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)

Recent pharmacological investigations have support the hypothesis that spinal modulation of nociception as well as motor coordination is related to the activity of spinal interneurons and that certain spinal transmitters are involved in the control of both regulatory systems. Opioids and benzodiazepines, i.e. endorphin- or GABA-induced mechanisms, may be of importance for spinal treatment of spasticity in the near future. In order to clinically evaluate the interactions of these spinal processes we performed in vitro-experiments, animal studies and clinical investigations on the compatibility and antispastic efficacy of spinally administered opiates and benzodiazepines. Preclinical studies on tissue- and CSF-tolerance of different benzodiazepines (pH, tonometry, turbidimetry, histological findings in animals) are in favour of midazolam, a water-soluble compound, which is active against pharmacologically induced spasms in animals (strychnine application in cats with chronical catheterization of the subarachnoid space) after lumbar intrathecal injection. Using an appropriate dosage of intrathecal midazolam selective blockade of spasticity of the hind legs may be demonstrated with integrated EMG. Clinical investigations (neurological assessment using rating scores for spasticity) in 16 patients, including a double-blind comparison of epidural morphine or midazolam, indicate that both drugs are effective against spinal spasticity of different origin. Efficacy of spinally applied agents depends on the severity of spasms and on the duration and extent of systemic pretreatment.
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PMID:[Spasticity treatment with spinal morphine or midazolam. In vitro experiments, animal studies and clinical studies on compatibility and effectiveness]. 294 90

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 high-affinity uptake of [3H]serotonin, [3H]glutamate, and [3H]gamma-aminobutyric acid [( 3H]GABA) and the Na+-independent binding of [3H]glutamate and [3H]GABA were studied using spinal cord preparations obtained from normal mongrel dogs and from dogs made paraplegic by midthoracic spinal cord crush. Lumbosacral regions of the spinal cord were removed either before (1 week) or after (3 to 8 weeks) onset of spasticity. A myelin-free synaptosomal fraction was obtained by centrifugation and used for studying high-affinity uptake and for preparing synaptic plasma membranes for Na+-independent binding experiments. For the paraplegic groups, the uptake of 30 nM [3H]serotonin was 66 and 18% of control values after 1 and 3 weeks, respectively. Eadie-Hofstee analysis of [3H]serotonin uptake showed a 90% reduction in Vmax for the paraplegic group relative to control values, thereby indicating the expected loss of descending serotonergic pathways. The high-affinity uptakes of 1 microM [3H]glutamate and [3H]GABA were the same in both the control and nonspastic paraplegic groups after 1 week. However, after 3 weeks, the uptakes of [3H]glutamate and [3H]GABA were 60-70% higher for the spastic group than for the control animals. For both amino acids, Eadie-Hofstee plots revealed no difference in Km and higher Vmax for the spastic group relative to control values. After 1 and 3 weeks, the Na+-independent binding of 5 nM [3H]glutamate was 40-85% higher and the binding of 10 nM [3H]GABA was 40-60% lower for the paraplegic groups relative to the values for the control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations of amino acid transmitter systems in spinal cords of chronic paraplegic dogs. 614 26

Recent evidence suggests that an excitant amino acid may be a neurotransmitter at acoustic nerve synapses in cochlear nucleus (CN). Release of excitant amino acids is reportedly reduced by baclofen, a lipophilic GABA-mimetic used to treat the spasticity of multiple sclerosis and spinal injury. Microiontophoresis of (-)baclofen suppressed spontaneous and tone-evoked activity in CN neurons. GABA inhibited the responses of most neurons responsive to (-)baclofen. However, iontophoresis of these two substances onto the same CN neuron resulted in dramatic differences in time course to maximum effect and to recovery. Onset and offset of (-)baclofen-induced firing reduction were gradual at all doses (currents), but even the highest doses rarely caused total suppression of firing. Inhibition of firing by GABA was abrupt, and total suppression was frequently observed over the range of doses used. GABA desensitization (fading) commonly occurred while the (-)baclofen response never faded. The same CN neurons were also suppressed by D-alpha-aminoadipate, which blocks certain excitatory amino acid receptors, while the GABA antagonist bicuculline had no effect on the (-)baclofen response. These findings support the hypothesis that an excitant amino acid may be a transmitter at acoustic nerve synapses in CN.
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PMID:Baclofen reduces tone-evoked activity of cochlear nucleus neurons. 632 78

The action of the GABA-receptor agonist, progabide , was investigated in a double-blind study with cross-over to placebo. The stretch and flexor reflexes and voluntary power were measured in 16 patients with spasticity. 2-week treatment periods were used; the median daily oral dosage of progabide was 24.3 mg/kg. The Achilles tendon (T) reflex was significantly suppressed whereas the Hoffmann (H) reflex remained unchanged: the T/H ratio was thus reduced. Hmax /M (direct motor)max ratio and the vibration-induced suppression of the T- and H-reflexes were unchanged. These findings indicate an effect of progabide on the spindles or on the controlling fusimotor system (probably acting on spinal interneurons), whereas influence on presynaptic inhibition and alpha-motoneuron excitability is unlikely. The flexor reflex threshold was increased during progabide treatment and latency at threshold decreased towards normal latency. This indicates some influence of progabide on flexor reflex activity attributed to reinforcement of action of GABAergic interneurons at the spinal level. Isokinetic measurement of voluntary power of knee extension revealed particularly good progress for the fastest movements during progabide treatment, whereas isometric measurement of sustained handgrip remained unchanged, probably reflecting a reduction of spasticity without reduction of voluntary power in non-spastic muscles.
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PMID:The effect of the GABA-agonist, progabide, on stretch and flexor reflexes and on voluntary power in spastic patients. 637 1

In a 75-year-old man acute intestinal pseudo-obstruction was observed during treatment with baclofen 20 mg daily. After discontinuation of the baclofen he recovered completely. No other cause of intestinal obstruction could be demonstrated. Baclofen is an agonist of spinal GABA receptors. It is used in the treatment of spasticity caused by multiple sclerosis or other diseases of the spinal cord, in particular traumatic lesions. Physicians should be aware of this possible adverse effect of baclofen.
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PMID:[Intestinal pseudo-obstruction during use of baclofen]. 747 21

In twenty-five SCI subjects, antispasticity effects of three putative antispasticity agents [clonidine (an alpha-2 noradrenergic agonist), cyproheptadine (a 5-HT2 antagonist) and baclofen (a GABA-B agonist)] were tested in terms of changes in leg tone as graded by the Ashworth scale (AS), in terms of the vibratory inhibition of the H-reflex (VII) and in terms of the ability of the knee to swing passively in the pendulum test as quantified by video motion analysis. When compared to the no drug period, all three drug treatments showed an antispasticity effect on the AS, the VII and the amplitude of the first swing and the relaxation index of the pendulum test, p. < 0001. Surprisingly, cyproheptadine and baclofen produced a greater reduction in the VII than clonidine, p. < 01. The amplitude of the first swing in the pendulum test correlated well with the AS, r = .88, and the antispasticity effects of the drugs produced improvements in both measures, a reduced AS and increased amplitude of knee swing in the pendulum test. Therefore, video motion analysis of the pendulum test is as valid a measure of spasticity as the Ashworth scale and is not limited by subjectivity of the examiner.
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PMID:A comparison of clonidine, cyproheptadine and baclofen in spastic spinal cord injured patients. 796 12

We previously reported an extended kindred with autosomal dominant uncomplicated hereditary spastic paraplegia (HSP) and found close linkage between the disorder and microsatellite polymorphisms on chromosome 15q. Multipoint linkage analysis reached a maximum LOD score (10.16) between D15S128 and D15S156, a region that includes genes encoding alpha5 and beta3 subunits of GABAA receptor. Theoretically, abnormal GABA-mediated neurotransmission could produce spasticity and possibly other changes of HSP. We used genetic linkage analysis to evaluate these two HSP candidate genes and observed obligate recombinants for polymorphisms immediately adjacent to (or within untranslated regions of) genes encoding alpha5 and beta3 GABAA receptor subunits. Although these genes are linked tightly to the HSP locus, our findings conclusively exclude these genes from being responsible for HSP in this kindred.
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PMID:Hereditary spastic paraplegia linked to chromosome 15q: Analysis of candidate genes. 861 96

The results of stimulating human subjects with the LISS Cranial Stimulator (LCS) and the LISS Body Stimulator (LBS) include an increase or decrease in the activities of certain neurotransmitters and neurohormones and the reduction of associated pain, insomnia, depression, and spasticity. The effects were documented in human subjects with measurements of the serum concentration of the various agents and assessments of the symptoms being performed before and after stimulation. The stimulators had a carrier frequency of 15,000 hz, which utilizes the bulk capacitance of the body, and a 15 hz modulating bioactive frequency. The second modulating frequency presently used, 500 hz, reduces the energy input to the patient by half. Significant increases in levels of CSF serotonin and beta endorphin were recorded post stimulation. There were also elevations in the levels of plasma serotonin, beta endorphin, GABA and DHEA together with diminished levels of cortisol and tryptophan. Concomitant with these changes were significant improvements in the symptoms of pain, insomnia, spasticity, depression, and headache.
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PMID:Physiological and therapeutic effects of high frequency electrical pulses. 880 93

Suppression of increased muscle tone by epidural spinal cord stimulation, an invasive method for treating spasticity, increases segmental concentrations of inhibitory amino acid neurotransmitters, particularly glycine. The role of glycine in spasticity and spinal shock was explored further in rabbits with ischemic spinal cord injuries that produced spastic paraparesis or flaccid paraplegia. H-reflexes were monitored following posterior tibial nerve stimulation and plantar surface recording. Spasticity was quantified by using H/M ratios. Spastic animals were intrathecally infused with 100 mmol/l solutions of glycine and related compounds. Glycine agonists suppressed tone whereas glycine antagonists increased tone. In addition, microdialysis sampling from the cord was done in injured, non-infused animals and aspartate, GABA, glutamate, glycine and taurine were measured. Flaccid animals had glycine levels two-three times higher than spastic or control animals. High concentrations of glycine within spinal cord segments is associated with spinal shock. Glycine and related compounds may be useful as treatment for excessive tone.
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PMID:The role of glycine in spinal shock. 923 88


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