MXPA00001364A - Use of cytidine-containing and cytosine-containing compounds as treatments for stimulant exposure - Google Patents

Abstract

Disclosed herein is a method for reducing stimulant dependencies in mammals that involves administration of a therapeutically-effective amount of a cytosine-containing or cytidine-containing compound, such as CDP-choline.

Description

USE OF COMPOUNDS CONTAINING CITIDINE AND CONTAINING CITOSIN AS TREATMENTS FOR EXPOSURE TO STIMULANTS Background of the Invention This invention relates to methods for the treatment of abuse and addiction to stimulants. In the mid-1980s, the use of stimulant cocaine reached epidemic levels in the United States, and abuse of this drug is still widespread today. In 1995, the Substance Abuse and Mental Health Administration reported that almost 2.5 million Americans admitted to occasional cocaine use, and 600,000 admitted to frequent cocaine use. The adverse social and health consequences that arise from this use of cocaine are significant. First, there is the hidden payment of emotionally and psychologically damaged families dealing with a family member who is dependent on cocaine. And second, there is the adverse exposure to potentially damaging health consequences associated with the use and abuse of cocaine. Although historically the frequency of hospital admissions associated with cocaine abuse has been relatively low (from 0.35 to 3 percent), hospital visits that arise from a cocaine-related event seem to be increasing. In addition, the case report literature that illustrates catastrophic neurological and cerebrovascular complications in cocaine users is also growing rapidly, and the incidence of cocaine-related strokes has been characterized by reaching epidemic proportions. Surprisingly, many cocaine-related deaths are not associated with any major pathology of the brain after autopsy, and yet patients have been shown to show signs associated with moderate to severe cognitive dysfunction. Moreover, experts in this area have observed that, even during periods of cocaine abstinence, cognitive abnormalities persist, suggesting that brain dysfunction occurs, and remains beyond the period of acute cocaine intoxication. The "clinically silent" nature of these abnormalities implies that substantial numbers of cocaine users may be afflicted with defects not yet diagnosed. The etiologies of these subtle changes have not been elucidated, although vasoconstriction and vaso-spasm induced by cocaine have been implicated. To date, there are no approved pharmacotherapies for cocaine abuse and dependence, although the need for such therapies is clear. SUMMARY OF THE INVENTION In general, the invention provides a method for the treatment of a mammal exposed to a stimulant, which involves administering to the mammal a therapeutically effective amount of a compound containing cytidine or containing cytosine. In preferred embodiments, 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 animal being treated has a dependence on the stimulant or an urge of the stimulant; and the mammal you are treating is a pregnant woman or a child with an antenatal exposure to a stimulant. In another aspect, the invention provides a method for the treatment of cerebral vasoconstriction sequelae in a mammal, which involves administering a therapeutically effective amount of a cytosine-containing or cytidine-containing compound to the mammal. In several preferred embodiments, vasoconstriction is induced by cocaine; vasoconstriction is induced by a substance that causes vasoconstriction; the mammal is a human being; 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). "Treatment" means the medical management of a patient with the intention of a cure, abatement, or prevention of a dependency, so that a recurrence or associated disease, pathological condition, or disorder does not result. This term includes active treatment, that is, treatment directed specifically towards the improvement of the dependence or associated cure of a disease, pathological condition, or disorder, and also includes the causal treatment, that is, the treatment directed towards the removal of the cause of the dependence or associated disease, pathological condition, or disorder. In addition, this term includes a palliative treatment, that is, a treatment designed for the relief of symptoms, instead of curing dependence, disease, pathological condition, or disorder; a preventive treatment, that is, a treatment aimed at the prevention of dependence or associated disease, pathological condition, or disorder; and a supportive treatment, i.e., a treatment employed to complement another specific therapy directed towards the improvement of the dependence or associated disease, pathological condition, or disorder; the term "treatment" also includes a symptomatic treatment, that is, a treatment directed toward the constitutional symptoms of dependence or of an associated disease, pathological condition, or disorder. "Exposure" and "exposed" means the condition of undergoing a stimulant, either inadvertently, or in an intentional manner. This term will include any mechanism to introduce the stimulant to the mammal, the most typical being insufflation, inhalation, and intravenous administration. This term also includes exposure to a stimulant when it occurs in combination with other compounds not considered stimulants. The term exposure can also represent a single or multiple incidents. "Stimulant" means any substance that temporarily increases functional activity, and preferably cardiac, respiratory, cerebral, nervous, vascular, motor, or vaso-motor functional activity. Preferred stimulants include, without limitation, cocaine, amphetamines, methamphetamine, and methylphenidate. "Therapeutically effective amount" means an amount of a cytidine-containing or cytosine-containing compound sufficient to produce a healing, curative, or attenuating effect, either in the treatment of an exposure to a stimulant, or a dependence on stimulants. "Cytidine-containing compound" means 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-51-diphosphocholine often prepared as cytidine-5'-diphosphocholine [sodium salt], and also known as citicoline.

"Compound containing cytosine" means any compound that includes, as a component, cytosine. "Dependency" means any form of behavior that indicates an altered or reduced capacity 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 toward the desire, planning, acquisition, and use of stimulants. This term also includes the psychic urgency of a drug, which may or may not be accompanied by a physiological dependency, as well as a state where there is a compulsion to take a drug, either continuously or in a periodic manner, in order to to experience its psychic effects, or to avoid the discomfort of its absence. The forms of "dependence" include habituation, that is, an emotional or psychological dependence on a compound to obtain relief from stress and emotional distress, as well as a physical or physiological dependence, that is, the use of a compound to prevent withdrawal symptoms. "Antennatal exposure" means the exposure of a subject to a stimulant before birth by the mother before delivery, the mother having prior to delivery an exposure as described herein. "Urgency" means a behavior that reflects a consuming desire, craving, or longing for a stimulant. This term may refer to aspects of the behaviors that are components of a dependency. "Sequelae of cerebral vasoconstriction" means any condition at once and resulting from the constriction of the blood vessels in the brain, caused by a motor nerve or chemical compound, for example any disease, pathology, disorder, or dependence subsequent to exposure to stimulants. This term includes cerebral ischemia, neuropathologies, neurological deficits, altered brain chemistry, reduced levels of task mastery, cognitive spoilage, behavioral changes, vegetative responses, mental deterioration, altered parameters of conditioned abstinence and auditory response, and motor activity damage. . These conditions can be characterized by altered levels of phosphomonoesters (PME), phosphodiesters (PDE), phosphocreatine (PCr), nucleotide triphosphates (NTP), inorganic phosphorus (Pi), the PCr / Pi ratio, the ß-NTP ratio / PCr, cerebral phosphorus metabolites, phospholipid precursors, cellular and organelle phospholipid synthesis, membrane synthesis, tyrosine hydroxylase activity, dopamine and dopamine metabolism, bioenergetic function, release of fatty acid, neutral acids, degradation of phosphatidylcholine and glycerophospholipid, glucose, pyruvate, acetylcholine, norepinephrine, vasodilation, sinatopsomal phosphorylation, cell proliferation, neuronal injury, edema, mitochondrial ATPase, and ATPase sensitivity of Na + -K +, phospholipase A2 activation / EEG parameters, cardiovascular and respiratory parameters. The term will include any of the above conditions altered alone or in combination. The present invention provides a number of advantages. It is important that it provides one of the first therapies for the treatment of stimulant dependencies (such as cocaine dependencies). In addition, the cytidine-containing compounds used herein are relatively non-toxic, and -CDP-choline, in particular, is understood to be drug-kinetically, and is known to be well tolerated by mammals. Detailed Description of the Invention The drawings will be briefly described first. Brief Description of the Drawings Figure 1 is a diagram illustrating a timeline and the points at which different procedures were performed throughout the experimental protocol described herein. Figures 2A and 2B are histograms illustrating changes in the possibility of using cocaine in patients classified as "active" (Figure 2A) versus "clean" (Figure 2B), when treated with CDP-choline (* indicates the meaning in p <0.05 in relation to the baseline). The unshaded bars represent the patients in the baseline, and the shaded bars represent the patients after the treatment. The y-axis is a visual analog scale (VAS) in millimeters, where 100 represents "almost always", and 0 represents "nothing". The visual analog scale is designed to quantify subjective mood statements. Figures 3A and 3B are histograms illustrating changes in the percentage of cocaine urgency levels exhibited by patients when treated with CDP-choline (t indicates a trend relative to the baseline). The unshaded bars represent the patients in the baseline, and the shaded bars represent the patients after the treatment. The scale is the same as that described in Figures 2A and 2B. Figure 4 is a histogram illustrating an improved cognitive processing capacity in patients who are "active" users treated with CDP-choline, measured in the P300 ERP test. Figure 5 is a histogram illustrating the functioning of iconic memory in patients classified as "active" when treated with CDP-choline. The unshaded bars represent the patients in the baseline, and the shaded bars represent the patients after the treatment. Figures 6A and 6B are Magnetic Resonance Imaging (MRl), which illustrates the notorious cerebral vasoconstriction following the intravenous administration of cocaine. Projection images of maximal axial intensity are indicated on the baseline (Figure 6A), and 20 minutes following administration of intravenous cocaine (0.4 milligrams / kilogram) (Figure 6B). Cocaine induced signal loss in the distal segments of the middle cerebral arteries (upper arrowheads), and in the posterior cerebral arteries (lower arrowheads), indicating vasoconstriction. A = anterior, P = posterior, L = left, and R = right. Figure 7 is a diagram illustrating the effects of cocaine on cardiovascular parameters, such as heart rate (HR), and systolic (Sys) and diastolic (Dias) blood pressures. Figure 8 is a diagram illustrating the effects of cocaine on cerebral vasoconstriction, as measured by magnetic resonance angiography (MRA). Figure 9 is a diagram illustrating the percentage of differences in the cerebral phosphorus metabolite profiles of methadone maintenance (MM) patients, as measured by phosphorus magnetic resonance spectroscopy. Figure 10 is an illustration of the molecular structure of CDP-choline [sodium salt], also known as citicoline. The invention described herein provides a method for the treatment of stimulant abuse and its symptoms, as well as dependence on stimulants and associated self-destructive behaviors. The invention focuses on the abuse and addiction of cocaine, although other dependencies of stimulants can be treated similarly. For this purpose, the invention provides the use of compounds containing cytidine or containing cytosine to alleviate the symptoms of abuse and dependence. A preferred cytidine-containing compound is CDP-choline (also referred to as citicoline, or CDP-choline [sodium salt]). As described herein, it has been found that CDP-choline has two important therapeutic properties. First, CDP-choline improves brain chemistry in patients suffering from cocaine abuse symptoms as a result of cocaine-induced cerebral vasoconstriction. And second, CDP-choline alleviates the dependence exhibited by active cocaine users. In addition, the results described here demonstrate that the symptoms of cocaine abuse are quite possibly functions of cocaine-induced cerebral vasoconstriction. These results also show that the symptoms of opiate abuse and dependence (specifically, abuse and dependence of heroin), induce alterations in some of the, but not all, brain chemistry indices, and that some of these parameters in patients with heroin addictions improve with methadone in a similar way to the observed improvements in patients with cocaine addictions treated with CDP-choline. The present invention, therefore, makes possible methods and reagents for the treatment of abuse of stimulants, such as cocaine abuse, by providing the original data from human trials. The following detailed examples are provided for the purpose of illustrating, and not limiting, the invention. EXAMPLE 1 CDP-Choline is an Effective Treatment for Cocaine Abuse and Dependence A small double-blind clinical trial of CDP-choline was conducted against placebo, to alter the urgency of cocaine, and modify the responses to stimuli related to cocaine. cocaine. A total of 14 cocaine users were recruited into stone passing a psychiatric, medical, and clinical laboratory evaluation, and they provided an informed consent to participate in this outpatient treatment study. The subjects were completely randomized, and the resulting demographic profiles are shown in Table 1.

Table 1. Demographic of Study Population * Oral dose of 500 milligrams twice a day. The subjects participated in two evaluation sessions, each separated by two weeks, during which the subjects received placebo or CDP-choline (500 milligrams twice a day). Frequent evaluations were made for adverse effects and urine studies during treatment. The research design is illustrated in Figure 1. In each of two assessment sessions, subjects were required to report to the laboratory to fill out a number of subjective mood state questionnaires. After this initial evaluation, the subjects then sat in a room of attenuated sound and light, and were prepared for the standard EEG / ERP recording and physiological monitoring. After a baseline period of 1 hour, the first of three videos was shown. Subsequent videos were shown at 1-hour intervals. The three videos included: (1) a neutral film of life in the coral sea; (2) an emotionally charged section of the movie "An American Were Olf in London" (An American Wolf Man in London); and (3) a stretch of two men buying, preparing, and smoking cocaine in stone. Continuous measurements of physiological and electrophysiological brain mapping were made before and after each videotape. In addition, the subjects were required to respond to a series of questionnaires that were designed to assess the subject's degree of urgency for cocaine. These included questions such as: "What is the possibility that you use cocaine?"; "Are you planning to use cocaine?"; and "How much do you want to use cocaine?" . Finally, a test battery was given for the reaction time and the psychomotor function. The CalCAPMR is a series of 10 different tasks, each one becoming more difficult as the test proceeds. Safety Assessments The results of adverse reaction evaluations revealed that CDP-choline not only had no side effects, but that subjects were unable to detect if they had received an active or placebo dose. No changes were observed in the state of health or in the chemical analysis of blood or urine. At the baseline, three subjects from the placebo group and one from the CDP-choline group had non-clinical brady-day of the breast. A subject who received CDP-choline developed a slight, non-relevant increase in the P-R cardiac interval. Finally, there were no changes in heart rate or blood pressure. Population Dynamics A post-hoc analysis revealed that both the placebo and CDP-choline groups contained two distinct populations of stone cocaine users. "Active" users were defined as those who were currently using cocaine at the time of recruitment. These reports were confirmed using urine drug screens. The "clean" users were those who had been free of cocaine during the past 6 to 12 months. The distribution of active and clean users is illustrated in Table 2.

Table 2. Distribution of "Active" versus "Clean" Users in the Study Population This distinction appeared to be very important in characterizing the efficacy of CDP-choline. Cocaine Dependency / Urgency Assessment The responses to the Pre-Questionnaires regarding the "possibility of using cocaine" revealed a statistically significant decrease in this variable in active cocaine users who had been treated with CDP-choline, comparing with those patients treated with a placebo (Figures 2A and 2B). As another measure of whether CDP-choline treatment could reduce cocaine dependence on "active" versus "clean" users, patients were asked about the likelihood of their "cocaine use planning" and their "desire to use cocaine". use cocaine "(Figures 3A and 3B). Although they were not statistically significant, there were strong tendencies (p = 0.06-0.08) of reductions in these parameters in the "active" users. A similar reduction was observed in the question of "possibility of use", even after patients submitted to the video illustrating the use of stone cocaine (data not shown). To test the ability of CDP-choline to improve cognitive function in cocaine users, a P300 ERP test was performed on "active users" (Figure 4). The P300 ERP test is a measure of memory that encodes performance during the evaluation of a novel stimulus. The reductions in amplitude are generally interpreted as reflecting reduced cognitive processing. Figure 4 shows that (compared to baseline) the reduction in P300 amplitude was modest and insignificant in "active" users treated with CDP-choline, while the reduction in "active" users treated with placebo was significantly greater . To further test the ability of CDP-choline to improve cognitive function in cocaine users, patients treated or not treated with CDP-choline were tested for their ability to discriminate forms, using the CalCAPMR test (Figure 6). Shape discrimination was measured by showing subjects three geometric shapes simultaneously, and asking them to press a key when two were identical in shape and color. This task required subjects to make quick comparisons and measured their ability to retain iconic memory. Patients classified as "active" users who were treated with CDP-choline showed a trend towards a significant improvement in their reaction time (145 milliseconds) in the Form Discrimination, compared to the untreated "active" users (Figure 5) . Summary of Human Clinical Trial Results In this human trial designed to test the effectiveness of CDP-choline in the treatment of cocaine abuse and dependence, the following observations were made: 1. CDP-choline improved short-term memory and cognitive function in patients with cocaine exposure. 2. Patients with cocaine dependence or urgency benefited from CDP-choline treatment. 3. CDP-choline is non-toxic, well tolerated, and not detectable by subjects. These results indicate that CDP-choline is a useful aid in current therapies for cocaine abuse, particularly * in individuals who are currently active users. Without being bound by a particular theory, these results are possibly due to the weak dopamine agonist activity of CDP-choline. In addition, these results indicate that, due to its low toxicity, CDP-choline may be useful for the treatment of pregnant women, adolescents, and babies born to cocaine-dependent women. This last group is of particular importance, because the ability of CDP-choline to reduce stroke symptoms suggests that this therapy can also reverse many of the harmful micro-infarcts that occur during exposure to cocaine in the uterus. .

To date, there are no approved pharmacotherapies for cocaine abuse or dependence. The administration of CDP-choline, therefore, therapeutically provides an important approach to minimize the detrimental effects of cocaine abuse and dependence, and to expedite the recovery process. In addition, based on the mechanism of action of CDP-choline, 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, abuse and dependence on amphetamine, methamphetamine, and methylphenidate. EXAMPLE 2 Cocaine-Induced Brain 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. Noninvasive serial imaging of the major cerebral arteries was conducted at the baseline and 20 minutes following the administration of cocaine, using magnetic resonance angiography (MRA). Magnetic resonance angiography is highly sensitive to disturbances of blood flow. Vasoconstriction results in a loss of vessel signal intensity at the site of, and distal to, the constricted region, and magnetic resonance angiography has proven useful in detecting acute cerebral vasospasm. This technique is non-invasive and does not use ionizing radiation, facilitating repeated study study designs within the subject. Subjects We excluded subjects who did not have a history of cocaine use or who had a diagnosis of cocaine abuse or dependence in this study. A group of 24 healthy, medically and neurologically normal men aged 29 + 5 years (mean ± standard deviation) was selected, who reported the casual use of cocaine (mean = 8, range = 3 to more than 40 exposures in their life). , primarily by insufflation) to participate in the study. Subjects provided an informed written consent with the approval of the Institutional Review Board of McLean Hospital. Subjects underwent a complete physical and neurological examination, including ECG and hematology before the study, and provided a medical history, including estimates of illicit drug use. On the day of the study, subjects provided breathing and urine samples to detect the recent use of alcohol or illicit drugs. The breathing samples were analyzed with an Aleo Sensor III Breathalyzer (Intoximeters Inc., St. Louis, MO). Urine samples were analyzed for the presence of cocaine, amphetamines, phencyclidine, opiates, barbiturates, benzodiazepines, and tetrahydrocannabinol with a Triage ™ Test (Biosite Diagnostics, San Diego, CA). All subjects had breath alcohol samples and negative urine traces. Each subject had an 18G angio-catheter inserted in a vein overlapping the antecubital fossa for the administration of cocaine or placebo. Subjects were adapted with non-invasive cardio-vascular monitoring equipment (In Vivo Research, Inc., Orlando, FL), which included a 4-conductor electrocardiogram (ECG), blood pressure cuff, and pulse oximeter, to provide monitoring continuous ECG, blood pressure, and heart rate. Magnetic Resonance Scan Magnetic resonance imaging was conducted with a Tesla Signa Scanner 1.5 (General Electric, Milwaukee, Wl). Weighted sagittal locator imaging (TE / TR: 19/600 milliseconds) images were used to place magnetic resonance angiography imaging devices. They were collected with angiogram image formation points of 60 axial images with the option of magnetization transfer of three-dimensional flight time (3D TOF), with flow compensation and saturation. The following acquisition parameters were used: TE / TR: 35/20 milliseconds; FOV: 19 centimeters; matrix: 256 x 192; slice thickness: 1.2 mm; 1 NEX, image formation time: 7.5 minutes. Each set of images produced a single axial maximum intensity projection (MIP) image that was analyzed to determine the effects of the drug. Then cocaine (0.2 or 0.4 milligrams / kilogram) or placebo was administered by slow intravenous injection for 1 minute; all doses were given in a double-blind manner. Seventeen minutes after the administration of the drug, a 3D TOF series was initiated after the drug, presenting a midpoint of the image sequence 20 minutes after the administration of the drug. Analysis of Images Axial MIP images of the baseline and subsequent to cocaine / placebo of each subject were analyzed to determine the changes induced by the drug. Two expert evaluators, blinded to the drug administration of the study, independently analyzed the 24 sets of images. Before the analysis, the two evaluators agreed on the criteria that would be used to determine the alterations between the images of the baseline and after the drug. The subtle image differences discernible by both assessors, including the change in caliber of moderate and large sized arteries, and focal narrowing or complete signal loss in a larger arterial structure, were considered as alterations. The sets of images were rated as unchanged, ambiguous, or altered. A concordance was established when both assessors agreed to their independent exploration evaluations. A weighted kappa statistic of 0.64 for the inter-rater agreement showed a very high degree of agreement among the raters (p = 0.002, two sides, unweighted kappa = 0.70, p < 0.0001) (Fleiss, JL, et al., Educ Psychol.Med., 33: 613-619, 1973). Results of the Cocaine-Induced Brain Vasoconstriction Study The baseline cardiovascular parameters were normal in all subjects, with a heart rate (HR) averaging 68 + 2 beats per minute (average + standard error), and systolic blood pressures (Sys ) and diastolic (Days) averaging 126 + 3 and 70 + 3 mm Hg, respectively (Figure 7). Slight increases in HR, Cys, and Dias were observed in the placebo group (Figure 7), and were attributed to the effects of expectation. Both doses of cocaine raised the heart rate by the duration of the experiment, with peak * increases in HR, Cys, and Dias (Figure 7) occurring approximately 6 to 10 minutes following the administration of the drug. Twenty minutes after the administration of cocaine or placebo, at the midpoint of the acquisition of the magnetic resonance angiography, HR and Dias remained elevated in all the subjects to whom cocaine was administered, and Cys remained elevated in the subjects those that were administered 0.4 milligrams / kilogram of cocaine (Figure 7). A global dose effect of cocaine (repeated ANOVA measurements) was detected for HR and Dias at the time point of 20 minutes (Figure 7). The analysis of images revealed a relationship between the administration of cocaine and the angiographic alteration. All images of the baseline were judged normal. The evaluators determined that 5 of 8 subjects who received 0.4 milligrams / kilogram of cocaine, experienced angiographic alterations indicative of cerebral vasoconstriction. These were from subtle differences in arterial caliber, to more significant alterations, including focal narrowing or complete signal loss from a larger arterial structure. These alterations were detected in the posterior cerebral artery, in the middle cerebral arteries (Figure 6), in the vertebral arteries, and in the arteries of anterior and posterior communication. Three of 9 subjects who received 0.2 milligrams / kilogram of cocaine had angiographic alterations in several arteries, including the arteries of anterior communication, and the posterior and middle cerebral arteries. One of 7 subjects who received placebo was taken out of the study because of an MRI angiography scan after the altered placebo. Figure 8 shows the observed classification of angiogram results stratified by cocaine dosing for all sets of images. Statistical analysis of the explorations concurrently evaluated using a linear-linear association model (Agresti, A, Categorical Data Analysis, John Wiley & amp;; Sons, New York, 1990) for the ordered categories of 0 = unchanged, 1 = ambiguous, and 2 = altered, indicated a significant association of an increasing prevalence of altered scans with an increasing dose of cocaine (p = 0.041, one side ). When discordantly evaluated explorations were included, the significance of the association decreased slightly (p = 0.056). These findings demonstrated an apparent relationship between cocaine administration and altered magnetic resonance angiography exploration; moreover, this effect seemed to be related to the dose. A stratified analysis of this small sample by frequency of cocaine use in self-reported life (1 to 10 times, 11 to 40 times, or more than 40 times), revealed a dose response relationship statistically stronger (p. < 0.001), suggesting that prior cocaine use may have a cumulative effect in the promotion of angiographic changes indicating vasoconstriction. The study design precluded the direct measurement of plasma cocaine levels in the present study population. However, we obtained plasma cocaine levels by gas chromatographic analysis (Teoh, SK et al., J. Clin, Psychopharmacology 13: 87-99, 1993) of comparable subjects to whom cocaine was administered by identical protocols. Cocaine levels were found in peak plasma of 230 + 10 and 90 ± 10 nanograms / milliliter, from 6 to 8 minutes following the intravenous administration of doses of 0.4 (n = 3) and 0.2 (n = 6) milligrams / kilogram of cocaine, respectively. Plasma cocaine levels of 180 + 30 and 80 + 10 nanograms / milliliter were found 20 minutes after administration, corresponding to the time of the midpoint of the present acquisition of magnetic resonance angiography, followed by a dose of 0.4. and 0.2 milligrams / kilogram of cocaine, respectively. These values and their course are closely parallel to those published in a recent report of the time course of cocaine level in venous plasma following intravenous cocaine administration (Evans, SM et al, J. Pharmacol, Therap. : 1345-1356, 1996). Summary of Results The above results are the first to document that intravenous administration of a relatively low dose of cocaine to otherwise healthy humans can induce angiographic changes that indicate cerebral vasoconstriction. This finding suggests that low doses of cocaine are sufficient to induce cerebrovascular dysfunction. The data also reflect a dose-effect relationship between cocaine and vasoconstriction. This finding suggests that moderate to heavy cocaine users, who may reach plasma cocaine levels that far exceed those who are likely to be reached in this study, may experience a higher incidence of cerebral vasoconstriction. Because cerebral vasoconstriction has been linked to hypoperfusion, and because persistent hypoperfusion has been associated with neuronal dysfunction, the present findings indicate that the use of moderate to heavy cocaine is likely to be associated with neuronal damage. Cumulative Effects of Cocaine, and the Etiology of Chronic Cerebral Dysfunction Induced by Cocaine Although it is assumed that chronic cocaine abuse is a requirement to produce persistent perfusion defects and cognitive dysfunction, it is currently unclear what the threshold level of exposure to cocaine is that results in these conditions. The cognitive dysfunction observed in chronic cocaine abusers is related to the amount of cocaine used, suggesting a cumulative effect of cocaine on brain function. The present study documents a relationship between the previous use of cocaine, and the propensity to experience vasoconstriction, suggesting that cocaine may have a cumulative effect on the production of cerebrovascular dysfunction in addition to its acute vasoconstrictor effect. In this aspectHi. , the use of cocaine in self-reported life more than 10 times, almost doubled the risk of experiencing an angio-graphic change induced by cocaine (75 percent), compared with the risk experienced by subjects who reported 10 or less episodes of cocaine use in life (38 percent). The present data suggest that the incidence of cerebral vasoconstriction induced by cocaine can be increased in individuals that scale from the use of experimental cocaine to casual or recreational cocaine. The present study was conducted at a single point in time following the administration of cocaine, precluding the analysis of the time dependence of cocaine-induced vasoconstriction. Because cocaine-induced vasoconstriction is a transient phenomenon, and because our time frame for detection was short, it is conceivable that more subjects experienced vasoconstriction than what was detected in the current study. Additionally, we could not resolve whether cocaine or its metabolites, some of which are potent vasoconstrictors, mediate vasoconstriction. Cocaine metabolites may play an important role in the induction of delayed cerebral vasoconstriction, because their levels increase gradually over several hours, and in extreme cases persist for up to several weeks. Consequently, they can trigger prolonged cerebral vasoconstriction associated with reduced cerebral perfusion. The present study used intravenous cocaine administration as the drug delivery method, while intra-nasal administration and smoking the "crack" alkaloid form (stone), are the most common forms of administration. It has been suggested that the mode of administration of cocaine is related to the cerebrovascular effect, leading the intravenous route to hemorrhagic strokes, and leading "crack" smoking (stone) to both ischemic and hemorrhagic strokes. Therefore, it is possible that different forms of cocaine, or different routes of administration, may produce indices or severities other than vasoconstriction. However, our discovery of a dose-effect relationship between cocaine and vasoconstriction suggests that once a sufficient concentration of cocaine is reached in plasma, there is a possibility of cerebral vasoconstriction. Moreover, the results of this clinical trial demonstrate a real and substantial dose-effect relationship between cocaine and cerebral vasoconstriction. These results underestimate the risks of individual doses of cocaine in the promotion of cerebrovascular abnormalities, particularly in individuals with other risk factors. The data also strongly suggest that there is an increased risk of cerebrovascular dysfunction in individuals who are frequent or chronic users of cocaine, and that this dysfunction may be progressive. Together, these findings emphasize the potential dangers of cocaine use on cerebrovascular function, and document the importance of cytosine-containing or cytidine-containing treatments, such as CDP-choline, that protect against, or correct, vasoconstriction or Your symptoms. EXAMPLE 3 Brain Phosphorus Metabolism in Abusers of Heroin-Dependent Polydrogas During Maintenance with Methadone Heroin abusers have cerebral metabolic and perfusion abnormalities that persist beyond the period of drug intoxication and acute withdrawal (London, ED, and collaborators, 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. Psychiatry 47: 73-81, 1990; Walsh, SL et al., Neuropsychopharmacology 10: 157-170, 1994). However, no study to date has examined the neurochemical effects of the most widely used intervention for the treatment of opiate abuse, methadone. Methadone has shown efficacy in improving psychiatric symptoms and overall health in opiate abusers (McLellan, AT et al., JAMA 247: 1423-1428, 1982; Ball, JC et al., The effectiveness of methadone maintenance treatment: Patients, programs, services, and outcome, New York, Springer-Verlag, 1991). However, it is unknown if these clinical improvements are related to better brain function. Consequently, the present study was conducted in abusers of heroin-dependent polydrugs chronically treated with methadone, to evaluate the rates of cerebral biochemistry using phosphorus magnetic resonance spectroscopy (31P MRS). The 31P MRS allows the non-invasive measurement of the integrity of the brain membrane and the bio-energetic state. To conduct this clinical study, abusers of heroin-dependent polydrug (9 women and 6 men, aged 40 + 4 years, mean + standard deviation) were recruited from a maintenance clinic with outpatient methadone (MM). Potential subjects with a history of alcohol abuse or infection by VEH were excluded from the study. This population was subdivided into two groups based on the duration of methadone maintenance treatment: the short-term group (n = 7, 40 + 24 weeks), and the long-term group (n = 8, 137 + 53 weeks) . The dose of methadone administered to these subjects was on the scale of 60 to 80 milligrams per day, and was statistically equivalent in the two groups of duration of methadone maintenance treatment. All medical histories, including the biweekly random urine toxicology test throughout the course of methadone maintenance therapy, were reviewed in order to determine the demography of the study population. Positive urine tests for the following substances were found more than 10 percent of the time: methadone-98 percent; benzodiazepines-39 percent; opiates-37 percent; cocaine-18 psr cent. Clean urine studies were found 26 percent of the time. These frequencies were statistically equivalent across the subgroups of maintenance duration with methadone. A comparison group of matched age was studied (6 women and 10 men, ages 40 + 4 years) with no history of substance abuse or neurological or psychiatric disorder, with identical procedures. All subjects provided written informed consent with the Institutional Review Board of McLean Hospital. All subjects provided breathing and urine samples immediately before the examination to determine if a recent use of alcohol or illicit drug had occurred. The breathing samples were analyzed with an Aleo Sensor III Breathalyzer (Intoximeters Inc., St. Louis, MO). A positive breath alcohol sample was the basis for exclusion from the study. Urine samples were analyzed for the presence of illicit drugs with a Triage ™ Test (Biosite Diagnostics, San Diego, CA). A positive urine test for illicit drug use was not a basis for exclusion in the methadone maintenance population, because it was assumed that this group would have a continuous use of the drug. The frequency of the Triare positive test for all substances was statistically equivalent across the subgroups of maintenance duration with methadone. Image Formation Spectra were acquired in a Tesla General Electric Signa Scanner 1.5, using a quadrature phosphor head coil, of linear, double tuned protons. An axial whole brain slice volume of 50 millimeters thick was prescribed through the orbito-frontalis / occipital cortexes, as described (Christensen, JD et al., Magn.Reson.Med. 35: 658-663, 1996). ). The spectra were processed with VARPRO / MRUI (van den Boogaart, A et al., NMR Biomed, 8: 87-93, 1995). An expansion filter of 5 Hz exponential line was applied, and seven peaks were fitted to Gaussian lines by automated adjustment: phosphomonoesters (PME), inorganic phosphorus (Pi), phosphodiesters (PDE), phosphocreatine (PCR), and β-nucleoside, α-nucleoside, and β-nucleoside phosphates. The total phosphorus signal (sum of all peak areas) was statistically equivalent across the groups, allowing the use of the metabolite measurement percentage, the ratio of the area of each metabolite peak divided by the total phosphorus area, to the comparisons between groups (Klunk, W and collaborators, Neurobiol.Aging 15: 133-140, 1994). Statistical analyzes were performed using two-sided, unpaired tests. Results The molar percentages of PME and PDE were significantly higher, and the molar percentage of CRP was reduced significantly in the methadone maintenance population (Figure 9). When stratified into subgroups of short and long-term methadone maintenance treatment, different profiles of brain phosphorus metabolite abnormalities emerged. The short-term methadone maintenance group had a% PME,% PDE, and high ß-NTP / PCR ratio, and% PCr,% NTP, and reduced PCr / Pi ratio. In contrast, the long-term methadone maintenance group differed from the healthy comparison group only in that it had reduced levels of% CRP. This group differed from the short-term methadone maintenance group that had higher levels of% CRP, and lower levels of% PDE (Figure 9). Summary Previous findings indicated elevated PME and PDE, as well as reduced PCr levels in abusers of heroin-dependent polydrugs. This may reflect membrane dysfunction and deterioration of oxidative metabolism secondary to perfusion defects. The profile of metabolites is unique compared to discoveries in cocaine abusers, in whom only elevations of PME and PDE were observed, and in abusers of cocaine-dependent polydrugs, in whom high levels of PME were found, and reduced levels of ß-NTP. This suggests that polydrug abuse populations with different patterns of primary substance abuse may have discrete phosphorus metabolite profiles. The present data is very interesting, because it also documents an apparent normalization of most cerebral phosphorus metabolites in subjects who have undergone prolonged maintenance therapy with methadone. In this regard, only PCr levels were abnormal in the long-term methadone maintenance group; PCr and PDE levels were significantly higher and lower (more normal) in this group, compared to the short-term methadone maintenance group. This apparent improvement is consistent with a previous study documenting improved cerebral perfusion in short-term abstinence from heroin abuse (Rose, JS et al., Psychiatry Research: Neuroi aging 67: 39-47, 1996). What is additionally encouraging from the present data is that metabolite improvements were observed in subjects with continuous use of illicit substances (positive urine for opiate almost 40 percent of the time). This indicates that abstinence is not required for the normalization of certain aspects of brain function. Together, the present findings suggest that cerebral phosphorus metabolites are useful markers of brain health and treatment efficacy in individuals with a history of polydrug abuse. As also indicated by the previous study, certain aspects of altered phosphorus metabolites in heroin addicts are unique compared to discoveries in cocaine abusers. Other aspects of this altered metabolism, such as membrane dysfunction and impairment of oxidative metabolism secondary to perfusion defects, are common to both drug abusers, and therefore, can be treated with compounds containing cytosine or containing cytidine, such as CDP-choline. EXAMPLE 4 Compounds Containing Cytidine and Containing Cytosine The human assays described herein make exclusive use of the cytidine-containing compound, CDP-choline, also known as citicoline, received from Interneuron Pharmaceuticals, Inc. However, because the cytidine fraction of this compound is responsible for the beneficial effects observed in these assays, any of a variety of compounds containing cytidine or containing cytosine are suitable for the treatment of the afflictions described herein. Examples of useful cytidine-containing or cytosine-containing compounds can include any compound that comprises 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 compounds containing cytidine and containing cytosine is provided to illustrate, rather than 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 given in Figure 10.

As noted above, a particular source of CDP-choline is Interneuron Pharmaceuticals, Inc. The compound obtained from this source has the following characteristics: Chemical formula: C14H25N4? 11P2Na Molecular weight: 510.31 Physical and chemical characteristics: completely soluble in water as a 10 percent solution; practically insoluble in 100 percent ethanol. The pH in water is between 6.5 and 7.5. One available clinical dosage form of CDP-choline for oral administration is an oblong tablet of 500 milligrams. Each tablet contains 522.5 milligrams of CDP-choline sodium, equivalent to 500 milligrams of CDP-choline. There are also coupled placebo tablets available. The excipients contained in both active and placebo tablets are talc, magnesium stearate, colloidal silicon dioxide, hydrogenated castor oil, sodium carboxymethylcellulose, and microcrystalline cellulose. CDP-choline is a naturally occurring compound that is synthesized from cytidine-5'-triphosphate and phosphocholine, with the combined production of inorganic pyrophosphate in a reversible reaction catalyzed by the CTP enzyme: phosphocholine citidyl transferase (Weiss , Metabolism and Actions of CDP-choline as an Exogenous Compound and Administrered Exogenously as Citicholine, Life Sciences 56: 637-660, 1995).

EXAMPLE 5 Administration of Compounds Containing Citidine and Crue Contain Cytosine Cytidine-containing and cytosine-containing compounds, such as CDP-choline, are naturally occurring endogenous compounds. CDP-choline itself is synthesized in a sodium salt form for clinical use (see Figure 10). A clinical dosage form for oral administration is an oblong tablet of 500 milligrams. Each tablet contains 522.5 milligrams of CDP-choline sodium, equivalent to 500 milligrams of CDP-choline. For easier administration, these tablets can be cut into smaller pieces, or crushed. Preferably, the cytosine-containing and cytidine-containing compounds, such as CDP-choline, are administered in a dosage of at least 500 milligrams twice a day by oral administration. Orally administered CDP-choline is bioavailable, with more than 99 percent of CDP-choline and / or its metabolites absorbed, and less than 1 percent excreted in the faeces. CDP-choline, administered either orally or intravenously, is rapidly converted into the two major circulating metabolites, choline and cytidine. The main routes of excretion are the lung (12.9 percent) and urine (2.4 percent), the rest of the dose (83.9 percent) apparently metabolized and retained in the tissues.

Other 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. Conventional pharmaceutical practice is employed to provide formulations or compositions suitable for administering these compositions to patients. Oral administration is preferred, but any other appropriate route of administration may be employed, for example, parenteral, intravenous, subcutaneous, intramuscular, intracranial, intra-orbital, ophthalmic, intra-ventricular, intra-capsular, intra-spinal administration , intra-cisternal, intra-peritoneal, intra-nasal, or aerosol. The therapeutic formulations may be in the form of liquid solutions or suspensions (such as, for example, for intravenous administration); for oral administration, the formulations may be in the form of liquids, tablets, or capsules; and for intra-nasal formulations, in the form of powders, nasal drops, or aerosols. Methods well known in the art for making the formulations are described, for example, in "Remington's Pharmaceutical Sciences", Mack Publishing Company, Easton, PA. Formulations for parenteral administration, for example, may contain excipients, sterile water, or serum, polyalkylene glycols, such as polyethylene glycol, oils of vegetable origin, or hydrogenated naphthalenes. If desired, slow-release or sustained-release delivery systems can be used. Biodegradable and biocompatible lactide polymers, lactic / glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers can 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. The formulations for inhalation may contain excipients, for example lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or they may be oily solutions to be administered in the form of nasal drops, or as a gel. In general, compounds containing cytosine or containing cytidine, such as CDP-choline, are administered in an appropriate dosage so that the effect is achieved, and are usually administered in a unit dosage form. As noted above, the preferred route of administration for most indications is oral. An effective amount of a cytidine-containing or cytosine-containing compound is used to treat the conditions described herein. The exact dosage of the compound may depend, for example, on 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 selected dosage should be sufficient to prevent, ameliorate, or treat the condition, or one or more symptoms thereof, without producing significant toxic or undesirable side effects. In the case of CDP-choline, no cases of overdose have been reported. The toxicity of CDP-choline is largely self-limiting, and the ingestion of large amounts in pre-clinical studies shows common cholinergic symptoms (salivation, lacrimation, urination, defecation, and vomiting). Other Modes Preferably, 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 domesticated pet or livestock. Any cognitive or behavioral problems associated with the types of altered brain chemistry described herein, can be ameliorated with compounds containing cytidine or containing cytosine, such as CDP-choline. In addition, normal brain chemistry can also be improved by the administration of compounds containing cytidine or containing cytosine, the result being improvements in cognitive functioning.

For any of these additional uses, the cytidine-containing or cytosine-containing compound is administered by the general methods described herein. All publications and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each publication or independent patent application was indicated in a specific and individual manner as incorporated by reference. Although the invention has been described in relation to its specific embodiments, it will be understood that it may have further modifications, and it is intended that this application cover any variations, uses, or adaptations of the invention, generally following the principles of the invention, and including the departures from the present disclosure which come into the known or customary practice within the field to which the invention pertains, and may be applied to the essential features stipulated hereinbefore, and as follows within the scope of the appended claims. Other embodiments are within the claims.

Claims (27)

1. CLAIMS 1. A method of treating a mammal exposed to a stimulant, comprising administering to said mammal a therapeutically effective amount of a cytidine-containing compound.
2. 2. The method of claim 1, wherein said stimulant is cocaine.
3. 3. The method of claim 1, wherein said cytidine-containing compound is cytidine.
4. 4. The method of claim 1, wherein said cytidine-containing compound further comprises choline.
5. The method of claim 1, wherein said cytidine-containing compound is CDP-choline.
6. 6. The method of claim 1, wherein said cytidine-containing compound is CDP.
7. The method of claim 1, wherein said mammal is a human being.
8. The method of claim 7, wherein said human being 9.
9. The method of claim 7, wherein said human is anxious for a stimulant.
10. The method of claim 7, wherein said human being has a stimulant dependency.
11. 11. A method of treating sequelae of cerebral vasoconstriction in a mammal, comprising administering to said mammal a therapeutically effective amount of a cytidine-containing compound.
12. 12. The method of claim 11, wherein said cerebral vasoconstriction is a result of exposure to cocaine.
13. The method of claim 11, wherein said cerebral vasoconstriction results from exposure to a substance that causes cerebral vasoconstriction.
14. The method of claim 11, wherein said mammal is a human.
15. 15. The method of claim 11, wherein said cytidine-containing compound is cytidine.
16. 16. The method of claim 11, wherein said cytidine-containing compound further comprises choline.
17. The method of claim 11, wherein said cytidine-containing compound is CDP-choline,
18. 18. The method of claim 11, wherein said cytidine-containing compound is CDP.
19. 19. A method of treating a mammal exposed to a stimulant, comprising administering to said mammal a therapeutically effective amount a cytosine-containing compound.
20. The method of claim 19, wherein said mammal is a human.
21. The method of claim 19, wherein said human being is a pregnant woman or a child with antenatal exposure to a stimulant.
22. 22. The method of claim 19, wherein said human being has a craving for stimulant.
23. 23. The method of claim 19, wherein said human being has a dependence on stimulant.
24. 24. A method of treating sequelae of cerebral vasoconstriction in a mammal, comprising administering to said mammal a therapeutically effective amount of a cytosine-containing compound.
25. 25. The method of claim 24, wherein said cerebral vasoconstriction is a result of exposure to cocaine.
26. 26. The method of claim 24, wherein said cerebral vasoconstriction results from exposure to a substance that causes cerebral vasoconstriction.
27. 27. The method of claim 24, wherein said mammal is a human. There is disclosed herein a method for reducing mammalian stimulant dependencies, which involves the administration of a therapeutically effective amount of a cytosine-containing or cytidine-containing compound, such as CDP-choline.