (en) | 2000-12-28 |
JP2003501387A (en) | 2003-01-14 |
EP1185268B1 (en) | 2005-08-17 |
DE60022033T2 (en) | 2006-03-30 |
ES2243273T3 (en) | 2005-12-01 |
ATE302006T1 (en) | 2005-09-15 |
DE60022033D1 (en) | 2005-09-22 |
AU766748B2 (en) | 2003-10-23 |
GB9913458D0 (en) | 1999-08-11 |
EP1185268A1 (en) | 2002-03-13 |
CA2376215A1 (en) | 2000-12-14 |
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