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PubMed2000

Characterization of methylphenidate exposures reported to a regional poison control center.

OBJECTIVE: To investigate the frequency, risk population, symptoms, reason, and outcome surrounding human methylphenidate exposures reported to a regional poison control center. DESIGN: Retrospective case series. SETTING/PATIENTS: All human methylphenidate exposures reported to a regional poison control center during a 2-year period were included. MAIN OUTCOME MEASURES: Data collected included age, dose, reason for exposure, symptoms (type and severity), treatment, and outcome. Age data for all other exposures reported during the same time period were also compiled. RESULTS: The study included 289 patients. Overall, 31% developed symptoms, most commonly tachycardia, agitation, and lethargy. No patient developed severe symptoms, although a less favorable outcome was seen with intentional vs unintentional exposures. When compared with the age data for all other exposures reported during the same time period, a trimodal vs bimodal pattern was seen, with the novel peak occurring in 6- to 9-year-old children. Within this age group, therapeutic error was the most common reason for exposure. CONCLUSIONS: Methylphenidate exposure was associated with symptom development in 31% of cases. An unusually high incidence of therapeutic error was noted surrounding its use, most commonly in the 6- to 11-year-old age group, defining a unique population at risk for toxic exposure. This initial data may allow targeted poisoning prevention efforts for this age group. Arch Pediatr Adolesc Med. 2000;154:1199-1203.

Adolescent↗
PubMed1993

Intravenous pentazocine and methylphenidate abuse during pregnancy. Maternal lifestyle and infant outcome.

OBJECTIVE: To report the effects of intravenous abuse of pentazocine hydrochloride and methylphenidate hydrochloride during pregnancy. DESIGN: Retrospective chart review. PATIENTS: All pregnant women and their offspring, whose hospital records indicated prenatal abuse of pentazocine and methylphenidate during the 2-year study period. RESULTS: The median for maternal age was 22 years and the median number of prenatal visits was two. Twenty mothers had sexually transmitted diseases, 27 abused alcohol, 10 abused other drugs, and all smoked cigarettes. Eight infants were premature, and 12 were growth retarded. Four infants had congenital anomalies: fetal alcohol syndrome (two [twins]), structural heart defect (one), and polydactyly (one). Eleven infants were treated for neonatal abstinence syndrome. Seventeen infants had normal developmental quotients, and four had low-normal developmental quotients. CONCLUSIONS: Intrauterine exposure to pentazocine and methylphenidate appears to be associated with prematurity, growth retardation, and signs of neonatal withdrawal, but not with any particular teratogenic anomaly or severe developmental delay.

Adolescent↗
PubMed1977

Psychologic and neuroendocrine response to methylphenidate.

The value of neuroendocrine techniques for providing information regarding the pathophysiology of psychotic disorders is largely dependent on clarification of the relationships among psychologic state, neural activity, and neuroendocrine regulation. This study presents a strategy for examining the interface between neurochemical activity, psychologic state, and neuroendocrine regulation. Psychologic state and serum growth hormone (GH) and cortisol were monitored following administration of methylphenidate hydrochloride, a drug that appears to preferentially affect central dopamine regulation. While individuals varied in both their endocrine and psychologic responses to methylphenidate, the general effects were GH elevation, euphoria, and activation with elation, the most pronounced psychologic effect. Subjects who showed GH elevation became elated while those who did not show a GH response did not become elated. Elation and GH release following administration of methylphenidate may be mediated by the same neurochemical events.

Adult↗
PubMed1979

The effects of methylphenidate on the mother-child interactions of hyperactive children.

Twenty hyperactive boys were observed while interacting with their mothers during a free play and task period on each of three occasions (no drug, drug, placebo). A triple-blind, drug-placebo crossover design was used to study the effects of methylphenidate on these interactions. A complex objective coding system was used to score the children's responses to various maternal behaviors as well as the mother's responses to a variety of children's behaviors. Results indicated that these children were more compliant with maternal commands during drug treatment. In response, mothers displayed increased attention to compliance while reducing their directiveness toward the boys. However, the hyperactive boys receiving methylphenidate initiated fewer social interactions and tended to show greater nonresponding. Thus, methylphenidate may improve the compliance of hyperactive children but tends to decrease their sociability.

Child↗
PubMed1985

Methylphenidate and children with attention deficit disorder. Dose effects on classroom academic and social behavior.

The short-term, dose-response effects of methylphenidate hydrochloride were evaluated on academic and social classroom measures in 29 children with attention deficit disorder. In a double-blind, cross-over design with order randomized, children received a placebo for two weeks and three doses of methylphenidate hydrochloride (0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg) for one week each. Dependent measures included the output and accuracy of performance in grade-appropriate reading comprehension workbooks and arithmetic problems, spelling word acquisition, and observations of disruptive and on-task behavior. Beneficial drug effects and linear dose-response curves on all dependent measures were found. The results suggest that beneficial methylphenidate effects on classroom behavior may be accompanied by enhanced academic achievement in some hyperactive children.

Achievement↗
PubMed1988

Methylphenidate-induced information processing dysfunction in nonschizophrenic patients.

To examine the relationship of aminergic overactivity to information processing, we gave methylphenidate hydrochloride, oxazepam, or placebo to 12 nonpsychotic patients in one-week blocks in a double-blind, randomized design. Methylphenidate induced a pattern of information processing dysfunction similar to that seen in schizophrenic patients, strengthening the linkage of the schizophrenia-information processing dysfunction-aminergic overactivity relationship. Further, the time course of the observed deficits in both schizophrenic and methylphenidate-induced states is strikingly compatible with the temporal mapping pattern of monoaminergic neuronal systems. More research is needed to identify definitively the aminergic influences on attentional functioning. A psychophysical task-pharmacologic probe strategy should prove useful.

Adult↗
PubMed1999

Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder.

BACKGROUND: This study examined changes in attention-deficit hyperactivity (ADHD) behaviors and motor and vocal tics during long-term treatment with methylphenidate. METHODS: Thirty-four prepubertal children with ADHD and chronic multiple tic disorder (who had participated in an 8-week, double-blind, placebo-controlled methylphenidate evaluation) were evaluated at 6-month intervals for 2 years as part of a prospective, nonblind, follow-up study. Treatment effects were assessed using direct observations of child behavior in a simulated (clinic-based) classroom and behavior rating scales completed by parents and physician. Videotapes of the simulated classroom were scored by coders who were blind to treatment status. RESULTS: There was no evidence (group data) that motor tics or vocal tics changed in frequency or severity during maintenance therapy compared with diagnostic or initial double-blind placebo evaluations. Behavioral improvements demonstrated during the acute drug trial were maintained during follow-up. There was no evidence (group data) of clinically significant adverse drug effects on cardiovascular function or growth at the end of 2 years of treatment. CONCLUSIONS: Long-term treatment with methylphenidate seems to be safe and effective for the management of ADHD behaviors in many (but not necessarily all) children with mild to moderate tic disorder. Nevertheless, careful clinical monitoring is mandatory to rule out the possibility of drug-induced tic exacerbation in individual patients.

Attention Deficit Disorder with Hyperactivity↗
PubMed1999

Liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry enantiomeric separation of dl-threo-methylphenidate, (Ritalin) using a macrocyclic antibiotic as the chiral selector.

Vancomycin, a macrocyclic antibiotic, is an amphoteric glycopeptide produced by Streptomyces orientalis which has proven to be a viable chiral selector for high performance liquid chromatograph (HPLC) (D. W. Armstrong, Y. Tang, S. Chen, Y. Zhou, C. Bagwill and J-R. Chen, Anal. Chem. (1994; 66: 1473). While it is related to other glycopeptide antibiotics, vancomycin has a number of unique structural features, including 18 stereogenic centers, five aromatic rings, and two side chains one of which is a carbohydrate dimer. Therefore, a vancomycin-based stationary phase appears to be multimodal in that it can be utilized in both normal-phase and reversed-phase liquid chromatography. Consequently, the enantiomeric separation may be operative via several mechanisms, including pi-pi complexation, dipole stacking, inclusion, hydrogen bonding, or combinations of these interactions. LC/MS/MS is a powerful tool for quantitative analysis when evaluated on the basis of speed, specificity, reliability and sensitivity. For these reasons, the present paper explored the feasibility of bonded macrocyclic glycopeptide phases for chiral LC/MS/MS quantitative analysis. Methylphenidate was used as a model compound. A rapid chiral bioanalytical method (<7.5 min) for the determination of the enantiomers of methylphenidate was developed. A lower limit of quantification (LLOQ) of 87 pg/mL was attained for the human plasma assay. This is to our knowledge the first example of enantioselective reversed-phase LC/MS/MS for methylphenidate. The chiral column was relatively cost effective and exhibited excellent performance with no separation deterioration observed after approximately 2500 injections.

Atmospheric Pressure↗
PubMed2002

Increased urine phenylethylamine after methylphenidate treatment in children with ADHD.

The urine levels of beta-phenylethylamine, 3-methoxy-4-hydroxyphenyl glycol, homovanillic acid, and 5-hydroxyindoleacetic acid were measured to clarify the neurochemical mechanism in attention deficit hyperactivity disorder. beta-Phenylethylamine levels were significantly lower in attention deficit hyperactivity disorder individuals (n = 37) than in controls (n = 21). The 22 children with attention deficit hyperactivity disorder were treated with methylphenidate, and they were further divided into methylphenidate responders (n = 18) and nonresponders (n = 4). beta-Phenylethylamine levels significantly increased after methylphenidate therapy in responders, whereas they did not increase in nonresponders.

Attention Deficit Disorder with Hyperactivity↗
PubMed1981

Behavioral and neurochemical interactions of dextroamphetamine and methylphenidate in rats.

The effects of dextroamphetamine and methylphenidate on locomotor activity and brain levels of norepinephrine and dopamine were compared in male Sprague-Dawley rats. Both drugs produced a dose-related increase in locomotor activity during the hour immediately following intraperitoneal administration. However, combined administration of drugs elicited only the effect of dextroamphetamine. Brain levels of norepinephrine and dopamine also increased 1 hr after dextroamphetamine dosing. Methylphenidate did not exhibit these effects and antagonized the neurochemical changes produced by dextroamphetamine. Although both drugs are considered to exert their effects by indirect activation of brain catecholamine systems, differences in their mechanism of action appear to result in a lack of additive or antagonistic effects when dextroamphetamine and methylphenidate are coadministered. These findings may have clinical significance with respect to the use of such agents in minimal brain dysfunction.

Aging↗
PubMed2002

"Nonhedonic" food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.

The drive for food is one of the most powerful of human and animal behaviors. Dopamine, a neurotransmitter involved with motivation and reward, its believed to regulate food intake in laboratory animals by modulating its rewarding effects through the nucleus accumbens (NA). Here we assess the involvement of dopamine in "nonhedonic" food motivation in humans. Changes in extracellular dopamine in striatum in response to nonhedonic food stimulation (display of food without consumption) were evaluated in 10 food-deprived subjects (16-20 h) using positron emission tomography (PET) and [11C]raclopride (a D2 receptor radioligand that competes with endogenous dopamine for binding to the receptor). To amplify the dopamine changes we pretreated subjects with methylphenidate (20 mg p.o.), a drug that blocks dopamine transporters (mechanism for removal of extracellular dopamine). Although the food stimulation when preceded by placebo did not increase dopamine or the desire for food, the food stimulation when preceded by methylphenidate (20 mg p.o.) did. The increases in extracellular dopamine were significant in dorsal (P < 0.005) but not in ventral striatum (area that included NA) and were significantly correlated with the increases in self-reports of hunger and desire for food (P < 0.01). These results provide the first evidence that dopamine in the dorsal striatum is involved in food motivation in humans that is distinct from its role in regulating reward through the NA. In addition it demonstrates the ability of methylphenidate to amplify weak dopamine signals.

Adult↗
PubMed1994

Pharmacokinetics and in vivo specificity of [11C]dl-threo-methylphenidate for the presynaptic dopaminergic neuron.

dl-threo-Methylphenidate (Ritalin) was labeled with carbon-11 (t1/2:20.4 minutes) in order to measure its pharmacokinetics, to evaluate it as a radiotracer for the presynaptic dopaminergic neuron, and to examine its sensitivity to the loss of dopaminergic neurons. Positron emission tomographic (PET) studies were carried out in the baboon to determine specificity for the presynaptic dopaminergic neuron and in humans to assess sensitivity to neuronal loss. Studies with [11C]dl-threo-methylphenidate ([11C]MP) in baboon demonstrated high regional uptake in the striatum. Peak uptake (0.04%/cc) occurred at 5-15 minutes post-injection. The half-time for clearance from peak uptake for [11C]MP was 60 minutes and the ratio between the radioactivity in the striatum and that in the cerebellum (ST/CB) ranged from 2.2 to 2.6 at 40 minutes. Repeated measures in the same baboon showed < or = 8% variability in the ST/CB ratio. Pretreatment with unlabeled methylphenidate (0.5 mg/kg) or GBR12909 (1.5 mg/kg) 30 minutes prior to [11C]MP injection markedly reduced the striatal but not the cerebellar uptake of [11C]MP, demonstrating the saturable and specific binding of [11C]MP to a site on the dopamine transporter in the brain. In both cases, the ratio of striatum to cerebellum (ST/CB) after pretreatment was reduced by about 43%. The ratios of distribution volumes at the steady-state for the striatum to cerebellum (ST/CB) for these two separate studies in the same baboon were reduced by 37 and 38%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1986

Role of monoamine pathways in the control of attention: effects of droperidol and methylphenidate in normal adult humans.

Methylphenidate (0.65 mg/kg), droperidol (15 micrograms/kg) or placebo were administered to normal adult males undertaking a dichotic auditory attention task. Performance following placebo, as measured by the ability of subjects to detect nominated target words and discriminate them from phonemically distracting words, was superior when attention was focused on one ear than when divided between the ears. Following droperidol, target detection and discrimination were reduced for both divided and focused attention and in the latter case responses were also slowed. However, these effects were small compared to the striking withdrawn behaviour of the subjects, who reported an unwillingness to attend to external events. Methylphenidate reversed all of these effects when administered following droperidol. Administered alone, methylphenidate had no effect on dichotic measures of attention but had marked effects on spontaneous behaviour, when most subjects reported a substantial increase in both the field and distractibility of attention. These results are interpreted as implicating central dopaminergic pathways in the regulation of attention without precluding a role for other neurotransmitter systems including ascending noradrenaline and serotonin pathways to cerebral cortex. The disparity between these objective and subjective assessments of the effects of the drugs on attention is discussed in terms of the degree of mental effort voluntarily brought to bear by subjects in the selective allocation of their attentional capacity.

Adolescent↗
PubMed1975

Cholinergic modulation of an opposed effect of d-amphetamine and methylphenidate on the rearing response.

Rats given d-amphetamine (1 mg/kg) engage in frequent, short-duration rearing responses, whereas rats given methylphenidate (1 mg/kg) make less frequent, long-duration responses. The effects on this behavior of mixing d-amphetamine or methylphenidate with scopolamine or physostigmine suggest that this opposed action on rearing response duration is related to cholinergic-catecholaminergic balance. The anticholinergic agent scopolamine produces changes in rearing response duration similar to those produced by d-amphetamine, while the cholinergic agent physostigmine lengthens response duration and further potentiates this effect of methylphenidate.

Animals↗
PubMed1980

Effects of methylphenidate on learning a 'beginning reading vocabulary' by normal adults.

The effects of methylphenidate on reading was studied by having nine adults learn a beginning vocabulary of 96 Chinese characters under placebo and 5 mg and 10 mg methylphenidate by two teaching methods which differed in the rate at which new items were introduced for practice. Using lists composed of 12 characters and their English equivalents, all items were presented prior to the start of practice trials (simultaneous method), or each item was introduced only as the subject practiced items previously presented (progressive method). Learning performance was analyzed in terms of total errors and errors made at two criterion stages in list acquisition. Overall performance was significantly facilitated by the low (5 mg) dose or methylphenidate, but only with the simultaneous method. Significant drug effects were also obtained at criterion stages which were associated with high error rates. It was concluded that drug effects are likely to be most pronounced in difficult learning situations and that dosage appears to be an important variable for consideration in further studies.

Adult↗
PubMed1981

Effects of lithium carbonate on methylphenidate-induced mood, behavior, and cognitive processes.

Evidence is presented which suggests that lithium modifies the mood and behavioral alterations resulting from IV methylphenidate. Specifically, lithium significantly reduces the level of arousal-activation, euphoria-grandiosity, and the total score of manic-state ratings following a methylphenidate challenge. In addition, lithium appears to be capable of modifying the growth hormone response to methylphenidate.

Adult↗
PubMed1980

The effects of naloxone on methylphenidate-induced mood and behavioral changes: a negative study.

The effects of naloxone on IV methylphenidate-induced mood, behavior, and neurohumoral changes were assessed in eight psychiatric inpatients. While methylphenidate alone produced anticipated changes, the indications for significant naloxone-methylphenidate interactions were minimal. It is speculated that larger doses of naloxone might be required to produce modification of the psychostimulant effects.

Behavior↗
PubMed1975

Comparison of progressive-ratio performance maintained by cocaine, methylphenidate and secobarbital.

Cocaine, methylphenidate and secobarbital were compared on a drug maintained progressive-ratio procedure in baboon subjects. Trials, scheduled throughout the day, occurred at a minimum interval of 3 hrs after completion of the preceding trial. A ratio response requirement on the "initiate" lever was required during each trial which terminated in a single intravenous infusion of drug. A drug was introduced on the progressive-ratio procedure with a low ratio requirement in order to obtain a baseline performance of a high stable frequency of trial completion. The ratio requirement was systematically increased every 7 days until the "breaking point" when the rate of completing trials fell below a criterion level. Within-subject comparison revealed that cocaine produced higher breaking points than methylphenidate at the same absolute dose, 0.4 mg/kg. At the range of doses studied, manipulation of doses of methylphenidate (0.1-0.8 mg/kg) and cocaine (0.4-1.6 mg/kg) had little effect on breaking point. In contrast, increasing doses of secobarbital (6.0 and 12.0 mg/kg) produce higher breaking points within the same subjects.

Animals↗