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US20040067956A1 - Treatment of motor fluctuations - Google Patents

Treatment of motor fluctuations Download PDF

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Publication number
US20040067956A1
US20040067956A1 US10/415,817 US41581703A US2004067956A1 US 20040067956 A1 US20040067956 A1 US 20040067956A1 US 41581703 A US41581703 A US 41581703A US 2004067956 A1 US2004067956 A1 US 2004067956A1
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use according
replacement therapy
compound
motor fluctuations
treatment
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Jonathan Brotchie
Michael Hill
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Motac Neuroscience Ltd
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Motac Neuroscience Ltd
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the prevention and alleviation of motor fluctuations which arise as adverse effects of dopamine-replacement therapy.
  • One of the main uses of dopamine-replacement therapy is in the treatment of diseases of the basal ganglia. Movement and other disorders due to dysfunction of the basal ganglia and related brain structures are of major socioeconomic importance. Such disorders can occur as a consequence of inherited or acquired disease, idiopathic neurodegeneration or they may be iatrogenic.
  • the spectrum of disorders is very diverse, ranging from those associated with poverty of movement (akinesia, hypokinesia, bradykinesia) and hypertonia (e.g. Parkinson's disease, some forms of dystonia) to the involuntary movement disorders (hyperkinesias or dyskinesias e.g. Huntington's disease, levodopa-induced dyskinesia, ballism, some forms of dystonia).
  • Parkinsonism is one of the most prevalent movement disorders and comprises a syndrome of symptoms characterised by slowness of movement (bradykinesia), rigidity and/or tremor. Parkinsonian symptoms are seen in a variety of conditions, most commonly in idiopathic parkinsonism (i.e. Parkinson's Disease) but also following treatment of schizophrenia, manganese poisoning, head injury and the like.
  • the primary pathology underlying movement disorders is degeneration of the dopaminergic projection from the substantia nigra to the striatum.
  • the principal symptomatic treatments are based upon dopamine-replacement with levodopa or dopamine receptor agonists.
  • these strategies have limitations, especially following long-term treatment.
  • One such limitation associated with dopamine replacement therapy is the development of motor fluctuations in a subject undergoing treatment.
  • motor fluctuations we mean a subject begins to show a variable response to dopamine replacement therapy such that for periods of time the therapeutic agents exhibit good efficacy whereas for other periods of time the agents appear to have little effect.
  • Motor fluctuations can manifest as a ‘wearing-off’ of anti-parkinsonian efficacy, where a good anti-parkinsonian effect of the dopamine-replacement therapy does not last as long as initially observed, and ‘on-off’ syndrome where the patient experiences disabling fluctuations in mobility (i.e. switching between parkinsonian and treated in an unpredictable manner).
  • compositions for use in the prevention or reduction of motor fluctuations associated with dopamine replacement therapy comprising a therapeutically effective amount of a compound which enhances 5-hydroxytryptamine 1a receptor activity, or activation, and a pharmaceutically acceptable vehicle.
  • a method for the prevention or reduction of motor fluctuations associated with dopamine replacement therapy comprising administering to a person or animal in need of such treatment a therapeutically effective amount of a compound which enhances 5-hydroxytryptamine 1 a receptor activity, or activation.
  • 5-hydroxytryptamine 1a (5-HT 1a ) receptors are a subclass of receptors for 5-hydroxytryptamine (also known as Serotonin), which are found in neural tissues.
  • the invention is based upon our studies relating to the neural mechanisms underlying movement disorders. Although we do not wish to be bound by any hypothesis, we believe that movement disorders involve abnormal activity of basal ganglia output pathways and in many cases this is brought about by abnormal function of striatal efferent pathways. These consist of a “direct” pathway to the medial or internal segment of the globus pallidus and the pars reticulata of the substantia nigra and an “indirect” pathway to the lateral or external segment of the globus pallidus. We believe compounds which enhance 5-HT 1a receptor activity, or activation normalise the activity of the striatal efferent pathways and thereby reduce the development of fluctuations in motor activity seen in subjects on dopamine replacement therapy.
  • WO 00/16777 discloses that dopamine D2 agonists may be used in combination with 5-HT 1a receptor agonists to treat parkinsons disease (i.e to alleviate akinesia, rigidity and tremor).
  • parkinsons disease i.e to alleviate akinesia, rigidity and tremor.
  • compounds which enhance 5-HT 1a receptor activity, or activation may be used for preventing and alleviating motor fluctuations according to the present invention.
  • Motor fluctuations are not a symptom of Parkinson's disease but arise as a consequence of its treatment.
  • the inventors findings are in fact surprising in the light of WO 00/16777 because its is known that the brain mechanisms underlying parkinsonian symptoms are not the same as those underlying motor fluctuations. In fact, as skilled person will appreciate that the mechanisms of parkinsonism are diametrically opposed to those of motor fluctuations.
  • WO 93/13766 discloses to the use of a class of 5-HT 1a receptor agonists in the treatment of involuntary movement disorders. However, there is no suggestion that such agonists may be used to treat motor fluctuations as defined herein.
  • the compound may modulate any type of 5-HT receptor provided that 5-HT 1a receptor activity is enhanced (e.g. Serotonin per se may be used as an example of a 5-HT 1a receptor agonist). However it is preferred that the compound selectively enhances the activity of 5-HT 1a receptors. By “selectively” we mean the compound enhances 5-HT 1a receptor activity or activation to a greater extent than other types of 5-HT receptor (e.g. other 5-HT 1 receptors or 5-HT 2 receptors).
  • 5-HT 1a receptor agonists ((i) above) are preferred compounds for use according to the invention.
  • Selective 5-HT 1a receptor agonists which are suitable for treating motor fluctuations associated with dopamine replacement therapy include:
  • selectivity of 5-HT 1a agonists is by comparing binding affinities of a particular compound for each subclass of a receptor.
  • Preferred selective 5-HT 1a agonists have a higher binding affinity for the 5-HT 1a receptor than for the other 5-HT receptors.
  • the compounds are particularly useful for treatment of motor fluctuations which arise as a side-effect of dopamine replacement therapy for parkinsons disease.
  • the compounds are preferably used for the treatment of fluctuations associated with L-DOPA treatment for parkinsonism.
  • the compounds may be used to treat subjects already exhibiting motor fluctuations but may also be used when prophylactic treatment is considered medically necessary. For instance, when it is considered necessary to initiate L-DOPA therapy and it is feared that motor fluctuations may develop.
  • the compounds are used to treat a subject for whom a clinician has observed that the efficacy of a dopamine-replacement therapy is wearing-off. Under such circumstances the inventors have found that reduction of motor fluctuations according to the present invention has a particularly beneficial effect on the subject being treated.
  • the compounds enable the subject to tolerate and therefore benefit from the dopamine replacement therapy and also, surprisingly, appear to reverse the wearing-off of the efficacy of the dopamine replacement therapy. Accordingly the compounds are able to extend duration of action of dopamine replacement therapies.
  • Another preferred use of the compounds is to treat subjects suffering “on-off” syndrome (i.e. they switch between the treated and non-treated condition in an unpredictable manner).
  • the inventors have found that compounds used according to the invention are able to surprisingly improve the “on-time” of a dopamine replacement therapy for subjects who have developed “on-off” syndrome. Accordingly the compounds are useful for producing a more stable action of dopamine replacement therapies.
  • the compounds may be used as a monotherapy (e.g. use of the compound alone in advance of, or following, dopamine replacement therapy); as an adjunct to medicaments to prevent the development of unwanted motor effects caused by the medicament (e.g. as an adjunct to L-DOPA given to treat parkinsonian patients) or alternatively the compounds may be given in combination with other compounds or treatments which also alleviate motor fluctuations (e.g. ⁇ 2 adrenoreceptor antagonists, COMT inhibitors).
  • compositions used according to the invention may take a number of different forms depending, in particular on the manner in which the composition is to be used.
  • the composition may be in the form of a powder, tablet, capsule, liquid, ointment, cream, gel, hydrogel, aerosol, spray, micelle, liposome or any other suitable form that may be administered to a person or animal.
  • the vehicle of the composition of the invention should be one which is well tolerated by the subject to whom it is given and enables delivery of the compounds to the brain.
  • composition of the invention may be used in a number of ways. For instance, systemic administration may be required in which case the compound may be contained within a composition which may, for example, be ingested orally in the form of a tablet, capsule or liquid. Alternatively, the composition may be administered by injection into the blood stream. Injections may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion). The compounds may also be administered by inhalation (e.g. intranasally).
  • Compounds enhancing 5-HT 1a receptor activity may also be administered centrally by means of intracerebral, intracerebroventricular, or intrathecal delivery.
  • the compound may also be incorporated within a slow or delayed release device.
  • a slow or delayed release device Such devices may, for example, be inserted under the skin and the compound may be released over weeks or even months.
  • Such a device may be particularly useful for patients on continuous dopamine replacement therapy (e.g. for Parkinsonism).
  • the devices may be particularly advantageous when a compound is used which would normally require frequent administration (e.g. at least daily ingestion of a tablet or daily injection).
  • the amount of a compound required is determined by biological activity and bioavailability which in turn depends on the mode of administration, the physicochemical properties of the compound employed and whether the compound is being used as a monotherapy or in a combined therapy.
  • the frequency of administration will also be influenced by the above mentioned factors and particularly the half-life of the compound within the subject being treated.
  • a daily dose of between 0.01 ⁇ g/kg of body weight and 1.0 g/kg of body weight of a compound which enhances 5-HT 1a receptor activity may be used for the treatment of motor fluctuations depending upon which specific compound is used more preferably the daily dose is between 0.1 mg/kg of body weight and 50 mg/kg of body weight.
  • a suitable dose of 8-OH-PIPAT for treating motor fluctuations associated with L-DOPA therapy of subjects with Parkinson's disease is between 0.1 mg/kg/day and 100 mg/kg/day (depending upon the health status of the individual). It is preferred that between 0.25 mg/kg/day and 30 mg/kg/day of 8-OH-PIPAT is given to a person daily. For instance, it is most preferred that about 10 mg/kg/day 8-OH-PIPAT is given for treating motor fluctuations associated with therapy with 8 mg/kg L-DOPA.
  • suitable doses of 8-OH DPAT, Buspirone or BP-544 are preferably 0.5-30 mg/kg.
  • Daily doses may be given as a single administration (e.g. a daily tablet for oral consumption or as a single daily injection).
  • the compound used may require administration twice or more times during a day.
  • 8-OH-PIPAT for administration to L-DOPA treated patients with Parkinson's disease may be administered as two (or more depending upon the severity of the motor fluctuations) daily doses of between 25 mg and 5000 mg in tablet form.
  • a patient receiving treatment may take a first dose upon waking and then a second dose in the evening (if on a two dose regime)-or at 3 or 4 hourly intervals thereafter.
  • a slow release device may be used to provide optimal doses to a patient without the need to administer repeated doses.
  • a preferred means of using protein or peptide compounds which enhance 5-HT 1a receptor activity for the treatment of motor fluctuations is to deliver the compound to the brain by means of gene therapy.
  • gene therapy may be used to increase expression of 5-HT 1a receptors, increase expression of enzyme(s) responsible for the synthesis of endogenous 5-HT 1a receptor agonists (e.g. Serotonin per se), decrease expression of a protein which promotes breakdown or desensitisation of 5-HT 1a receptors or decrease expression of a protein which promotes breakdown of 5-HT 1a receptor agonists.
  • a delivery system for use in a gene therapy technique comprising a DNA molecule encoding for a protein which directly or indirectly enhances 5-hydroxytryptamine 1a receptor activity, said DNA molecule being capable of being transcribed to allow the expression of said protein and thereby treating motor fluctuations.
  • the delivery systems according to the fourth aspect of the invention are highly suitable for achieving sustained levels of a protein, which directly or indirectly enhances 5-HT 1a receptor activity over a longer period of time than is possible for most conventional therapeutic regimes.
  • the delivery system may be used to induce continuous protein expression from cells in the brain that have been transformed with the DNA molecule. Therefore, even if the protein has a very short half-life as an agent in vivo, therapeutically effective amounts of the protein may be continuously expressed from the treated tissue.
  • the delivery system of the invention may be used to provide the DNA molecule (and thereby the protein which is an active therapeutic compound according to the present invention) without the need to use conventional pharmaceutical vehicles such as those required in tablets, capsules or liquids.
  • the delivery system of the present invention is such that the DNA molecule is capable of being expressed (when the delivery system is administered to a patient) to produce a protein which directly or indirectly has activity for enhancing 5-HT 1a receptor activity.
  • directly we mean that the product of gene expression per se has the required activity.
  • indirectly we mean that the product of gene expression undergoes or mediates (e.g. as an enzyme) at least one further reaction to provide a compound effective for enhancing 5-HT 1a receptor activity and thereby treating motor fluctuations.
  • the DNA molecule may be contained within a suitable vector to form a recombinant vector.
  • the vector may for example be a plasmid, cosmid or phage.
  • Such recombinant vectors are highly useful in the delivery systems of the invention for transforming cells with the DNA molecule.
  • Recombinant vectors may also include other functional elements.
  • recombinant vectors can be designed such that the vector will autonomously replicate in the cell. In this case, elements that induce DNA replication may be required in the recombinant vector.
  • the recombinant vector may be designed such that the vector and recombinant DNA molecule integrates into the genome of a cell. In this case, DNA sequences which favour targeted integration (e.g. by homologous recombination) are desirable.
  • Recombinant vectors may also have DNA coding for genes that may be used as selectable markers in the cloning process.
  • the recombinant vector may also further comprise a promoter or regulator to control expression of the gene as required.
  • the DNA molecule may (but not necessarily) be one that becomes incorporated in the DNA of cells of the subject being treated. Undifferentiated cells may be stably transformed leading to the production of genetically modified daughter cells (in which case regulation of expression in the subject may be required e.g. with specific transcription factors or gene activators). Alternatively, the delivery system may be designed to favour unstable or transient transformation of differentiated cells in the subject being treated. When this is the case, regulation of expression may be less important because expression of the DNA molecule will stop when the transformed cells die or stop expressing the protein (ideally when the motor fluctuations have been treated or prevented).
  • the delivery system may provide the DNA molecule to the subject without it being incorporated in a vector.
  • the DNA molecule may be incorporated within a liposome or virus particle.
  • the “naked” DNA molecule may be inserted into a subject's cells by a suitable means e.g. direct endocytotic uptake.
  • the DNA molecule may be transferred to the cells of a subject to be treated by transfection, infection, microinjection, cell fusion, protoplast fusion or ballistic bombardment.
  • transfer may be by ballistic transfection with coated gold particles, liposomes containing the DNA molecule, viral vectors (e.g. adenovirus) and means of providing direct DNA uptake (e.g. endocytosis) by application of the DNA molecule directly to the brain topically or by injection.
  • viral vectors e.g. adenovirus
  • means of providing direct DNA uptake e.g. endocytosis
  • FIG. 1 is a graph illustrating the effect of the 5-HT 1a -receptor agonist 8-OH-PIPAT on L-DOPA-induced fluctuations in locomotion in the MPTP-lesioned marmoset model of Parkinson's disease.
  • Marmosets ( Callithrix jacchus ) (bred in a closed colony at the University of Manchester) are rendered parkinsonian by subcutaneous injection of 2 mg kg ⁇ 1 MPTP for 5 consecutive days. The marmosets are allowed to recover for a minimum of 10 weeks until their parkinsonism becomes stable.
  • Locomotion was measured over a six hour period using Benwick activity monitors. These locomotion monitors consist of a visually-shielded open-field arena, the perimeter of which is surrounded by a series of infra-red beams arranged at 5 cm intervals. PC-based software (Amlogger) assesses the number of beams broken. The number of beams broken as part of a locomotor movement (mobile counts) was measured.
  • FIG. 1 illustrates the effect of 8-OH PIPAT treatment on L-DOPA-induced mobility in the MPTP-lesioned marmoset model of Parkinson's disease. Locomotor activity was assessed quantitatively every 5 minutes for the duration of the experiment using computer-based activity monitors. Co-administration of the 5-HT 1a receptor agonist 8-OH-PIPAT with L-DOPA resulted in an increase in L-DOPA-stimulated ‘on-time’. These data indicate that enhancing neurotransmission at 5-HT 1a receptors is useful in the treatment of motor fluctuations associated with dopamine-replacement therapy in Parkinson's disease.
  • the MPTP-lesioned primate is the ‘gold standard’ preclinical model of Parkinson's disease. Therefore, these data are highly predictive of a beneficial therapeutic effect of stimulators of 5-HT 1a receptor activity in patients receiving L-DOPA therapy.

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GBGB0027020.7A GB0027020D0 (en) 2000-11-03 2000-11-03 Treatment of movement disorders
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PCT/GB2001/004774 WO2002036107A2 (en) 2000-11-03 2001-10-29 Treatment of motor fluctuations with 5-hydroxytryptamine 1a receptor activity enhancing coumpounds

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
US20050245587A1 (en) * 1999-10-22 2005-11-03 Motac Neuroscience Limited Treatment of dyskinesia
US20070249621A1 (en) * 2006-02-28 2007-10-25 The United States Government As Represented By The Department Of Veterans Affairs Pharmacological treatment of parkinson's disease
US20230241062A1 (en) * 2020-08-31 2023-08-03 Sumitomo Pharma Co., Ltd. Therapeutic drug for motor complications in parkinson's disease

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Publication number Priority date Publication date Assignee Title
GB0027020D0 (en) 2000-11-03 2000-12-20 Univ Manchester Treatment of movement disorders
MX372641B (es) * 2012-10-22 2020-06-15 Merz Pharmaceuticals Llc Formulaciones de levodopa para el alivio rapido de la enfermedad de parkinson.
WO2020087031A1 (en) 2018-10-26 2020-04-30 The Research Foundation For The State University Of New York Combination serotonin specific reuptake inhibitor and serotonin 1a receptor partial agonist for reducing l-dopa-induced dyskinesia

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US6455536B1 (en) * 1998-07-18 2002-09-24 The Victoria University Of Manchester Treatment of dyskinesia
US20050245587A1 (en) * 1999-10-22 2005-11-03 Motac Neuroscience Limited Treatment of dyskinesia
US20060069039A1 (en) * 2002-09-17 2006-03-30 Alan Crossman Treatment of dyskinesia
US20070293505A1 (en) * 2006-06-16 2007-12-20 Mccreary Andrew C Combination preparations comprising slv308 and a dopamine agonist

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CA2431641A1 (en) 2002-05-10
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EP1339398B1 (de) 2008-09-03
AU2001295804B2 (en) 2007-01-04
PT1339398E (pt) 2008-11-03
US9668995B2 (en) 2017-06-06
DK1339398T3 (da) 2009-01-26
JP2010241827A (ja) 2010-10-28
GB0027020D0 (en) 2000-12-20
WO2002036107A3 (en) 2003-01-16
EP1339398A2 (de) 2003-09-03
ES2311549T3 (es) 2009-02-16
WO2002036107A2 (en) 2002-05-10
CY1108628T1 (el) 2014-04-09
DE60135675D1 (de) 2008-10-16
JP5189240B2 (ja) 2013-04-24
JP2004512360A (ja) 2004-04-22
US20110178178A1 (en) 2011-07-21

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