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Journal ArticleDOI

Gaba derivative in spasticity. (Beta-(4-chlorophenyl)-gamma-aminobutyric acid, Ciba 34.647-Ba).

01 Aug 1970-Acta Neurologica Scandinavica (Acta Neurol Scand)-Vol. 46, Iss: 3, pp 257-266
TL;DR: The search has been continued for GABA-like substances which more easily cross the blood-brain barrier, preferably agents which can be administered orally, and the GABA derivative p(4-chloropheny1)-y-aminobutyric acid is such a substance, and studies of it are reported below.
Abstract: There is every reason to continue the search for compounds which exert a beneficial effect on spasticity, both because improved possibilities of treatment are desirable and because such compounds may be conducive to elucidating the pathophysiological mechanisms of spasticity. In the course of time, a great variety of agents have been given a trial; and since 1954 when Florey reported that extract from mammalian brain contained a neuro-inhibitory substance, such agents have attracted great attention. This applies, in particular, to gamma-aminobutyric acid (GABA) , which has been shown to be the active principle in Florey's extract (Bazemore et al. 1956, 1957). GABA has been assumed to be the transmitter substance at the inhibitory synapses ; but this problem has not yet been clarified. It would be reasonable to study the effect of GABA on spasticity; but as the blood-brain barrier is relatively impermeable to GABA, it is difficult to administer to human beings. The search has therefore been continued for GABA-like substances which more easily cross the blood-brain barrier, preferably agents which can be administered orally. The GABA derivative p(4-chloropheny1)-y-aminobutyric acid is such a substance, and studies of it are reported below.
Citations
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Journal ArticleDOI
TL;DR: The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.
Abstract: BACKGROUND Spasticity is a common problem in MS patients causing pain, spasms, loss of function and difficulties in nursing care. A variety of oral and parenteral medications are available. OBJECTIVES To assess the absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis (MS) patients. SEARCH STRATEGY Randomised controlled trials (RCTs) of anti-spasticity agents were identified using MEDLINE, EMBASE, bibliographies of relevant articles, personal communication, manual searches of relevant journals and information from drug companies. SELECTION CRITERIA Double-blind, randomised controlled trials (either placebo-controlled or comparative studies) of at least seven days duration. DATA COLLECTION AND ANALYSIS Two independent reviewers extracted data and the findings of the trials were summarised. Missing data were collected by correspondence with principal investigators. A meta-analysis was not performed due to the inadequacy of outcome measures and methodological problems with the studies reviewed. MAIN RESULTS Twenty-three placebo-controlled studies (using baclofen, dantrolene, tizanidine, botulinum toxin, vigabatrin, prazepam and threonine) and thirteen comparative studies met the selection criteria. Only thirteen of these studies used the Ashworth scale, of which only three of the six placebo-controlled trials and none of the seven comparative studies showed a statistically significant difference between test drugs. Spasms, other symptoms and overall impressions were only assessed using unvalidated scores and results of functional assessments were inconclusive. REVIEWER'S CONCLUSIONS The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.

223 citations

Journal ArticleDOI
TL;DR: There were no findings indicating an accumulation of the drug in plasma during long-term medication, in accordance with the concept that the type of spasticity is crucial in reaching an improvement from baclofen treatment in patients with spastic pareses.

218 citations

Journal ArticleDOI
TL;DR: The limited data on baclofen toxicity in patients with renal disease suggest that administration of the drug in these persons may carry an unnecessarily high risk, but the benefit/risk assessment is favourable.
Abstract: Baclofen is used for treatment of the spasticity of spinal origin that is a common sequela of spinal cord injury and multiple sclerosis; spasticity occurs in about 50% of patients affected by these disorders. In open-label studies of oral baclofen, the drug improved spasticity in 70–87% of patients; additionally, improvement in spasms was reported in 75–96% of patients. In double-blind, crossover, placebo-controlled trials, baclofen was reported to be effective, producing statistically significant improvements in spasticity. Tizanidine is the antispasticity drug that has been most widely compared with oral baclofen; studies have generally found the two drugs to have equivalent efficacy. However, tizanidine has better tolerability, in particular weakness was reported to be occur less frequently with tizanidine than with baclofen. The main adverse effects of oral baclofen include: sedation or somnolence, excessive weakness, vertigo and psychological disturbances. The incidence of adverse effects is reported to range from 10% to 75%. The majority of adverse effects are not severe; most are dose related, transient and/or reversible. The main risks of oral baclofen administration are related to withdrawal: seizures, psychic symptoms and hyperthermia can occur. These symptoms improve after the reintroduction of baclofen, usually without sequelae. When not related to withdrawal; these symptoms mainly present in patients with brain damage and in the elderly. The limited data on baclofen toxicity in patients with renal disease suggest that administration of the drug in these persons may carry an unnecessarily high risk. Intrathecal baclofen is indicated for use in patients with spasticity of spinal origin unresponsive to treatment with maximum doses of oral baclofen, tizanidine and/or dantrolene. The benefits of continuous intrathecal baclofen infusion have been demonstrated: >80% and >65% of patients have improvement in tone and spasms, respectively. The main risks of intrathecal baclofen infusion are symptoms related to overdose or withdrawal; the latter is more important because of the associated severe effects on clinical status and the possibility of death, but it is responsive to rapid treatment. Overdose primarily arises from drug test doses or human error during refill and programming of the pump, and withdrawal most commonly occurs as a result of a problem with the delivery system. Since the adverse consequences do not exceed the benefits of oral and intrathecal baclofen for patients with spinal spasticity, the benefit/risk assessment is favourable.

197 citations

Journal ArticleDOI
TL;DR: Racemic and l-baclofen partly antagonized electro-ionotrophoretically and it was conlcuded that the biologica activity of bacl ofen resides with the l-enantiomer.

191 citations

Journal ArticleDOI
TL;DR: It was concluded that Baclofen affects transmission by selectively suppressing the release of the excitatory amino acids glutamate and aspartate from nerve terminals, and an increase in glycine turnover suggests an additional effect on inhibitory glycinergic interneurons in the spinal cord.
Abstract: Slices of guinea-pig cerebral cortex were used to investigate the effects of the antispastic drug β-(p-chlorophenyl)-γ-aminobutyrate (Baclofen, Lioresal) on the release and metabolism of several amino acids. Electrical stimulation of slices evoked (1) a relatively large release, probably from nerve terminals, of 14C-labelled tissue glumate, aspartate and γ-aminobutyrate (GABA) synthesized via metabolism of D-[U-14C]glucose and (2) a relatively small release, probably not from nerve terminals, of 14C-labelled tissue alanine and threonine-serine-glutamine and of exogenous radiolabeled glutamate, aspartate, GABA and α-aminoisobutyrate that had been taken up from the medium. Baclofen (4μM) preferentially inhibited the release of 14C-labelled tissue glutamate and aspartate. It had no effect on the concentrations and specific radio-activities of most of the labelled tissue amino acids in the slices. However, it increased the turnover of 14C-labelled tissue glycine approx 4-fold and elevated the specific radio activity of tissue alanine by 40%. It was concluded that Baclofen affects transmission not by modulating the release of the inhibitory amino acid GABA, but by selectively suppressing the release of the excitatory amino acids glutamate and aspartate from nerve terminals. Provided that this action obtains in the spinal cord, it may at least partly underlie the antispastic action of Baclofen as glutamate and aspartate are presumed to be the transmitters released from terminals of non-nociceptive primary afferent fibers and excitatory interneurons, respectively. The Baclofen-induced increase in glycine turnover suggests an additional effect on inhibitory glycinergic interneurons in the spinal cord.

179 citations

References
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Journal ArticleDOI
TL;DR: The objective was to obtain increased specific activity (activity per unit weight of material) rather than maximal yields of activity.
Abstract: THE inhibitory activity of extracts of brain and spinal cord on the generation of impplses by the stretch -tor neuron of the cray6sh has been reported previously (FLORIN, 1954). The agent (or agents) responsible for this action was called Factor I. In a previous communication in this Journal (ELLIOTT and FUIREY, 1956) the results of other published studies on Factor I were summarized, a method for the assay of Factor I activity was described and the effects of a number of known substances on the stretch receptor preparation were noted. In the study now reported the assay method has been applied in the isolation from bed brain of a substance with high Factor I activity. This substance has been identilied as y-aminobutyric acid. EXPERIMENTAL A s 9 and amffs. Following every step in the purification, samples of the products were held for assay. The assay of Factor I activity was carried out as described by ELuarr and F L ~ R ~ Y (1956). Bridy this method consists in the application of the unltnown makid, freed from organic solvent and dissolved in a buffered saline solution, to the crayfish stretch receptor preparation. Various dilutions of the material arc tested until a concentration, the “minimum blocking concentration,” is reached which just blocks the spontaneous discharges of the stretch receptor neuron for 10 sec. Since the sensitivity of test ~ ~ ~ ~ a r a t i o n s varies, the minimum blocking concentration of a reference solution containing Factor Iis determined before and after each unknown. A singk reference solution was used throughout the present work; samples were taken as requ id from the stock reference solution which was stored in the frozen state. The activity of the unknown solution was thus compared with that of the reference solution and the concentration of Factor I was expressed in ‘c.u.r.’ (crayfish units reference) per ml. A concentration of 1 c.u.r. per mi is about the minimum blocking concentration with many stretch receptor preparations. Table 1 summarizeS the results of the steps in the isolation procedure described below. It should be understood that the objective was to obtain increased specific activity (activity per unit weight of material) rather than maximal yields of activity.

205 citations

Journal ArticleDOI
01 Feb 1954
TL;DR: In this paper, an Inhibitory and an Excitatory Factor of Mammalian Central Nervous System, and their Action on A Single Sensory Neuron are discussed. But the authors do not consider the effects of these factors on a single sensory neuron.
Abstract: (1954). An Inhibitory and an Excitatory Factor of Mammalian Central Nervous System, and Their Action on A Single Sensory Neuron. Archives Internationales de Physiologie: Vol. 62, No. 1, pp. 33-53.

129 citations

Journal ArticleDOI
10 Nov 1956-Nature
TL;DR: Partially purified preparations of the Factor have been found to imitate the action of inhibitory neurons in crustaceans and to block synaptic transmission in autonomic ganglia2 and monosynaptic spinal reflexes4 of mammals.
Abstract: EXTRACTS of brain and spinal cord of mammals inhibit impulse generation in stretch receptor neurons of the crayfish1. The substance or substances responsible for this action has been referred to as Factor I1. In mammals this factor is present only in the central nervous system1,2. Partially purified preparations of the Factor have been found to imitate the action of inhibitory neurons in crustaceans1,3 and to block synaptic transmission in autonomic ganglia2 and monosynaptic spinal reflexes4 of mammals. Factor I preparations were also found to activate the hypoglossal nucleus and often to stimulate polysynaptic spinal reflexes4. The inhibitory effects of Factor I in the spinal cord could be prevented by a subconvulsive dose of strychnine4. Partial purifications of Factor I have been obtained1,2,4 by taking advantage of the observations that the factor is thermostable, dialysable, stable to acid and alkali, not precipitated by lead acetate or perchloric acid, soluble in methanol, moderately soluble in ethanol and insoluble in other organic solvents.

107 citations