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)

The routine therapy of multiple sclerosis (MS) in world-wide use today is comprised of four measures: Antiinflammatory and antiedematous treatment with ACTH or Synacthen, respectively, and corticosteroids: only during acute episodes. - High dosage, short duration, no long-term therapy. Immunosuppression with azathioprine (Imurek): Due to the relatively high risk only to use in malignant courses (frequent and severe bouts). Basic therapy with unsaturated fatty acids (sunflower oil, Naudicelle). Influencing circumscribed target symptoms (spasticity, micturition difficulties, constipation, etc.). In addition, physiotherapeutic, psychagogic and, if necessary, nursing and social measures are included. More than a decade's experience with ultrasound therapy of the lymphatic ring as developed by Selzer in over 300 MS-patients gives the impression of a reduction in bout frequency and severity. A statistical evaluation of therapeutic efficiency has so far been impossible for well-known disease-specific reasons, which hold true for all MS-treatment methods. Great practical importance within a foreseeable space of time may be reached by efforts to influence disturbance in nerve conduction and synaptic transmission as specifically caused by the demyelination process. The successful medicinal deceleration of sodium inactivation, inhibition of potassium activation and extension of the action potential, as well as specifically influencing the neurotransmitters responsible for the disturbed synaptic transmission could lead to a total recovery or improvement of dysfunction in a great many cases. Such a "global symptomatic therapy" might indeed not change the course of disease, but bring about great progress to the patient.
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PMID:[Therapy of multiple sclerosis]. 298 2

Baclofen is an analog of the inhibitory neurotransmitter, GABA, which is used clinically to control spasticity. Recent evidence has accumulated showing this compound to have profound inhibitory effects upon hippocampal neural activity at both the cellular and circuit levels, and to attenuate epileptiform bursting in the hippocampal slice. However, it does not appear as an anticonvulsant on most traditional drug screens. Baclofen can produce inhibition by increasing potassium conductance, and therefore may fail to appear efficacious in typical anticonvulsant screens due to techniques that cause rapid and massive increases in interstitial potassium. We tested the hypothesis that baclofen is less effective at attenuating epileptiform bursting in the hippocampal slice under conditions of elevated extracellular potassium. Male Sprague-Dawley rats were decapitated and hippocampal slices were prepared. Epileptiform bursting was induced by bathing the slices in an artificial cerebrospinal fluid solution which contained either 7.0 mM K+ or 30 microM bicuculline methiodide, or by stimulus train-induced bursting. In each of these media, baclofen was applied in a random presentation of concentration format. Baclofen attenuated epileptiform bursting in both bicuculline and elevated K+, although considerably higher concentrations were necessary to attenuate bursting in high K+ than in bicuculline or after stimulus train-induced bursting. These results further support the antiepileptic actions of baclofen and provide evidence that this drug may be of value for attenuating epileptiform activity when there is not a tonic elevation of interstitial brain potassium.
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PMID:Attenuation of epileptiform bursting by baclofen: reduced potency in elevated potassium. 378 Sep 17

The adamantane derivative memantine (1-amino-3,5-dimethylaminoadamantane, D-145, Akatinol) is clinically used as well in the therapy of neurogenic motor diseases (e.g. spasticity) as in the treatment of cerebral disorders like coma, cerebrovascular and geronto-psychiatric disturbances. The aim of the paper is to summarize experimental evidences that may help to explain the clinical observations. Biochemical, pharmacological, and electrophysiological studies show that memantine interferes with the metabolism of the transmitters dopamine, noradrenaline (norepinephrine), and serotonin and modulates synaptic transMission. In order to explain the antispastic activity of memantine, a spinal action must be assumed in addition to the supraspinal effect on transmitter systems. Since memantine reduces the membrane resistance as well as the membrane conductance of sodium, potassium, and chloride ions, it is very likely that memantine Is directly involved in the generation of action potentials.
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PMID:[Pharmacodynamics and pharmacokinetics of memantine]. 635 2

4-Aminopyridine (4-AP) is a potassium channel blocking agent with the ability to restore conduction in demyelinated internodes of axons of the spinal cord. The present investigation sought to obtain electrophysiologic evidence of the effect of 4-AP in ameliorating central conduction deficits in a group of patients (n = 6) with spinal cord injury (SCI). The group was selected on the basis of having temperature-dependent central conduction deficits. 4-AP (24-25 mg total dose) was delivered intravenously at 6 mgh-1 or 15 mgh-1 while somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were recorded as indices of central conduction. Two patients exhibited marked increases in the amplitude of cortical SEPs, and in one of these, 4-AP brought about a reduced central conduction time from L1 to cortex. Four patients revealed increased amplitude MEPs with concomitant reduction in latency indicative of enhanced conduction in corticospinal or corticobulbospinal pathways. Two of these patients demonstrated increased voluntary motor unit recruitment following 4-AP. Clinical examination revealed reduced spasticity (n = 2), reduced pain (n = 1), increased sensation (n = 1), improved leg movement (n = 3), and restored voluntary control of bowel (n = 1). These results support the hypothesis that 4-AP induces neurologic benefits in some patients with SCI. They are also consistent with the emerging concept that pharmaceutical amelioration of central conduction deficits caused by focal demyelination may contribute to the management of a select group of patients with compressive or contusive SCI.
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PMID:4-Aminopyridine-sensitive neurologic deficits in patients with spinal cord injury. 783 83

The potassium channel blocking drug 4-aminopyridine (4-AP) was administered to eight patients with chronic spinal cord injury, in a therapeutic trial based on the ability of the drug to restore conduction of impulses in demyelinated nerve fibers. The study was performed using a randomized, double-blind, crossover design, so that each patient received the drug and a vehicle placebo on different occasions, separated by 2 weeks. Drug and placebo were delivered by infusion over 2 h. An escalating total dose from 18.0 to 33.5 mg was used over the course of the study. Subjects were evaluated neurologically before and after the infusion. Two subjects returned for a second trial after 4 months and were examined daily for 3 to 4 days following drug infusion. Side effects were consistent with previous reports. Administration of the drug was associated with significant temporary neurologic improvement in five of six patients with incomplete spinal cord injury. No effect was detected in two cases of complete paraplegia and one of two severe incomplete cases (Frankel class B). Improvements in neurologic status following drug administration included increased motor control and sensory ability below the injury, and reduction in chronic pain and spasticity. The effects persisted up to 48 h after infusion of the drug, and patients largely returned to preinfusion status by 3 days. Compared with the more rapid elimination of the drug, these prolonged neurologic effects appear to involve a secondary response and are probably not a direct expression of potassium channel blockade.
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PMID:4-Aminopyridine in chronic spinal cord injury: a controlled, double-blind, crossover study in eight patients. 832 Jul 29

Paroxysmal choreoathetosis/episodic ataxia is a heterogeneous neurological syndrome usually inherited in an autosomal dominant manner. Recently, the association of one form of episodic ataxia (defined by the presence of additional myokymia) with point mutations in the potassium channel gene KCNA1 was described. This gene locus on chromosome 12p (HGMW-approved symbol CSE) was excluded in a large pedigree with paroxysmal choreoathetosis and additional spasticity. Linkage to chromosome 1p where a cluster of related potassium channel genes is located, was demonstrated. Genotyping of 18 affected and 11 unaffected family members with 28 microsatellites over a region of 45 cM proved linkage with a lod score of 7.2 at a recombination fraction theta = 0 to D1S451/421/447/GGAT4C11. Crossing-over events in 9 patients and 4 unaffected offspring suggested a probable assignment of the gene to a region of 2 cM between D1S443 and D1S197.
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PMID:A gene for autosomal dominant paroxysmal choreoathetosis/spasticity (CSE) maps to the vicinity of a potassium channel gene cluster on chromosome 1p, probably within 2 cM between D1S443 and D1S197. 880 84

We describe here familial dyskinesia and facial myokymia (FDFM), a novel autosomal dominant disorder characterized by adventitious movements that sometimes appear choreiform and that are associated with perioral and periorbital myokymia. We report a 5-generation family with 18 affected members (10 males and 8 females) with FDFM. The disorder has an early childhood or adolescent onset. The involuntary movements are paroxysmal at early ages, increase in frequency and severity, and may become constant in the third decade. Thereafter, there is no further deterioration, and there may even be improvement in old age. The adventitious movements are worsened by anxiety but not by voluntary movement, startle, caffeine, or alcohol. The disease is socially disabling, but there is no intellectual impairment or decrease in lifespan. A candidate gene and haplotype analysis was performed in 9 affected and 3 unaffected members from 3 generations of this family using primers for polymorphic loci closely flanking or within genes of interest. We excluded linkage to 11 regions containing genes associated with chorea and myokymia: 1) the Huntington disease gene on chromosome 4p; 2) the paroxysmal dystonic choreoathetosis gene at 2q34; 3) the dentatorubral-pallidoluysian atrophy gene at 12p13; 4) the choreoathetosis/spasticity disease locus on 1p that lies in a region containing a cluster of potassium (K+) channel genes; 5) the episodic ataxia type 1 (EA1) locus on 12p that contains the KCNA1 gene and two other voltage-gated K+ channel genes, KCNA5 and KCNA6; 6) the chorea-acanthocytosis locus on 9q21; 7) the Huntington-like syndrome on 20p; 8) the paroxysmal kinesigenic dyskinesia locus on 16p11.2-q11.2; 9) the benign hereditary chorea locus on 14q; 10) the SCA type 5 locus on chromosome 11; and 11) the chromosome 19 region that contains several ion channels and the CACNA1A gene, a brain-specific P/Q-type calcium channel gene associated with ataxia and hemiplegic migraine. Our results provide further evidence of genetic heterogeneity in autosomal dominant movement disorders and suggest that a novel gene underlies this new condition.
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PMID:Familial dyskinesia and facial myokymia (FDFM): a novel movement disorder. 1131 Jun 26

Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of gamma-aminobutyric acid(A) (GABAA) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl-) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl- equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.
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PMID:Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. 2020 12

Disease-modifying treatments (DMTs), which are the foundation of multiple sclerosis (MS) care, reduce clinical exacerbations (relapses) and slow disease progression; however, improving quality of life (QOL) is an unmet need for many individuals with MS. DMTs, including interferon-beta, glatiramer acetate, natalizumab, mitoxantrone, and fingolimod, reduce the rate and severity of relapses, the accumulation of brain and spinal cord lesions as shown on magnetic resonance imaging (MRI), and disability progression. Many studies link diminished QOL with specific MS symptoms (fatigue, impaired mobility, spasticity, etc). Even in patients already receiving DMTs, symptoms and QOL may improve with additional agents that treat specific symptoms, thereby improving patient function and ability to perform activities of daily living (ADLs). Patients have reported that mobility impairment is one of the worst aspects of MS. Almost half of patients treated with DMTs reported no improvement in mobility. However, blocking the voltage-dependent potassium channels on the surface of demyelinated nerve fibers may improve signal conduction. Dalfampridine, a potassium channel blocker, received Food and Drug Administration (FDA) approval for all forms of MS specifically to improve walking, which was demonstrated by increased walking speed. By improving walking in some patients with MS, the effects of dalfampridine may complement those of DMTs and address the stated priorities of many patients.
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PMID:Functional improvement and symptom management in multiple sclerosis: clinical efficacy of current therapies. 2176 53

3,4-diaminopyridine (DAP) and 4-aminopyridine (AP) block potassium channels and can improve action potentials in demyelinated nerve fibres. We identified ten randomised placebo-controlled trials investigating AP/DAP as symptomatic treatment in multiple sclerosis. There is evidence that AP and DAP improve muscle strength in the lower extremities and that AP increases walking speed, and it might improve Expanded Disability Status Scale scores, spasticity and fatigue. There is a lack of evidence-based guidelines of treatment and studies investigating the effect on participation/activity and quality of life.
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PMID:[Aminopyridines for symptomatic treatment of multiple sclerosis]. 2215 10


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