To report an unusual cause of intrathecal drug delivery failure in baclofen pump device.
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Microinjection of muscimol, a GABAA agonist (500, 1500 and 2500 pmol/100nl) into the VTA had no significant effect on MAP and HR compared with the saline group and pre-injection values. Injection of bicuculline methiodide (BMI, 100 and 200 pmol/100 nl), a GABAA antagonist, caused a significant increase in the MAP (11.1±1.95mmHg, P<0.5) and a decrease in HR (-32.07±10.2, P<0.01). Microinjection of baclofen a GABAB receptor agonist (500 or 1000 pmole/100 nl) and phaclofen a GABAB receptor antagonist (500 or 1000 pmole/100 nl) had no significant effects on MAP and HR.
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A significant decrease in the mean Ashworth score on the more involved side (2.0 to 1.3) and an increase in gait speed (41 to 47cm/s) were noted at different intervals after ITB bolus injection. Ankle ROM significantly increased on the more involved (13 degrees to 15 degrees , P<.01) and less involved (22 degrees to 24 degrees , P<.05) sides. ROM significantly improved, significantly worsened, or showed no significant change in 42%, 34%, and 24% of individual joints, respectively. The peak change in ROM did not coincide with the peak decrease in Ashworth score. Peak changes in ROM and speed coincided more often (P<.001) in participants who increased gait speed after ITB bolus compared with those who decreased speed. The absolute change in ROM after ITB bolus injection correlated better with the concurrent changes in speed (r=.41, P<.001) than with the baseline speed (r=.18, P<.05).
To study the use and misuse (poisonings) of baclofen in the time period of 2007-2012 and to evaluate the severity and clinical symptoms of poisonings including ingested baclofen. The National Patient Register (NPR) was searched for admissions due to baclofen poisonings from 2007 to 2012. The search was conducted with ICD-10 codes for poisoning, self-harm and suicide, and coupled with the baclofen ATC code. All enquiries about baclofen to the Danish Poison Information Centre (DPIC) in the same period were evaluated. Demographic and clinical data were extracted, and the poisonings were classified according to the Poison Severity Score. The number of baclofen poisonings did not increase from 2007 to 2012. Thirty-eight admissions with baclofen poisoning were registered at the NPR; however, only one-third of the reviewed DPIC cases were registered at the NPR with the correct coding. In the group of severely poisoned patients (PSS 3), three patients had only ingested baclofen (mean 2000 mg; SD 500 mg) and eight patients had ingested baclofen together with alcohol or psychotropic drugs (mean 900 mg; SD 641 mg). All patients presented with deep coma and respiratory depression. Additionally, seizures and cardiovascular events (mild hypo- or hypertension and bradycardia) occurred. There is a substantial degree of underreporting of baclofen poisonings in Denmark. Symptoms of baclofen poisoning progress very fast, and toxicity was observed even with doses as low as 150 mg. We therefore recommend that observation and treatment of these patients should be carried out in an intermediate- or intensive care unit. The most important treatment is the maintenance of a protected airway and respiration.
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Activation of GABAB receptors in the Xenopus embryo, a simple vertebrate, causes presynaptic inhibition of transmitter release from glycinergic spinal neurons and an increase in action potential threshold. To investigate the underlying mechanisms of GABAB receptor action, we have made whole-cell voltage-clamp recordings from acutely isolated Xenopus embryo spinal neurons. The GABAB receptor agonist baclofen caused a reversible reduction in the amplitude of Ca2+ currents. This reduction of Ca2+ currents appeared to be voltage dependent as it was removed at very positive potentials. Since the specific GABAB antagonists CGP35348, phaclofen, and 2-hydroxysaclofen all blocked the reduction in Ca2+ currents, we concluded that the modulation of the Ca2+ current was mediated by GABAB receptors. We have investigated the pharmacological identity of the Ca2+ current modulated by baclofen using the selective blocker omega-conotoxin, fraction GVIA (omega-CgTX). omega-CgTX selectively blocked voltage-gated Ca2+ currents without affecting the voltage-gated Na+ current. omega-CgTX substantially occluded the action of baclofen, suggesting that GABAB receptors modulate an omega-CgTX-sensitive Ca2+ current. Since GABAB receptors mediate presynaptic inhibition, we have studied the involvement of the omega-CgTX-sensitive Ca2+ current in synaptic transmission in the intact spinal cord. Inhibitory interneuron axons were stimulated to evoke monosynaptic IPSPs in motoneurons, and recorded intracellularly. Since omega-CgTX blocked inhibitory transmission, we concluded that the omega-CgTX-sensitive Ca2+ current plays an essential role in transmitter release. If modulation of this current were to occur in nerve terminals, it could contribute to the GABAB receptor-mediated presynaptic inhibition of transmitter release.(ABSTRACT TRUNCATED AT 250 WORDS)
The recreational drug gamma-hydroxybutyrate (GHB) has euphoric effects and can induce sedation and body temperature changes. GHB is frequently combined with other recreational drugs although these interactions are not well characterised. The present study used biotelemetry to provide a fine-grained analysis of the effects of GHB on body temperature and locomotor activity in freely moving rats, and investigated interactions between GHB and 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine (METH) and various antagonist drugs. GHB (1000mg/kg) caused profound sedation for more than 2h and a complex triphasic effect on body temperature: an initial hypothermia (5-40min), followed by hyperthermia (40-140min), followed again by hypothermia (140-360min). A lower GHB dose (500mg/kg) also caused sedation but only a hypothermic effect that lasted up to 6h. The dopamine D(1) receptor antagonist SCH 23390 (1mg/kg), the opioid antagonist naltrexone (1mg/kg), the benzodiazepine antagonist flumazenil (10mg/kg), and the 5-HT(2A/2C) receptor antagonist ritanserin (1mg/kg) did not prevent the overall sedative or body temperature effects of GHB (1000mg/kg). However the GABA(B) antagonist SCH 50911 (50mg/kg) prevented the hyperthermia induced by GHB (1000mg/kg). Repeated daily administration of GHB (1000mg/kg) produced tolerance to the sedative and hyperthermic effects of the drug and cross-tolerance to the sedative effects of the GABA(B) receptor agonist baclofen (10mg/kg). A high ambient temperature of 28 degrees C prevented the hypothermia obtained with GHB (500mg/kg) at 20 degrees C, while GHB (500mg/kg) reduced the hyperthermia and hyperactivity produced by co-administered doses of MDMA (5mg/kg) or METH (1mg/kg) at 28 degrees C. These results further confirm a role for GABA(B) receptors in the hypothermic and sedative effects of GHB and show an interaction between GHB and MDMA, and GHB and METH, that may be relevant to the experience of recreational users who mix these drugs.
A previous study from this laboratory demonstrated that ongoing GABAergic neurotransmission in the nucleus tractus solitarii (NTS) functions to maintain baseline arterial pressure (AP). In that study, bilateral microinjection of nipecotic acid into the NTS was observed to elevate AP. Since nipecotic acid is a selective GABA uptake blocker, changes in GABA release should be reflected by changes in the response to nipecotic acid. The present study utilized this approach to assess endogenous GABA activity within the NTS of the spontaneously hypertensive rat (SHR). Male SHR, 16-20 weeks of age, were anesthetized with chloralose, paralyzed and ventilated. Age-matched Wistar-Kyoto (WKY) rats were studied as controls. Bilateral microinjection of nipecotic acid (10 nmol in 100 nl; a maximally effective dose) into the NTS elicited a pressor response which was significantly greater in the SHR than the response observed in the WKY rats. Similarly, direct stimulation of GABAB receptors in the NTS with (-)-baclofen 40 pmol, a maximally effective dose) elicited an increase in AP which was significantly greater in the SHR. In contrast, bilateral microinjection of the direct acting GABAA agonist muscimol (160 pmol, a maximally effective dose) resulted in a similar elevation of AP in both the SHR and WKY rats. These results suggest that the enhanced pressor response caused by endogenous GABA in the NTS of the SHR is due to a greater response evoked by stimulation of GABAB receptors. Thus, enhanced GABAB receptor-mediated neural transmission in the NTS may contribute to the expression or maintenance of hypertension in this genetic model of hypertension.
1. The role of gamma-aminobutyric acid (GABA) as an inhibitory transmitter in the central nervous system is well documented. Recently, GABAA and GABAB receptors have been identified in the peripheral nervous system, notably on primary afferent neurones (PAN). We have utilised a multi-superfusion system to investigate the effect of selective GABA receptor agonists and antagonists on the release of substance P (SP) from the rat trachea in vitro. 2. GABA (1-100 microM) did not affect spontaneous release of SP-like immunoreactivity (LI) but caused dose-related inhibition of calcium-dependent potassium (60 mM)-stimulated SP-LI release. The greatest inhibition of 77.7 +/- 18.8% was observed at 100 microM. 3. The inhibitory effect of GABA was mimicked by the GABAB receptor agonist, (+/-)-baclofen (1-100 microM), but not the GABAA receptor agonist, 3-amino-1-propane-sulphonic acid (3-APS, 1-100 microM). Baclofen (100 microM) had no effect on SP-LI release stimulated by capsaicin (1 microM). 4. The inhibitory effect of baclofen (30 microM) was significantly reduced by prior and concomitant exposure to the GABAB receptor antagonist, phacolofen (100 microM) but not the GABAA receptor antagonist, bicuculline (10 microM). Neither antagonist, alone, affected spontaneous or potassium-stimulated SP-LI release. 5. We conclude that activation of pre-synaptic GABAB receptors on the peripheral termini of PANs in the rat trachea inhibits SP-LI release and suggest that GABAB receptor agonists may be of value in the therapeutic treatment of asthma.
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To report the occurrence of acute bronchospasm in one asthmatic patient and increased bronchial reactivity in another following the administration of a single dose of oral baclofen.
In this double-blind clinical trial, 40 Iranian combat veterans with PTSD were randomly assigned to 2 groups. The first group received a combination treatment of 20 to 60 mg/d citalopram and 40 mg/d baclofen, and the second group received 20 to 60 mg/d citalopram plus placebo. Symptom severity was assessed by Clinician-Administered PTSD Scale at the beginning of the study and after 2, 4, 6, and 8 weeks. Global Assessment of Functioning and Hamilton Rating Scale for Anxiety and Depression were also used at the same periods. Data were analyzed with independent t test and paired t test using SPSS software version 13 (IBM, Armonk, NY).
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The effects of gamma-aminobutyric acid (GABA) and related compounds on the contractility of isolated rabbit uterus were examined. GABA and baclofen (10(-6)-10(-4) M) stimulated the spontaneous motility in a dose-dependent manner and showed cross-desensitization. The effect of baclofen was stereoselective for the (-)-enantiomer. Muscimol was ineffective, while bicuculline evoked marked contractions. Contractions elicited by submaximal electrical stimulation could be further increased by GABA and baclofen. The effects of GABA and baclofen on spontaneous contractility could not be antagonized by atropine, phentolamine, or tetrodotoxin. These findings indicate: (1) the presence of GABAB receptors in the rabbit uterus; (2) their involvement in the modulation of uterine contractility; (3) the extraneuronal location of uterine GABAB receptors which are thus most probably on smooth muscle cells; and (4) a possible role of inhibitory GABAA receptors in the modulation of spontaneous movements of the uterus.
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In our previous studies, we hypothesized that activation and subsequent collapse of GABA-mediated inhibition during tetanus is an important seizure-triggering mechanism in the kindled epileptogenic focus. To examine this hypothesis, in the present study, we investigated the effects of pharmacological manipulations of the kindled amygdala with several drugs, and measured the kindled seizures as well as the EEG events during tetanus. The results obtained were: (i) The selective GABA-A agonist, muscimol (1 and 5 nM/1 microliter), suppressed kindled seizures in a dose-dependent fashion, and the 5 nM muscimol significantly prolonged EEG suppression and reduced the number of oscillations in the subsequent rhythmic synchronous discharge. Similar effects followed systemic injection of diazepam (2 mg/kg). (ii) The selective GABA-B agonist, baclofen (5 nM), had no effect on kindled seizures nor on the EEG events during tetanus. (iii) The NMDA antagonist, 2-amino-5-phosphonovaleric acid (80 nM), significantly reduced the afterdischarge duration and significantly delayed the appearance of the rhythmic synchronous discharge. However, these effects were not observed immediately, but 24 to 72 h after microinjection. (iv) The muscarinic cholinergic antagonist, atropine (40 and 80 nM), suppressed kindled seizures in a dose-dependent fashion, but the atropine caused marked synchronous discharge both in the awake resting EEG and during tetanic stimulation. We conclude that the GABA-A system, including the benzodiazepine system, is more involved in the seizure-triggering mechanism of amygdala kindling than the GABA-B system, that there is an interaction between the GABA-A and NMDA system, and that the cholinergic participation is independent of the primary seizure-triggering mechanisms.
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GABA (gamma-aminobutyric acid) receptors in the brain have been classified into GABAA and GABAB types. The GABAA receptor is an ionotropic type that forms the GABA-gated Cl- channel. The structure of GABAA receptor has been intensively analyzed and found to consist of several subunits and the combination of these subunits is heterogeneous. Therefore, it is likely that multiple GABAA receptors are present and exert various inhibitory actions in the brain. On the other hand, the GABAB receptor, a metabotropic type, inhibits cAMP formation as well as inositol phosphates turnover. The inhibition of adenylyl cyclase activity is mediated by GTP-binding protein such as Gi and/or Go which is coupled with GABAB receptor. Studies of the purified GABAB receptor obtained by baclofen-affinity and immunoaffinity column chromatographic procedures have indicated that this receptor protein is approximately 80 kDa in molecular weight and heterogeneous as determined by SDS-polyacrylamide gel electrophoresis. Alcohol induces the activation of GABA-gated Cl- channel but this activation is found to be diminished following the establishment of alcohol dependence. Furthermore, alcohol dependence induces the increase of GABAB receptor binding, while suppressing the functional coupling between GABAB receptor and adenylyl cyclase, possibly altering the function of Gi/Go type of GTP-binding protein which is coupled to GABAB receptor in the brain. The pathophysiological significance of these changes in the establishment of alcohol dependence and/or alcohol withdrawal syndrome is also briefly discussed.
Early onset torsion dystonia (EOTD) is a rare movement disorder characterized by involuntary, repetitive, sustained muscle contractions or postures involving one or more sites of the body. A US study estimated the prevalence at approximately 1 in 30,000. The estimated prevalence in the general population of Europe seems to be lower, ranging from 1 in 330,000 to 1 in 200,000, although precise numbers are currently not available. The estimated prevalence in the Ashkenazi Jewish population is approximately five to ten times higher, due to a founder mutation. Symptoms of EOTD typically develop first in an arm or leg in middle to late childhood and progress in approximately 30% of patients to other body regions (generalized dystonia) within about five years. Distribution and severity of symptoms vary widely between affected individuals. The majority of cases from various ethnic groups are caused by an autosomal dominantly inherited deletion of 3 bp (GAG) in the DYT1 gene on chromosome 9q34. This gene encodes a protein named torsinA, which is presumed to act as a chaperone protein associated with the endoplasmic reticulum and the nuclear envelope. It may interact with the dopamine transporter and participate in intracellular trafficking, although its precise function within the cell remains to be determined. Molecular genetic diagnostic and genetic counseling is recommended for individuals with age of onset below 26 years, and may also be considered in those with onset after 26 years having a relative with typical early onset dystonia. Treatment options include botulinum toxin injections for focal symptoms, pharmacological therapy such as anticholinergics (most commonly trihexiphenydil) for generalized dystonia and surgical approaches such as deep brain stimulation of the internal globus pallidus or intrathecal baclofen application in severe cases. All patients have normal cognitive function, and despite a high rate of generalization of dystonia, 75% of those patients are able to maintain ambulation and independence, and therefore a comparatively good quality of life, with modern treatment modalities.
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1. In the present study, in vitro electrophysiology and receptor autoradiography were used to determine whether rat vagal afferent neurones possess gamma-aminobutyric acid (GABA)A receptors. 2. GABA (1-100 microM) and isoguvacine (3-100 microM) caused a concentration-dependent depolarization of the rat isolated nodose ganglion preparation at room temperature. When applied to the tissue 20 min before the agonist, SR95531 (3 microM) and bicuculline (3 microM) caused a parallel shift to the right of the GABA and isoguvacine concentration-response curves, yielding shifts of 81 fold and 117 fold for SR95531 and 4 fold and 12 fold for bicuculline, respectively. 3. Baclofen (10 nM-100 microM) was unable to elicit a depolarization of the rat isolated nodose ganglion preparation at either room temperature or at 36 degrees C, whilst 5-aminovaleric acid (10 microM), a GABAB receptor antagonist, was unable to antagonize significantly the GABA-induced depolarization at either room temperature or at 36 degrees C. 4. [3H]-SR95531 (7.2 nM), a GABAA receptor-selective antagonist, bound topographically to sections of rat brainstem. Specific binding was highest in the medial nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus nerve (DMVN). Binding was also observed in certain medullary reticular nuclei, in particular the parvocellular reticular nucleus. 5. Unilateral nodose ganglionectomy caused a reduction in GABAA binding site density in the medial NTS from 93 +/- 7 to 68 +/- 6 d.p.m./mm2. This procedure also caused a reduction in GABAA binding site density in the side of the NTS contralateral to the lesion, from 151 +/- 12 to 93 +/- 7 d.p.m./mm2. Sham surgery had no effect on the binding of [3H]-SR95531 in rat brainstem. 6. The present data provide evidence for the presence of GABAA receptors located on the soma and central terminals of rat vagal afferent neurones. Additionally, a population of GABAA receptors is evidenced postsynaptically in the rat NTS with respect to vagal afferent terminals. These data are discussed in relation to the functional pharmacology of GABA in this region of the NTS.
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Random selection of normal sperm samples.
Excitatory postsynaptic currents (EPSCs) were induced in layer II-V pyramidal cells in the frontal cortex of the young rat (postnatal day 14-21) by stimulation of layers II/III in the presence of bicuculline using the whole-cell patch-clamp technique. EPSCs usually consisted of fast and slow components that were sensitive to CNQX and APV, respectively. In response to paired stimuli of identical strength, paired pulse depression (PPD) was seen for these EPSCs. The PPD of fast EPSCs was most pronounced at an interstimulus interval (ISI) of 200-300 msec and ceased to occur at ISIs greater than 3-5 sec, while the PPD of slow EPSCs became most pronounced at an ISI of 500-1000 msec and ceased to occur at ISIs greater than 10 sec. The PPD of fast EPSCs was attenuated by (-)-baclofen (1-5 microM) and removed by 2-hydroxy-saclofen (0.2-0.4 mM). By contrast, the PPD of slow EPSCs consisted of early and late components that were attenuated by (-)-baclofen and muscarine (1-5 microM), respectively. The late PPD of slow EPSCs induced in the presence of baclofen was removed by pirenzepine (1-3 microM). Thus, fast and slow components of glutamatergic EPSCs displayed two distinct PPDs. These results suggest that a part of the glutamatergic afferents likely arising from layer II/III pyramidal cells may terminate predominantly on NMDA receptors in pyramidal cells of the frontal cortex and receive distinct presynaptic inhibition through at least the muscarinic receptors.
A 34-year-old man with adrenoleukodystrophy (ALD) was scheduled for pump system insertion of intrathecal baclofen therapy under general anesthesia. ALD, a rare genetic disorder, is associated with a total body increase in long chain fatty acids caused by defective degradation, and includes various nervous system abnormalities, muscular weakness, in addition to adrenal insufficiency. He had contracture of the both legs, and muscular weakness of the left hand, and Mallampati class III, but no respiratory disability. In the operating room, we administered hydrocortisone 100 mg for steroid coverage, and low-dose midazolam, and fentanyl. As spontaneous breathing remained, we could easily see epiglottis and arytenoid cartilage by McGRATH. Therefore we selected rapid-induction of anesthesia with thiamylal, and rocuronium 40 mg, under cricoid pressure. We avoided propofol. Anesthsia was maintained with sevoflurane and remifentanil, monitoring BIS and train of four. No more rocuronium was administered, and anesthesia was uneventful. Intrathecal baclofen therapy is given to patients who have severe contracture. When we selected general anesthesia, we should be aware of the possibility of muscular weakness, and cannot intubate cannot ventilate scenario.
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Operant performance of non-food deprived rats (n=8) was assessed under progressive ratio (PR) and concurrent PR-fixed ratio schedules of food pellet and/or vegetable shortening reinforcement. Post operant baselines, rats were matched and divided into 2 groups based upon the schedule of shortening availability: High restriction binge group (H, 1-hr home cage shortening access each week on Monday, Wednesday, and Friday) and Low restriction (L, 1-hr shortening access daily). Chow and water were continuously available; only access to the shortening was restricted. After 8 weeks, operant performance was reassessed. Lever pressing for shortening increased in the H rats for all schedules, but was either unaffected or decreased in the L rats. Pellet responding under the concurrent schedules increased for both groups. The effects of four dosages of (R)-baclofen (0.3-1.8 mg/kg, i.p.) on operant performance were also assessed. For both groups, 1.0 mg/kg baclofen significantly reduced shortening responding relative to saline for all schedules except one, but had no or minimal effect on pellet responding. This suggests a specific effect of baclofen on responding maintained by fat. These results indicate that intermittent episodes of bingeing on fat can increase the reinforcing efficacy of fat and that GABAB receptor activation can attenuate this effect.
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Helium-oxygen pressure induces in rodents an increase of both locomotor and motor activity (LMA) and of the striatal dopamine release, which could result from a decrease of GABA transmission in the substantia nigra. The effects of the GABA(A) receptor agonist muscimol and of the GABA(B) receptor agonist baclofen on the striatal dopamine release were measured using differential pulse voltammetry. Behavioural studies were performed in freely moving rats using actimetry. Whatever the drug used under helium pressure, bilateral administration in the substantia nigra pars reticulata (SNr) or in the substantia nigra pars compacta (SNc) counteracted the evoked dopamine release. However, only the baclofen reduced the LMA, while the muscimol administration in the SNr, but not in the SNc, increased it. These results indicate that different subtypes of GABA receptors would be involved in the control of the DA release and in the occurrence of LMA under helium pressure.
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The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.
Neurological conditions including cerebral palsy, brain injury, and stroke often result in severe spasticity, which can lead to significant deformity and interfere with function. Treatments for spasticity include oral medications, intramuscular botulinum toxin type A injections, orthopedic surgeries, intrathecal baclofen pump implantation, and selective dorsal rhizotomy (SDR). Selective dorsal rhizotomy, which has been well studied in children with spastic diplegia, results in significant reduction in spasticity and improved function in children. To the authors' knowledge, there are no published outcome data for SDR in patients with spastic hemiparesis. The object of this study was to examine the effects of SDR on spastic hemiparesis.
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By use of rat liver or brain homogenate supernatants containing microsomes and/or mitochondria, it was found that the prototype GABAergic prodrug [3-(p-chlorophenyl)pyrrolidine (1)] underwent a series of alpha-oxidation transformations to a pair of amino acid metabolites and a pair of lactam metabolites [4-amino-3-(p-chlorophenyl)butanoic acid, baclofen (5); 4-amino-2-(p-chlorophenyl)butanoic acid (10); 4-(chlorophenyl)pyrrolidin-2-one and 3-(p-chlorophenyl)pyrrolidine-2-one (11)]. With the liver homogenates, the formation of the lactam metabolites was approximately 2 orders of magnitude greater than that of the amino acid metabolites, while with the brain homogenates, the amino acid and lactam pathways were of similar magnitude. For either tissue, for both the lactam and the amino acid series, attack at the less sterically hindered 5-position of the pyrrolidine ring was greater than the attack at the 2-position (5 greater than 10 and 6 greater than 11) with the exception of the liver homogenate mitochondrial fraction (6 less than 11). The parenteral administration of the prodrug 1 was found to give detectable brain levels of 5 as well as activity in an isoniazid-induced (GABA-inhibited) convulsion model.
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To assess the effect of continuous intrathecal baclofen infusion (ITB) on gait parameters of ambulant children with cerebral palsy (CP).
We report a 70-year-old man, who developed painful involuntary muscle contraction of the left leg after the lumbar discectomy, which exacerbated after a vertebral fracture of Th12. This involuntary movement was accompanied with the abnormal position of left leg simulating triple flexion response, and was induced by active or passive movement of his left knee and foot joints. Several drugs including benzodiazepines and dantrolene were ineffective, although treatment with baclofen or carbamazepine was effective. These findings suggest that hyperexcitability of the anterior horn cells following the disturbance of spinal inhibitory interneurons was involved. Electophysiological studies suggested the disturbance of left lumber nerve roots. The spinal root blocks from L3 to S1 were performed, after which the painful involuntary muscle spasm was resolved. The lumbar sympathetic ganglia block was also effective; suggesting that abnormal afferent neuronal input to spinal cord was caused by the nerve root trauma which triggered the formation of secondary abnormal network in the spine. Lumbar sympathetic ganglia block should be recommended to a therapeutic option for the refractory painful muscle spasm of the leg.
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The objective of this study was to analyze the relationship between epilepsy and intrathecal baclofen by investigating a consecutive sample of 150 children with cerebral palsy or spasticity of cerebral origin who underwent intrathecal baclofen. The medical charts of the 150 children were retrospectively reviewed. A series of 100 children with cerebral palsy, operated on other procedures, was reviewed as a control group. Forty percent of the 150 children had epilepsy before intrathecal baclofen pump implantation; 13.3% had a decrease in seizure frequency after intrathecal baclofen, while two children worsened and one child had seizures ex novo. We conclude that in children with spasticity of cerebral origin, intrathecal baclofen does not seem to aggravate or induce seizure activity.
Preclinical and clinical evidence show that the GABA B agonist, baclofen is a promising treatment for addictive disorders; however, until recently its mechanism of action in the human brain was unknown. In previous work we utilized a laboratory model that included a medication versus placebo regimen to examine baclofen's actions on brain circuitry. Perfusion fMRI [measure of cerebral blood flow (CBF)] data acquired 'at rest' before and on the last day of the 21-day medication regimen showed that baclofen diminished CBF bilaterally in the VS, insula and medial orbitofrontal cortex (mOFC). In the present study, we hypothesized that a single dose of baclofen would have effects similar to repeated dosing.
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On-line in vivo microdialysis was used to determine the effects of a 16-min handling period on release of dopamine (DA) in the nucleus accumbens and of DA and noradrenaline (NA) in the medial prefrontal cortex of awake, freely moving rats. DA and NA were determined in one HPLC run. Handling resulted in an immediate and strong increase of both catecholamines in the prefrontal cortex. Maximal values for DA were 295%, and for NA 225%, of controls. DA in the nucleus accumbens was also increased (to 135% of controls) but only after a short delay. Local inhibition of ionotropic glutamate receptors by continuous reversed dialysis of the drugs 6-cyano-7-nitroquinoxaline, D-2-amino-5-phosphonopentanoic acid, or dizocilpine did not significantly affect handling-induced increases in cortical DA and NA release. Neither did the agonist of metabotropic glutamate receptors, trans-(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), or the GABA-B agonist baclofen. Reversed dialysis of dizocilpine in the nucleus accumbens was equally ineffective, but ACPD inhibited the increase in DA release in this area. Stimulation of metabotropic glutamate receptors in the nucleus accumbens was previously reported to inhibit activation of DA release in that area after stimulation of glutamatergic or dopaminergic afferents. It is concluded that metabotropic receptors in the nucleus accumbens are important for the control of activation of DA release in the accumbens by physiological stimuli but that a similar mechanism is lacking in the prefrontal cortex.