WO1999007385A1 - Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure - Google Patents
Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure Download PDFInfo
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- WO1999007385A1 WO1999007385A1 PCT/US1998/016218 US9816218W WO9907385A1 WO 1999007385 A1 WO1999007385 A1 WO 1999007385A1 US 9816218 W US9816218 W US 9816218W WO 9907385 A1 WO9907385 A1 WO 9907385A1
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- cocaine
- cytidine
- cdp
- choline
- stimulant
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Definitions
- This invention relates to methods for the treatment of stimulant abuse and addiction.
- the invention features a method of treating a mammal exposed to a stimulant involving administering to the mammal, a therapeutically-effective amount of either a cytidine-containing or cytosine- containing compound.
- the mammal is a human; the stimulant is cocaine; the therapeutically effective compound is a cytidine-containing compound, for example, one that includes cytidine or CDP; the cytidine- containing or cytosine-containing compound further includes choline (and is, for example, CDP-choline); the mammal being treated has a stimulant dependency or stimulant craving; and the mammal being treated is a pregnant woman or a child with antenatal exposure to a stimulant.
- the invention features a method for treating cerebral vasoconstriction sequelae in a mammal, involving administering a therapeutically-effective amount of either a cytosine-containing or cytidine- containing compound to the mammal.
- the vasoconstriction is cocaine induced; the vasoconstriction is induced by a substance that causes vasoconstriction; the mammal is a human; the therapeutically effective compound is a cytidine-containing compound, for example, one that includes cytidine or CDP; and the cytidine-containing or cytosine-containing compound further includes choline (and is, for example, CDP-choline).
- treating is meant the medical management of a patient with the intent that a cure, amelioration, or prevention of a dependency or a relapse or associated disease, pathological condition, or disorder will result.
- This term includes active treatment, that is, treatment directed specifically toward improvement of the dependency or associated cure of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the dependency or associated disease, pathological condition, or disorder.
- this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the dependency, disease, pathological condition, or disorder; preventive treatment, that is, treatment directed to prevention of the dependency or associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the dependency or associated disease, pathological condition, or disorder.
- palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the dependency, disease, pathological condition, or disorder
- preventive treatment that is, treatment directed to prevention of the dependency or associated disease, pathological condition, or disorder
- supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the dependency or associated disease, pathological condition, or disorder.
- treating also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the dependency or an associated disease, pathological condition, or disorder.
- exposure and “exposed” is meant the condition of being subjected to a stimulant either inadvertently or intentionally.
- This term shall include any mechanism for introducing the stimulant to the mammal, the most typical being insufflation, inhalation, and intravenous administration. This term also includes exposure to a stimulant when presented in combination with other compounds not considered stimulants. The term exposure may also represent single or multiple incidents.
- stimulant any substance that temporarily increases functional activity, and preferably cardiac, respiratory, cerebral, nervous, vascular, motor, or vasomotor functional activity.
- Preferred stimulants include, without limitation, cocaine, amphetamines, methamphetamine, and methylphenidate.
- terapéuticaally-effective amount is meant an amount of a cytidine-containing or cytosine-containing compound sufficient to produce a healing, curative, or ameliorative effect either in the treatment of a stimulant exposure or stimulant dependency.
- cytidine-containing compound any compound that includes, as a component, cytidine, CMP, CDP, CTP, dCMP, dCDP, or dCTP.
- Preferred cytidine-containing compounds include, without limitation, CDP- choline and cytidine 5'-diphosphocholine frequently prepared as cytidine 5'- diphosphocholine [sodium salt] and also known as citicoline.
- cytosine-containing compound is meant any compound that includes, as a component, cytosine.
- dependency is meant any form of behavior that indicates an altered or reduced ability to make decisions resulting, at least in part, from the use of stimulants.
- Representative forms of dependency behavior may take the form of antisocial, inappropriate, or illegal behavior and include those behaviors directed at the desire, planning, acquiring, and use of stimulants.
- This term also includes the psychic craving for a drug that may or may not be accompanied by a physiological dependency, as well as a state in which there is a compulsion to take a drug, either continuously or periodically, in order to experience its psychic effects or to avoid the discomfort of its absence.
- Forms of "dependency” include habituation, that is, an emotional or psychological dependence on a compound to obtain relief from tension and emotional discomfort, as well as physical or physiological dependence, that is, use of a compound to prevent withdrawal symptoms.
- antenatal exposure is meant exposure of a subject to a stimulant before birth via the antepartal mother, the antepartal mother having had an exposure as described herein.
- craving is meant a behavior that reflects a consuming desire, longing, or yearning for a stimulant. This term may refer to aspects of behaviors that are components of a dependency.
- Cerebral vasoconstriction sequelae any condition following and resulting from the constriction of blood vessels in the cerebrum provoked by a motor nerve or chemical compound, for example, any disease, pathology, disorder, or dependency subsequent to stimulant exposure.
- This term includes cerebral ischemia, neuropathologies, neurological deficits, altered brain chemistry, reduced levels of task mastering, cognitive impairment, behavioral changes, vegetative responses, mental deterioration, altered conditioned avoidance and auditory response parameters, and motor activity impairment.
- Such conditions may be characterized by altered levels of phosphomonoesters (PME), phosphodiesters (PDE), phosphocreatine (PCr), nucleotide triphosphates (NTP), inorganic phosphorus (Pi), the PCr/Pi ratio, the ⁇ -NTP/PCr ratio, cerebral phosphorus metabolites, phospholipid precursors, cellular and organelle phospholipid synthesis, membrane synthesis, tyrosine hydroxylase activity, dopamine and dopamine metabolism, bioenergetic function, fatty acid release, neutral acids, phosphatidylcholine and glycerophospholipid degradation, glucose, pyruvate, acetylcholine, norepinephrine, vasodilation, synatopsomal phosphorylation, cellular proliferation, neuronal injury, edema, mitochondrial ATPase and Na + - K + ATPase sensitivity, phospholipase A 2 activation, EEG parameters, cardiovascular and respiratory
- the present invention provides a number of advantages. Importantly, it provides one of the first therapeutics for the treatment of stimulant dependencies (such as cocaine dependencies).
- stimulant dependencies such as cocaine dependencies.
- the cytidine-containing compounds utilized herein are relatively non-toxic, and CDP-choline, in particular, is pharmocokinetically understood and known to be well tolerated by mammals.
- Figure 1 is diagram depicting a time line and the points at which various procedures were performed throughout the experimental protocol described herein.
- Figures 2A and 2B are histograms depicting changes in the likelihood to use cocaine in patients classified as “active” (Fig. 2A) versus “clean” (Fig. 2B) when treated with CDP-choline ( * indicates significance at p ⁇ 0.05 relative to baseline).
- the unshaded bars represent patients at baseline, and the shaded bars represent patients post-treatment.
- the y axis is a visual analog scale (VAS) in millimeters where 100 represents "most ever” and zero represents “not at all.”
- VAS is designed to quantitate subjective mood statements.
- Figures 3A and 3B are histograms depicting changes in the percent levels of cocaine craving exhibited by patients when treated with CDP-choline ( f indicates a trend relative to baseline).
- the unshaded bars represent patients at baseline, and the shaded bars represent patients post-treatment.
- the scale is the same as described in Figure 2 A and 2B.
- Figure 4 is a histogram depicting improved cognitive processing ability in patients who are "active" users treated with CDP-choline as measured in the P300 ERP test.
- Figure 5 is a histogram depicting iconic memory performance in patients classified as "active" when treated with CDP-choline.
- the unshaded bars represent patients at baseline, and the shaded bars represent patients post- treatment.
- Figure 7 is a chart depicting the effects of cocaine on cardiovascular parameters such as heart rate (HR) and systolic (Sys) and diastolic (Dia) blood pressures.
- HR heart rate
- Sys systolic
- Dia diastolic
- Figure 8 is a chart depicting the effects of cocaine on cerebral vasoconstriction as measured by magnetic resonance angiography (MRA).
- Figure 9 is a chart depicting percent differences in cerebral phosphorus metabolite profiles of patients on methadone maintenance (MM) as measured by phosphorus magnetic resonance spectroscopy.
- Figure 10 is a depiction of the molecular structure of CDP-choline [sodium salt], also known as citicoline.
- the invention described herein features a method for the treatment of stimulant abuse and its symptoms, as well as stimulant dependency and associated self-destructive behaviors.
- the invention focuses on cocaine abuse and addiction although other stimulant dependencies may be similarly treated.
- the invention features the use of cytidine-containing or cytosine- containing compounds to alleviate symptoms of abuse and dependency.
- One preferred cytidine-containing compound is CDP-choline (also referred to as citicoline or CDP choline [sodium salt]).
- CDP-choline has been found to have two important therapeutic properties. First, CDP- choline improves brain chemistry in patients suffering from symptoms of cocaine abuse as a result of cocaine-induced cerebral vasoconstriction. And second, CDP-choline alleviates the dependency exhibited by active cocaine users.
- results described herein demonstrate that symptoms of cocaine abuse are very likely functions of cocaine-induced cerebral vasoconstriction.
- results demonstrate that symptoms of opiate abuse and dependency (specifically, heroin abuse and dependency) induce alterations in some, but not all, brain chemistry indices and that certain of those parameters in patients with heroin addictions are improved with methadone in a manner akin to improvements observed in patients with cocaine addictions treated with CDP-choline.
- the present invention therefore enables methods and reagents for the treatment of stimulant abuse, such as cocaine abuse, by providing original data from human trials.
- stimulant abuse such as cocaine abuse
- CDP-Choline is an Effective Treatment for Cocaine Abuse and Dependence
- a small double-blind clinical trial of CDP-choline versus placebo for altering cocaine craving and modifying responses to cocaine-related stimuli was conducted.
- a total of fourteen crack cocaine users were recruited by passing a psychiatric, medical, and clinical laboratory evaluation and provided informed consent to participate in this outpatient treatment study.
- the subjects were completely randomized and the resultant demographic profiles are shown in Table 1.
- CDP-choline not only had no side effects, but subjects were unable to detect whether they had received an active or placebo dose. No changes in health status or blood or urine chemistry analyses were observed. At baseline, three subjects in the placebo group and one in the CDP-choline group had nonclinical sinus bradycardia. One subject who received CDP-choline, developed a mild, non- relevant increase in the cardiac P-R interval. Finally, there were no changes in heart rate or blood pressure.
- CDP-choline improved short term memory and cognitive function in patients with a cocaine exposure.
- CDP-choline is nontoxic, well-tolerated, and was undetectable by the subjects.
- CDP-choline is a useful adjunct to current therapies for cocaine abuse, particularly in individuals who are currently active users. Without being bound to a particular theory, these results are likely due to CDP-choline's weak dopamine agonist activity. In addition, these results indicate that, because of its low toxicity , CDP-choline may be useful for treating pregnant women, adolescents, and babies born to cocaine-dependent women. This last group is of particular importance because CDP-choline's ability to reduce stroke symptoms suggests that this therapeutic may also reverse many of the detrimental micro-infarcts that occur during in utero exposure to cocaine.
- CDP-choline therefore provides an important approach to minimizing the detrimental effects of cocaine abuse and dependency and to speeding the recovery process.
- this and other cytidine-containing or cytosine-containing compounds are generally useful for the treatment of other types of stimulant abuse and dependence, including, but not limited to, amphetamine, methamphetamine, and methylphenidate abuse and dependence.
- EXAMPLE 2 Cocaine-Induced Cerebral Vasoconstriction in Humans This clinical study was designed to evaluate whether intravenous administration of low doses of pure, pharmaceutical grade cocaine hydrochloride could induce cerebral vasoconstriction in otherwise healthy human subjects. Serial noninvasive imaging of the major cerebral arteries was conducted at baseline and twenty minutes following cocaine administration, using magnetic resonance angiography (MRA). MRA is highly sensitive to blood flow perturbations.
- MRA magnetic resonance angiography
- Vasoconstriction results in vessel signal intensity loss at the site of and distal to the constricted region, and MRA has proven useful for detecting acute cerebral vasospasm. This technique is noninvasive and does not utilize ionizing radiation, facilitating within-subject repeated- measure study designs.
- Subjects with either no history of cocaine use or with a diagnosis of cocaine abuse or dependence were excluded from this study.
- Subjects provided written Informed Consent with McLean Hospital Institutional Review Board approval.
- Subjects underwent a complete physical and neurological exam including ECG and hematology prior to study, and provided a medical history including estimates of illicit drug usage.
- subjects provided breath and urine samples to detect recent alcohol or illicit drug use. Breath samples were analyzed with an Alco Sensor III Breathalyzer (Intoximeters Inc., St.
- Urine samples were analyzed for the presence of cocaine, amphetamines, phencyclidine, opiates, barbiturates, benzodiazepines, and tetrahydrocannabinol with a TriageTM Test (Biosite Diagnostics, San Diego, CA). All subjects had negative breath alcohol samples and urine screens. Each subject had an 18G angiocath inserted in a vein overlying the antecubital fossa for cocaine or placebo administration. Subjects were fitted with noninvasive cardiovascular monitoring equipment (In Vivo Research, Inc., Orlando, FL) including 4 lead electrocardiogram (ECG), blood pressure cuff, and pulse oximeter, to provide continuous monitoring of ECG, blood pressure, and heart rate.
- ECG electrocardiogram
- Magnetic resonance imaging was conducted with a 1.5 Tesla Signa Scanner (General Electric, Milwaukee, WI). Tl weighted sagittal localizer images (TE/TR: 19/600 msec) were used to position MRA imaging sets. Angiogram imaging sets of 60 axial images were collected with the three dimensional Time of Flight (3D TOF) magnetization transfer imaging option with flow compensation and saturation. The following acquisition parameters were used: TE/TR: 35/20 msec, FOV: 19 cm, matrix: 256 x 192, slice thickness: 1.2 mm, 1 NEX, imaging time: 7.5 minutes. Each image set produced a single axial maximum intensity projection (MIP) image which was analyzed for drug effects.
- MIP maximum intensity projection
- Baseline and post cocaine/placebo axial MIP images from each subject were analyzed for drag-induced changes.
- Two expert raters blinded with regard to study drag administration, independently analyzed the 24 image sets. Prior to analysis, the 2 raters agreed on criteria that would be used to determine alterations between baseline and post-drag images. Subtle image differences discernible by both raters, including change in the caliber of moderate and large sized arteries and focal narrowing or complete signal loss in a major arterial structure were considered as alterations. Image sets were scored as unchanged, ambiguous, or altered. Concordance was established when both raters agreed in their independent scan ratings.
- Image analysis revealed a relationship between cocaine administration and angiographic alteration. All baseline images were judged to be normal. Raters determined that 5 of 8 subjects who received 0.4 mg/kg cocaine experienced angiographic alterations indicative of cerebral vasoconstriction. These ranged from subtle differences in arterial caliber to more significant alterations, including focal narrowing or complete signal loss from a major arterial structure. These alterations were detected in the posterior cerebral artery, the middle cerebral arteries ( Figure 6), vertebral arteries, and the anterior and posterior communicating arteries. Three of 9 subjects who received 0.2 mg/kg cocaine had angiographic alterations in several arteries including the anterior communicating arteries and the posterior and middle cerebral arteries. One of 7 subjects who received placebo was ruled to have an altered post-placebo MRA scan.
- Figure 8 shows the observed classification of angiogram results stratified by cocaine dosage for all image sets.
- the present study used intravenous cocaine administration as the drag delivery method, while intranasal administration and smoking of the alkaloidal form "crack" are the more common forms of administration.
- the mode of cocaine administration has been suggested to be related to cerebrovascular effect, with the intravenous route leading to hemorrhagic strokes and "crack" smoking leading to both ischemic and hemorrhagic stroke.
- different forms of cocaine or different routes of administration may produce dissimilar rates or severity of vasoconstriction.
- our finding of a dose-effect relationship between cocaine and vasoconstriction suggests that once a sufficient plasma cocaine concentration is achieved, cerebral vasoconstriction likely occurs.
- Heroin abusers have cerebral metabolic and perfusion abnormalities that persist beyond the period of drag intoxication and acute withdrawal (London, ED, et al. Res. Comm. Subst. Abuse 10: 141-144, 1989; Rose, JS et al, Psychiatry Research: Neuroimaging 67:39-47, 1996).
- a number of opiates, including candidates for the treatment of opiate abuse, have been evaluated for their effects on brain function (London, ED, et al. Res. Comm. Subst. Abuse 10: 141-144, 1989; London, ED et al, Arch. Gen.
- 31 P MRS phosphorus magnetic resonance spectroscopy
- Spectra were acquired on a 1.5 Tesla General Electric Signa Scanner using a doubly-tuned, linear proton, quadrature phosphorus head coil.
- An axial whole brain slice volume of 50 mm thickness was prescribed through the orbitofrontal/occipital cortices as described (Christensen, JD et al, Magn. Reson. Med. 35:658-663, 1996).
- the total phosphoras signal (summation of all peak areas) was statistically equivalent across groups allowing use of the % metabolite measure, the ratio of the area of each metabolite peak divided by the total phosphorus area, for between-group comparisons (Klunk, W et al, Neurobiol. Aging 15: 133-140, 1994). Statistical analyses were performed using unpaired two-sided t-tests.
- the present data are quite interesting in that they also document an apparent normalization of most cerebral phosphoras metabolites in subjects who have undergone prolonged MM therapy.
- PCr levels were abnormal in the long-term MM group; PCr and PDE levels were significantly higher and lower (more normal) in this versus the short-term MM group.
- This apparent improvement is consistent with a prior study documenting improved cerebral perfusion in short-term abstinence from heroin abuse (Rose, JS et al, Psychiatry Research: Neuroimaging 67:39-47, 1996).
- What is further encouraging from the present data is that metabolite improvements were noted in subjects with ongoing illicit substance use (opiate positive urines nearly 40% of the time).
- Examples of useful cytidine-containing or cytosine-containing compounds may include any compound comprising one of the following: cytosine, cytidine, CMP, CDP, CTP, dCMP, dCDP, and dCTP.
- Preferred cytidine-containing compounds include CDP-choline and cytidine 5'-diphosphocholine [sodium salt].
- the above list of cytidine-containing and cytosine-containing compounds is provided to illustrate, rather than to limit the invention, and the compounds described above are commercially available, for example, from Sigma Chemical Company (St. Louis, MO).
- the molecular structure of CDP-choline [sodium salt] is provided in Figure 10.
- one particular source of CDP-choline is Interneuron Pharmaceutical, Inc. The compound obtained from this source has the following characteristics:
- CDP-choline for oral administration is a 500 mg oblong tablet. Each tablet contains 522.5 mg CDP- choline sodium, equivalent to 500 mg of CDP-choline. Matching placebo tablets are also available.
- the excipients contained in both active and placebo tablets are talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil, sodium carboxy-methylcellulose, and microcrystalline cellulose.
- CDP-choline is a naturally occurring compound that is synthesized from cytidine- 5 '-triphosphate and phosphocholine with accompanying production of inorganic pyrophosphate in a reversible reaction catalyzed by the enzyme CTP:phosphocholine cytidylyltransferase (Weiss, Metabolism and Actions of CDP-choline as an Exogenous Compound and Administered Exogenously as Citicholine, Life Sciences 56:637-660, 1995).
- Cytidine-containing and cytosine-containing compounds are naturally occurring endogenous compounds.
- CDP-choline itself is synthesized in a sodium salt form for clinical use (see Figure 10).
- One clinical dosage form for oral administration is a 500 mg oblong tablet. Each tablet contains 522.5 mg of CDP-choline sodium, equivalent to 500 mg of CDP-choline. For easier administration, such tablets may be cut into smaller pieces or crashed.
- cytosine-containing and cytidine-containing compounds, such as CDP-choline are administered at a dosage of at least 500 mg twice daily by oral administration.
- CDP-choline is bioavailable, with more than 99% of CDP-choline and/or its metabolites absorbed and less than 1% excreted in feces.
- CDP-choline administered either orally or intravenously, is rapidly converted into the two major circulating metabolites, choline and cytidine.
- Major excretion routes are lung (12.9%) and urine (2.4%); the rest of the dose (83.9%) is apparently metabolized and retained in tissues.
- formulations for treatment or prevention of the conditions described herein may take the form of a cytosine-containing or cytidine- containing compound, such as CDP-choline, combined with a pharmaceutically-acceptable diluent, carrier, stabilizer, or excipient.
- a pharmaceutically-acceptable diluent such as CDP-choline
- Conventional pharmaceutical practice is employed to provide suitable formulations or compositions to administer such compositions to patients.
- Oral administration is preferred, but any other appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intraorbital, ophthalmic, intraventricular, intracapsular, intraspinal, intracisternal, intraperitoneal, intranasal, or aerosol administration.
- Therapeutic formulations may be in the form of liquid solutions or suspensions (as, for example, for intravenous administration); for oral administration, formulations may be in the form of liquids, tablets, or capsules; and for intranasal formulations, in the form of powders, nasal drops, or aerosols.
- Formulations for parenteral administration may, for example, contain excipients, sterile water, or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, or hydrogenated napthalenes.
- slow release or extended release delivery systems may be utilized.
- Biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be used to control the release of the compounds.
- Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
- Formulations for inhalation may contain excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may be oily solutions for administration in the form of nasal drops, or as a gel.
- cytosine-containing or cytidine-containing compounds such as CDP-choline
- the preferred route of administration for most indications is oral.
- a cytidine-containing or cytosine-containing compound is employed to treat the conditions described herein.
- the exact dosage of the compound may be dependent, for example, upon the age and weight of the recipient, the route of administration, and the severity and nature of the symptoms to be treated. In general, the dosage selected should be sufficient to prevent, ameliorate, or treat the condition, or one or more symptoms thereof, without producing significant toxic or undesirable side effects.
- CDP-choline In the case of CDP-choline, there have been no reported cases of overdoses. CDP-choline toxicity is largely self-limiting, ingestion of large amounts in preclinical studies shows common cholinergic symptoms (salivation, lacrimation, urination, defecation, and vomiting).
- cytidine-containing and cytosine-containing compounds as described herein are used for the treatment of human patients, but may also be used to treat any other mammal, for example, any pet or domesticated livestock. Any cognitive or behavioral problems associated with the types of altered brain chemistry described herein may be improved with cytidine- containing or cytosine-containing compounds, such as CDP-choline.
- normal brain chemistry may also be enhanced by the administration of cytidine-containing or cytosine-containing compounds, with improvements in cognitive performance being the result.
- cytidine-containing or cytosine- containing compound is administered by the general methods described herein. All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.
Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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EP98939207A EP1005349B1 (en) | 1997-08-08 | 1998-08-05 | Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure |
DE69831000T DE69831000T2 (en) | 1997-08-08 | 1998-08-05 | USE OF CYTIDINE AND CYTOSIN-CONTAINING COMPOUNDS FOR THE TREATMENT OF SMOKING AGENT |
IL13443098A IL134430A0 (en) | 1997-08-08 | 1998-08-05 | Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure |
AT98939207T ATE300305T1 (en) | 1997-08-08 | 1998-08-05 | USE OF CYTIDINE AND CYTOSINE CONTAINING COMPOUNDS FOR TREATING STIMULANT GEL USE |
BR9811876-5A BR9811876A (en) | 1997-08-08 | 1998-08-05 | Use of compounds containing cytidine and containing cytosine as a treatment for exposure to stimulant |
AU87683/98A AU8768398A (en) | 1997-08-08 | 1998-08-05 | Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure |
IL134430A IL134430A (en) | 1997-08-08 | 2000-02-07 | Use of cytidine-containing and cytosine-containing compounds in the preparation of a medicament for the treatment of stimulant exposure |
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US08/908,997 | 1997-08-08 | ||
US08/908,997 US5958896A (en) | 1997-08-08 | 1997-08-08 | Cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure |
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US (2) | US5958896A (en) |
EP (1) | EP1005349B1 (en) |
AT (1) | ATE300305T1 (en) |
AU (1) | AU8768398A (en) |
BR (1) | BR9811876A (en) |
DE (1) | DE69831000T2 (en) |
ES (1) | ES2245037T3 (en) |
IL (2) | IL134430A0 (en) |
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US4115576A (en) * | 1974-04-02 | 1978-09-19 | Penn Nathar W | Compositions and method of employing the same for inhibiting alcohol intoxication |
ATE37984T1 (en) * | 1983-03-01 | 1988-11-15 | Crc Ricerca Chim | PHARMACEUTICAL COMPOSITION WHICH CONTAINS 5ACETAMIDO-3,5-DIDEOXY-D-GLYCERO-DGALACTONONULOSAMINE|URE CYTIDIN MONOPHOSPHATE. |
EP0188647B1 (en) * | 1985-01-24 | 1989-05-24 | NEOPHARMED S.p.A. | Acylated derivatives of cytidine-diphosphate-choline, process for their preparation and their therapeutic use |
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1997
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- 1998-08-05 EP EP98939207A patent/EP1005349B1/en not_active Expired - Lifetime
- 1998-08-05 AT AT98939207T patent/ATE300305T1/en not_active IP Right Cessation
- 1998-08-05 WO PCT/US1998/016218 patent/WO1999007385A1/en active IP Right Grant
- 1998-08-05 BR BR9811876-5A patent/BR9811876A/en not_active IP Right Cessation
- 1998-08-05 AU AU87683/98A patent/AU8768398A/en not_active Abandoned
- 1998-08-05 IL IL13443098A patent/IL134430A0/en active IP Right Grant
- 1998-08-05 ES ES98939207T patent/ES2245037T3/en not_active Expired - Lifetime
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001072288A2 (en) * | 2000-03-29 | 2001-10-04 | Ferrer Internacional, S.A. | Use of cdp-choline for the treatment of alcohol withdrawal syndrome |
WO2001072288A3 (en) * | 2000-03-29 | 2002-05-10 | Ferrer Int | Use of cdp-choline for the treatment of alcohol withdrawal syndrome |
JP2003528133A (en) * | 2000-03-29 | 2003-09-24 | フエルレル インターナショナル,ソシエダッド アノニマ | Use of CDP-choline to treat alcohol withdrawal symptoms |
US6894032B2 (en) | 2000-03-29 | 2005-05-17 | Ferrer Internacional, S.A. | Use of CDP-choline for the treatment of alcohol withdrawal syndrome |
KR100794891B1 (en) * | 2000-03-29 | 2008-01-14 | 페레르 인터내쇼날 에스.에이. | The medicament and the method for the treatment including cdp-choline or a pharmaceutically acceptable salt thereof |
CZ298933B6 (en) * | 2000-03-29 | 2008-03-12 | Ferrer Internacional, S. A. | Pharmaceutical composition |
JP4724348B2 (en) * | 2000-03-29 | 2011-07-13 | フエルレル インターナショナル,ソシエダッド アノニマ | Use of CDP-choline to treat alcohol withdrawal symptoms |
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ATE300305T1 (en) | 2005-08-15 |
EP1005349A1 (en) | 2000-06-07 |
ES2245037T3 (en) | 2005-12-16 |
IL134430A0 (en) | 2001-04-30 |
BR9811876A (en) | 2002-01-02 |
AU8768398A (en) | 1999-03-01 |
US5958896A (en) | 1999-09-28 |
IL134430A (en) | 2007-02-11 |
DE69831000D1 (en) | 2005-09-01 |
US6103703A (en) | 2000-08-15 |
DE69831000T2 (en) | 2006-04-20 |
EP1005349B1 (en) | 2005-07-27 |
EP1005349A4 (en) | 2002-07-17 |
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