Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026838 (spasticity)
 6,471 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse. Antispastic drugs act in the CNS either by suppression of excitation (glutamate) enhancement of inhibition (GABA, glycine), or a combination of the two. Only four drugs are currently approved by the US FDA as antispactic agents: baclofen, diazepam, dantrolene sodium, and tizanidine. However, there are a number of other drugs available with proven antispastic action. This chapter reviews the pharmacology, physiology of action, dosage, and results from controlled clinical trials on side effects, efficacy, and indications for 21 drugs in several categories. Categories reviewed include agents acting through the GABAergic system (baclofen, benzodiazepines, piracetam, progabide); drugs affecting ion flux (dantrolene sodium, lamotrigine, riluzole; drugs acting on monoamines (tizanidine, clonidine, thymoxamine, beta blockers, and cyproheptadine); drugs acting on excitatory amino acids (orphenadrine citrate); cannabinoids; inhibitory neuromediators; and other miscellaneous agents. The technique, advantages and limitations of intrathecal administration of baclofen, morphine, and midazolam are reviewed. Two consistent limitations appear throughout the controlled studies reviewed: the lack of quantitative and sensitive functional assessment and the lack of comparative trials between different agents. In the majority of trials in which meaningful functional assessment was included, the study drug failed to improve function, even though the antispastic action was significant. Placebo-controlled trials of virtually all major centrally acting antispastic agents have shown that sedation, reduction of global performance, and muscle weakness are frequent side effects. It appears preferable to use centrally acting drugs such as baclofen, tizanidine, and diazepam in spasticity of spinal origin (spinal cord injury and multiple sclerosis), whereas dantrolene sodium, due to its primarily peripheral mechanism of action, may be preferable in spasticity of cerebral origin (stroke and traumatic brain injury) where sensitivity to sedating effects is generally higher. Intrathecal administration of antispastic drugs has been used mainly in cases of muscle overactivity occurring primarily in the lower limbs in nonambulatory, severely disabled patients but new indications may emerge in spasticity of cerebral origin. Intrathecal therapy is an invasive procedure involving long-term implantation of a foreign device, and the potential disadvantages must be weighed against the level of disability in each patient and the resistance to other forms of antispastic therapy. In all forms of treatment of muscle overactivity, one must distinguish between two different goals of therapy: improvement of active function and improvement of hygiene and comfort. The risk of global performance reduction associated with general or regional administration of antispastic drugs may be more acceptable when the primary goal of therapy is hygiene and comfort than when active function is a priority.
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PMID:Traditional pharmacological treatments for spasticity. Part II: General and regional treatments. 982 84

Unprecedented developments in cannabinoid research within the past decade include discovery of a brain (CB1) and peripheral (CB2) receptor; endogenous ligands, anandamide, and 2-arachidonylglycerol; cannabinoid drug-induced partial and inverse agonism at CB1 receptors, antagonism of NMDA receptors and glutamate, and antioxidant activity; and preferential CB1 receptor localization in areas subserving spasticity, pain, abnormal involuntary movements, seizures, and amnesia. These endogenous structures and chemicals and mechanisms are potentially new pathophysiologic substrates, and targets for novel cannabinoid treatments, of several neurological disorders.
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PMID:Brain cannabinoid systems as targets for the therapy of neurological disorders. 997 82

Excessive accumulation of glutamate or other excitatory amino acids and the subsequent overactivity of NMDA receptors is currently thought to lead to neuronal injury in cerebral ischemia. Therefore, antagonists of the NMDA receptor may offer an approach for the treatment of ischemic brain injury. Dizocilpine (MK-801), an NMDA receptor-associated channel blocker, protects neurons in several rodent stroke models. However, this drug has numerous side effects and causes apoptosis of neonatal neurons. Recently, another NMDA receptor-associated channel blocker, memantine, has been shown to ameliorate NMDA-receptor mediated neurotoxicity in neuronal cell cultures and in focal cerebral ischemia models in adult rats without substantial side effects. Memantine has been used clinically in the treatment of Parkinson's disease and spasticity for a number of years. Here we tested the effects of memantine on focal stroke caused by photochemical thrombosis in neonatal rats and demonstrated a neuroprotective effect of memantine in this model. We also found excellent correlation between infarct size determined by magnetic resonance imaging (MRI) and histopathological analysis in the same animals. A single pre-ischemic dose of memantine (20 mg/kg) given 15 min prior to induction of stroke reduced the infarct size by 36.3% when compared to control animals treated with normal saline (P < 0.0001). At this dosage, memantine manifests few, if any, neurobehavioral side effects. Thus memantine appears to be both safe and effective in neonatal as well as adult animal models of stroke.
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PMID:Neuroprotection by the NMDA receptor-associated open-channel blocker memantine in a photothrombotic model of cerebral focal ischemia in neonatal rat. 1044 69

Adult motor neuron disease (amyotrophic lateral sclerosis [ALS]) is a neurodegenerative disorder characterized by loss of motor neurons in the cortex, brain stem, and spinal cord, manifested by upper and lower motor neuron signs and symptoms affecting bulbar, limb, and respiratory musculature. Clinically, the disease course is characterized by progressive weakness, atrophy, spasticity, dysarthria, dysphagia, and respiratory compromise, ultimately resulting in death or mechanical ventilation in the vast majority of patients. Patterns of presentation and pathological features of the disease, along with clinical and electrophysiologic criteria for diagnosis, are discussed in this review. Since 8% to 22% of patients survive more than 10 years without ventilator use, meticulous medical and rehabilitation management is extremely important to ensure optimal health and quality of life in these patients. Major issues in the care of individuals with ALS include weakness and spasticity, impairments in activities of daily living and mobility, communication deficits and dysphagia in those with bulbar involvement, respiratory compromise, fatigue and sleep disorders, pain, and psychosocial distress. Research in ALS changes rapidly, but is currently focused on potential etiologic factors such as glutamate excitotoxicity, role of oxidative stress, autoimmunity to calcium channels, and cytoskeletal abnormalities, as well as related treatment initiatives including glutamate modulators, neurotrophic factors, antioxidants, antiapoptotic factors, and gene therapy. Recently, mutations in the gene encoding Cu/Zn superoxide dismutase were identified in a subset of familial ALS patients. Riluzole, a glutamate antagonist and Na-channel blocker, became the only drug currently approved for treatment of ALS after studies showed a small positive effect on survival. Until a definitive treatment or cure for ALS is found, the multifaceted rehabilitation team approach remains the best hope for improving health and survival in this devastating illness.
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PMID:Evaluation and rehabilitation of patients with adult motor neuron disease. 1045 74

A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.
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PMID:Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. 1058 40

A specific microdialysis probe combined with high performance liquid chromatography analysis was used to compare the basal levels of extracellular amino acids (AAs) in the dorsal horn (DH) between two groups of patients undergoing spinal surgery for the treatment of peripheral neuropathic pain (n = 5) or disabling spasticity (n = 5). A stabilized concentration was reached in the dialysates 45 min after probe implantation for excitatory AAs (glutamate and aspartate) and inhibitory AAs (GABA and glycine). A significant increase in the ratios aspartate/GABA and aspartate/glycine was found in the group of patients suffering from neuropathic pain. This study shows the feasibility of a microdialysis investigation in the DH of patients during a neurosurgical operation and supports in humans the hypothesis of an imbalance between excitatory AAs and inhibitory AAs within the DH in neuropathic pain states, as suggested by previous animal studies.
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PMID:Amino acids in spinal dorsal horn of patients during surgery for neuropathic pain or spasticity. 1085 47

The aim of this study was to develop, for the first time in the human spinal dorsal horn (DH), an in vivo method for the study of amino acids (AAs). A microdialysis technique was used to sample AAs in the extracellular fluid of the DH apex in eight patients in whom surgery in the dorsal root entry zone (DREZ) was performed. Before making microsurgical lesions, specific concentric-type microdialysis probes were implanted over a 60-minute period in the DREZ and directed to the DH apex (10 implantations). The AA concentrations in the dialysates were determined using high-performance liquid chromatography with fluorescence detection. The concentrations of excitatory AAs (glutamate and aspartate) and inhibitory AAs (gamma-aminobutyric acid and glycine) decreased and were stabilized by 45 minutes after probe implantation, whereas the levels of nonneurotransmitter AAs (alanine and threonine) were not stabilized at 60 minutes. The ability of the probe to track the changes of extracellular AAs was demonstrated. Neither intra- nor postoperative microdialysis-related complications were observed (with a follow up of 18 months). The present study demonstrates that microdialysis can be performed safely in the human DH during DREZ lesioning. Despite technical and analytical limitations related to the intraoperative conditions, this technique offers new possibilities for clinical research on neurotransmitters involved in some relevant pathological states, especially in chronic pain and spasticity.
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PMID:Microdialysis study of amino acid neurotransmitters in the spinal dorsal horn of patients undergoing microsurgical dorsal root entry zone lesioning. Technical note. 1114 57

The Rett syndrome (RS) is a peculiar, sporadic, atrophic disorder, almost entirely confined to females. After the first six months of life there is developmental slowing with reduced communication and head growth for about one year. This is followed by a rapid destructive stage with severe dementia and loss of hand skills (with frequent hand wringing), apraxia and ataxia, autistic features and irregular breathing with hyperventilation. Seizures often supervene. Subsequently there is some stabilization in a pseudo-stationary stage during the preschool to school years, associated with more emotional contact but also abnormalities of the autonomic and skeletal systems. After the age of 15-20 years, a late motor deterioration occurs with dystonia and frequent spasticity but seizures become milder. RS has generally been considered an X-linked disorder in which affected females represent a new mutation, with male lethality. Linkage studies suggested a critical region at Xq28. In 1999, mutations in the gene MECP2 encoding X-linked methyl cytosine-binding protein 2 (MeCP2) were found in a proportion of Rett girls. This protein can bind methylated DNA. Analyses are leading to much further investigation of mutants and their effects on genes. Neuropathological and electrophysiological studies of RS are described. Description of neurometabolic factors includes reduced levels of dopamine, serotonin, noradrenaline and choline acetyltransferase (ChAT) in brain, also estimation of nerve growth factors, endorphin, substance P, glutamate and other amino acids and their receptor levels. The results of neuroimaging are surveyed, including volumetric magnetic resonance imaging (MRI) and positron emission tomography (PET).
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PMID:Rett syndrome: review of biological abnormalities. 1125 89

Glutamate is the major excitatory neurotransmitter of the central nervous system. Besides its importance in many physiological processes, increased glutamate release and subsequent excessive stimulation of the various glutamate receptors are thought to play critical roles in the pathophysiological mechanisms underlying many neurologic diseases. Experimental data suggest that blockade of glutamate receptors or inhibition of glutamate release has positive effects in many disease models. Glutamate antagonists are already in clinical use for the treatment of Parkinson's disease, epilepsy, spasticity, and neuropathic pain. Overall, glutamate antagonists have not been found clinically effective for neuroprotective treatment of cerebral ischemia or chronic neurodegenerative diseases, with one exception. Side effects of glutamate antagonists can be mainly attributed to central mechanisms and include psychosis, agitation, and disorientation. It is to be hoped that further development of new glutamate antagonists that block disease-relevant subtypes of glutamate receptors will lead to more effective drugs with fewer side effects.
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PMID:[Glutamate antagonists in neurology]. 1143 98

When spasticity produces a clinical disability by interfering with posture, motor capacity, nursing or daily living activities, medical treatment is recommended. It is mainly indicated when the muscle overactivity is diffusely distributed and should be implemented early, to prevent permanent musculoskeletal deformities or contractures. A pharmacological approach relies on the use of drugs which modulate neurotransmitters acting at the cortico-spinal level (GABA, glycine, glutamate, noradrenaline, serotonin). The aim of this treatment is to decrease spinal reflex excitability by reducing the release of excitatory neurotransmitters, or by potentiating the activity of inhibitory inputs. Evaluation of the efficacy of these drugs is determined by the therapeutic objectives which may be biomechanical, or functional. Diazepam increases presynaptic inhibition by stimulating GABA(A) receptors in the brainstem and spinal cord. In double-blind studies of patients with spinal cord lesions, antispastic efficacy has been shown, but side-effects are common. Baclofen stimulates GABA(B) receptors inducing a suppression of excitatory neurotransmitter release. Antispastic efficacy is sufficiently documented, but no definite effects on ambulation or activities of daily living have been proved. Tizanidine has an alpha2-agonist activity (at spinal and supraspinal level) and decreases the presynaptic activity of excitatory interneurones. The main clinical effects are a reduction in tonic stretch, polysynaptic reflexes, and co-contraction, with fewer side-effects but no definite functional change. The efficacy of several other antispastic drugs is documented in a few controlled studies, but the majority of information arises from open trials or anecdotal observations.
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PMID:The medical management of spasticity. 1191 47


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