Gene/Protein Disease Symptom Drug Enzyme Compound
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 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylphenidate treatment is used for Attention Deficit Hyperactivity Disorder and can improve learning and memory. Previously, improvements were considered a by-product of increased attention; however, we hypothesize that methylphenidate directly alters mechanisms underlying learning and memory, and therefore examined its effects on hippocampal long-term potentiation and long-term depression. Methylphenidate enhanced both mechanisms in the absence of presynaptic changes and in a noradrenalin beta-receptor-dependent manner. These findings can explain both the improved learning and memory and decreased learning selectivity found with methylphenidate treatment and constitute the first demonstration of direct actions of methylphenidate on mechanisms implicated in cognition.
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PMID:Methylphenidate amplifies long-term plasticity in the hippocampus via noradrenergic mechanisms. 1868 49

Fatigue is a highly distressing symptom of cancer associated with significant psychological morbidity and reduced quality of life. Cancer-related fatigue (CRF) has been underreported, underdiagnosed, and undertreated. Fatigue and depression may coexist in patients with cancer, and considerable overlap of symptoms often occurs. This has led researchers to examine the role of psychotropic medications to treat fatigue. Psychostimulants, wakefulness-promoting agents, antidepressants, and cholinesterase inhibitors have been studied for CRF treatment. Methylphenidate has been studied most and is effective and well tolerated despite common side effects. Some preliminary data support using modafinil for patients with CRF. Antidepressant studies have shown mixed results. Paroxetine shows benefit for fatigue, primarily when it is a symptom of clinical depression. Bupropion sustained release may have psychostimulant-like effects and, therefore, may be beneficial in treating fatigue. Donepezil, a cholinesterase inhibitor, has shown benefit only in open-label trials. Randomized, placebo-controlled trials with specific agents are needed to further assess the efficacy and tolerability of psychotropic medications in CRF treatment.
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PMID:Pharmacologic treatment options for cancer-related fatigue: current state of clinical research. 1884 22

Methylphenidate (MPH) is commonly prescribed in childhood and adolescence for the treatment of attention-deficit/hyperactivity disorders. In rodents, MPH exposure during preadolescence (postnatal days (PD) 20-35) causes decreased sensitivity to drug and natural rewards, while enhancing a negative emotional state characterized by increased sensitivity to aversive situations later in adulthood. It has been proposed that this behavioral profile may be mediated, at least in part, by changes in the expression of dynorphin, the endogenous ligand for kappa-opioid receptors (KORs). Because increases in dynorphin activity and activation of KOR induce aversive states, we examined the possibility that these behavioral deficits may be mediated by changes in KOR function, and that MPH-exposed rats would demonstrate increased sensitivity to the kappa-agonist U-50488. Sprague-Dawley male rats were treated with MPH (2 mg/kg) or its saline vehicle (VEH) during PD20-35. When adults (PD90+), these rats were divided into groups receiving saline, U-50488 (5 mg/kg), or nor-binaltorphimine (20 mg/kg), a kappa-antagonist, and their behavioral reactivity to various emotion-eliciting stimuli was assessed. Results show that MPH exposure decreases cocaine place conditioning and sucrose preference, while increasing vulnerability to anxiety (elevated plus maze)- and stress (forced swimming)-eliciting situations, and that these behavioral deficits can be intensified by U-50488, while being normalized by nor-binaltorphimine treatment. These results are consistent with the notion that dysregulated dynorphin/kappa-opioid systems may mediate deficits in behavioral responding after developmental MPH exposure. Moreover, these findings further support the idea of kappa-antagonists as potential pharmacotherapy for the treatment of anxiety- and depression-related disorders.
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PMID:Kappa-opioid system regulates the long-lasting behavioral adaptations induced by early-life exposure to methylphenidate. 1892 99

Nonmotor features of Parkinson's disease (PD) have only recently been getting the attention they deserve. Dementia, depression, and psychosis are often more devastating than motor dysfunction. Fatigue affects about half of all PD patients and has a major impact on quality of life. Fatigue is the single most important reason cited for medical disability insurance claims by PD patients in the United States. PD patients suffer from both physical and mental fatigue, described as both qualitatively and quantitatively different from the fatigue experienced prior to disease onset. Although fatigue is an early symptom and may be associated with depression, most PD patients with fatigue are not depressed. It is not associated with motor dysfunction but seems to worsen with disease progression. No physiologic differences have been found between fatigued and nonfatigued PD patients. The mechanism of fatigue in PD is unknown. It does not respond to treatment of the motor symptoms. Unlike physical fatigue in normal patients, PD patients often report that their fatigue improves with exercise. No treatment is known to be effective. Methylphenidate was reported to be beneficial in one study, whereas modafinil was not. My own approach to treating fatigue is to look first for other causes that may be treatable, such as sleep dysfunction, depression, or medical disorders. If one is not found, or if it is not treatable, I then institute a course of a low-dose stimulant if there is no cardiac or psychiatric contraindication. I use either amphetamine salts (starting at 10 mg), or methylphenidate (5 mg) taken in the morning and early afternoon, and increased weekly by one dose in the morning or afternoon. Some patients may take their doses unevenly, with more or less for the morning dose. Patients who tend to go to bed late at night may take their doses three times daily.
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PMID:Fatigue in Parkinson's disease patients. 1936 53

ABSTRACT The pertinent literature was reviewed on cardiovascular changes induced by psychostimulant medication treatment of hyperactive children. An assessment of 15 controlled studies using test doses of methylphenidate revealed a significant elevation of the resting heart rate in previously unmedicated children (mean + 11 beats/min) but, with continued drug treatment, only a minor insignificant increase (mean + 4 BPM) is observed. Methylphenidate resulted in no consistent or clinically meaningful blood pressure changes (8 studies) and no EKG irregularities (4 studies). Available data for dextroamphetamine and pemoline were less extensive, but showed essentially no significant cardiovascular changes in hyperactive youth. Stimulant overdoses in nonhyperactive children often led to hypertension and tachycardia, but were associated with only one cardiovascular fatality (amphetamine). Comparable studies of these stimulants in adults revealed: (1) tachycardia and hypertension following high test doses of methylphenidate, (2) hypertension but no tachycardia following high test doses of dextroamphetamine, (3) far greater cardiovascular changes following the parenteral administration of stimulants, (4) the development of a prominent degree of tolerance to the cardiovascular effects of stimulants with continued use, (5) very infrequent cardiovascular changes (3%) in medically ill, older adults following stimulant treatment for depression, and (6) infrequent cardiomyopathy and arteritis in association with amphetamine abuse, but not with pemoline or methylphenidate use. The stimulant-induced changes in children are modest in comparison with changes in cardiovascular functioning associated with normal daily activities, and are not comparable to the risks that can occur with tricyclic antidepressants. There appears to be a wide margin of cardiovascular safety when standard psychostimulants are taken orally in customary doses for long periods by hyperactive children. In view of the numerous negative studies, it probably is not essential to monitor heart rate, blood pressure, or EKG prior to or during routine psychostimulant treatment of children and adolescents with ADHD, unless there are comorbid cardiovascular abnormalities.
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PMID:Relative cardiovascular safety of psychostimulants used to treat attention-deficit hyperactivity disorder. 1963 Jun 10

It was discovered in 2000 that a deficit of hypocretin/orexin neurons is responsible for causing narcolepsy. Today, agonists for orexin receptors are being explored in order to establish an orexin replacement therapy, but the process is still at the stage of research. On the other hand, orexin antagonists are now undergoing clinical trials as a hypnotic. Activation of the dopamine system is effective against hypersomnia, and activation of the noradrenaline system is effective against cataplexy. Therefore, these two types of drugs have been used for treatment. Methylphenidate was mainly used, but recently modafinil has become mainstream. The action mechanism of methylphenidate is reuptake inhibition and release stimulation of dopamine. The action mechanism of modafinil is not fully explained, but is thought to be reuptake inhibition of dopamine. When methylphenidate was used for disorders other than narcolepsy, such as depression, dependence on the drug and abuse became an issue, and methylphenidate is no longer available for depression. It has been said that narcoleptic patients have a tendency to control the doses of methylphenidate at a low level of their own accord, and that they have a significantly low risk of developing a dependency on the drug. It has also been observed in mice with orexin deficit produced by molecular genetics that they have a significantly low development of dependency on amphetamine, a relative compound of methylphenidate. On the other hand, modafinil has been found to cause very little dependence, and is chosen as the principal drug in treatment. It was recently discovered that the histamine neurons, which are downstream of orexin neurons, are responsible for controlling arousal. It was also discovered that the CSF histamine was low in narcolepsy and other hypersomnia of central origin. Histamine H3 antagonists are being explored as a treatment for hypersomnia. H3 receptors are auto receptors located in the brain histamine neuron, and agonists act for suppression, antagonists for activation. They have shown good results in the animal experiments and phase 2 of clinical experiments.
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PMID:[Recent advance of treatments for narcolepsy and hypersomnia]. 1966 60

When attention deficit-hyperactivity disorder in children is truly problematic, methylphenidate, an amphetamine, can be tried as a last resort. Methylphenidate has short-term symptomatic efficacy but also many adverse effects, including a risk of sudden death. After having been evaluated, unsuccessfully, in depression, atomoxetine, a noradrenaline reuptake inhibitor, was authorised in some EU member states for use in attention-deficit/hyperactivity disorder. In France it has only received temporary authorisation for prescription on a named-patient basis. Two double-blind trials comparing atomoxetine versus methylphenidate provided somewhat different results, based on a symptom rating scale completed by the investigator after an interview with the parents. In a trial in 516 children treated for 6 weeks, the "response" rate was statistically higher than with methylphenidate (56% versus 45%). In the other trial in 330 children treated for 8 weeks, the response rate was about 80% in both groups. A meta-analysis of 9 placebo-controlled trials in a total of 1828 children showed that atomoxetine was more effective than placebo in the short term. The main adverse effects identified in clinical trials and pharmacovigilance studies conducted in the United Kingdom and the United States were gastrointestinal disorders (abdominal pain, reduced appetite, vomiting, and weight loss) and neuropsychological disorders (drowsiness, irritability, mood swings, aggressive behaviour). A meta-analysis of 12 trials and pharmacovigilance studies showed an increased risk of suicide. Atomoxetine also provokes seizures, arterial hypotension, tachycardia, and hepatic disorders. Little is known about the risk of abuse or dependence, or the long-term efficacy of treatment. Atomoxetine carries a risk of multiple drug interactions due to its metabolism by the cytochrome P450 isoenzyme 2D6 and its inhibitory effect on noradrenaline reuptake. In practice, atomoxetine has a similar safety profile to methylphenidate and is probably less effective. When drug therapy is warranted, it is better to continue to use methylphenidate, despite its adverse effects.
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PMID:Atomoxetine. Attention-deficit/hyperactivity disorder: no better than methylphenidate. 2045 29

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs who use psychostimulant 'cognitive enhancers'. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2-5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factor genes zif268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction potential of methylphenidate.
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PMID:Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum. 2070 93

Methylphenidate is a psychostimulant originally used for the treatment of attention-deficit disorder. Methylphenidate inhibits neuronal neurotransmitter transporters involved in the uptake of dopamine and norepinephrine at the level of the synapse. Inhibition of these transmitter transporters leads to increased concentrations of dopamine and norepinephrine in the synapse, which results in increasing alertness. The stimulant effect of methylphenidate has been used for the treatment of major depression, poststroke depression, cognitive enhancement in patients with brain tumors, neurodegenerative disorders, HIV disease, fatigue, and as a treatment for delirium and sedation associated with opioid use. Other areas where methylphenidate has been evaluated include gait disorders in the elderly individuals and the treatment of apathy in dementia. Analgesic effects have been demonstrated in preclinical models but true analgesic effects remain to be proven in humans. This article reviews the current use of methylphenidate for symptom management with a critical look at the evidence base for its efficacy in the conditions described.
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PMID:Methylphenidate: established and expanding roles in symptom management. 2214 57

Methylphenidate intoxication, due to accidental ingestion, is a common occurrence in pediatrics. Symptoms of extreme agitation are typically controlled with benzodiazepines or barbiturates. There is, however, a legitimate risk of mechanical ventilation due to respiratory depression with increasing doses of benzodiazepines. The authors describe a case of 7-y-old girl with methylphenidate toxicity where dexmedetomidine was successfully used to manage agitation and cardiovascular stimulation without respiratory compromise.
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PMID:Dexmedetomidine in a child with methylphenidate intoxication. 2256 28


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