Administration Of Baclofen Research Articles

The effects of intra-accumbal administration of the nicotinic acetylcholine receptor agonist cytisine on the operant oral self-administration of ethanol were prevented by the GABAB receptor agonist baclofen in rats

RationaleAlthough the mesocorticolimbic dopamine (DA) system is the main neurochemical substrate that regulates the addictive and reinforcing effects of ethanol (EtOH), other neurotransmitter systems, such as the acetylcholine (Ach) system, modulate DAergic function in the nucleus accumbens (nAcc). Previously, we reported that intra-nAcc administration of the nicotinic Ach receptor agonist cytisine increased oral EtOH self-administration. GABAB receptors in the nAcc are expressed in DAergic terminals, inhibit the regulation of DA release into the nAcc, and could modulate the effects of cytisine on oral EtOH self-administration. The present study assessed the effects of intra-nAcc administration of the GABAB receptor agonist baclofen (BCF) on the impacts of cytisine on oral EtOH self-administration. Methods: Male Wistar rats were deprived of water for 23.30 h and then trained to press a lever to receive EtOH on an FR3 schedule until a stable response rate of 80 % was achieved. After this training, the rats received an intra-nAcc injection of the nAch receptor agonist cytisine, BCF, and cytisine or 2-hydroxysaclofen, BCF, and cytisine before they were given access to EtOH on an FR3 schedule. Results: Intra-nAcc injections of cytisine increased oral EtOH self-administration; this effect was reduced by BCF, and 2-hydroxysaclofen blocked the effects of BCF. Conclusions: These findings suggest that the reinforcing effects of EtOH are modulated not only by the DA system but also by other neurotransmitter systems involved in regulating DA release from DAergic terminals.

Isaacs Syndrome in A Patient with Positive CASPR2 And LGI1 Antibodies: A Case Report and Literature Review

Isaacs Syndrome (IS) is an autoimmune disease characterized by fasciculations, dysautonomia, and hyperactivity of muscle fibers due to hyperexcitability of the peripheral nerve system. Patients with IS often express voltage-gated potassium channels (VGKCs), contactin-associated protein 2 (CASPR2), and leucine-rich gliomainactivated protein (LGI1) antibodies. Slower rates of grouped fasciculation, known as myokymia, are a common presentation in IS patients. Recently, carbamazepine has been considered as the first-line treatment to alleviate the symptoms of IS patients. In this report, the authors present a case of a female patient with ramps and unintended movements in the abdomen and both lower limbs. She was diagnosed with IS after the detection of myokymia in the needle electromyography (EMG) and a positive paraneoplastic panel for CASPR2 and LGI antibodies. The patient is now symptom-free due to the administration of Carbamazepine, Gabapentin, and Baclofen. Additionally, due to her potential risk for solid tumors, she is under regular follow-up.

Effects of Baclofen on Central Paroxysmal Positional Downbeat Nystagmus

Paroxysmal positional nystagmus frequently occurs in lesions involving the cerebellum, and has been ascribed to disinhibition and enhanced canal signals during positioning due to cerebellar dysfunction. This study aims to elucidate the mechanism of central positional nystagmus (CPN) by determining the effects of baclofen on the intensity of paroxysmal positional downbeat nystagmus due to central lesions. Fifteen patients with paroxysmal downbeat CPN were subjected to manual straight head-hanging before administration of baclofen, while taking baclofen 30 mg per day for at least one week, and two weeks after discontinuation of baclofen. The maximum slow phase velocity (SPV) and time constant (TC) of the induced paroxysmal downbeat CPN were analyzed. The positional vertigo was evaluated using an 11-point numerical rating scale (0 to 10) in 9 patients. After treatment with baclofen, the median of the maximum SPV of paroxysmal downbeat CPN decreased from 30.1°/s [interquartile range (IQR) = 19.6—39.0°/s] to 15.2°/s (IQR = 11.2—22.0°/s, Wilcoxon signed rank test, p < 0.001) with the median decrement ratio at 40.2% (IQR = 28.2—50.6%). After discontinuation of baclofen, the maximum SPV re-increased to 24.6°/s (IQR = 13.1—34.4°/s, Wilcoxon signed rank test, p = 0.001) with the median increment ratio at 23.5% (IQR = 5.2—87.9%). In contrast, the TCs of paroxysmal downbeat CPN remained unchanged at approximately 3.0 s throughout the evaluation. The positional vertigo also decreased with the medication (Wilcoxon signed rank test, p = 0.020), and remained unchanged even after discontinuation of medication (Wilcoxon signed rank test, p = 0.737). The results of this study support the prior presumption that paroxysmal CPN is caused by enhanced responses of the semicircular canals during positioning due to cerebellar disinhibition. Baclofen may be tried in symptomatic patients with paroxysmal CPN.

Features of lung damage in baclofen poisoning

To reveal pathological lung changes in baclofen poisoning and to assess their dynamics. The experiment included 20 mature (at age 20 weeks) male rats of Wistar line weighing 290-350 gr. The animals were divided into 3 study groups (5 rats in each) depending on experiment's duration after 85 mg/kg baclofen administration: 3, 4.5 and 24 h in the 1st, 2nd and 3rd groups, respectively. Control group consisted of 5 animals without baclofen administration. A number of pathological reactions, including circulatory disorder (venular and capillary congestion, hemorrhage in interalveolar septa, alveoli, sludge) and the appearance of emphysema loci (interalveolar septa at emphysema loci are thinned), alternating with atelectases and dystelectases. The area taken up by vessels after 4.5 h. baclofen administration was statistically significantly higher than in control group, and after 24 h. - statistically significantly higher than in 4.5 h. The area with white blood cells and WBC/IAP ratio after 4.5 h of baclofen administration were statistically significantly higher than in control group after 3 and 24 h of administration. The number of white blood cells, giving PAS positive reaction, increases during baclofen administration. The complex of pathological lung changes, revealed by ourselves, has a certain dynamics. The data on morphological lung changes combined with results of chemical examination can be used to diagnose baclofen poisoning and to determine the time elapsed since this medicine administration.

Assessment of histological changes in the lungs and Bax and Bcl-2 expression in bronchial epithelium, alveolar type 1 cells and neutrophils of rats in poisoning with baclofen

To study the histological changes in lung of rats, evaluate their dynamics and determine the Bax and Bcl-2 genes expression in bronchial epithelium, alveolar type 1 cells and neutrophils at different times after the administration of baclofen. The experiment was conducted on 20 mature (at the age of 20 weeks) male Wistar rats with a mass of 290-350 g, distributed in 4 groups (5 rats in each). Animals in the control group did not receive baclofen. Rats in experimental groups received baclofen at a dose of 85 mg/kg: in the 1st group, the experiment duration was 3 hours (time to maximum observed blood drug concentration); in the 2nd group - 4.5 h (drug half-life and time to maximum observed concentration of the main drug's metabolite - beta-[p-chlorophenyl])-gamma-hydroxybutyric acid in the blood); in the 3rd group - 24 h. A complex of pathological reactions developed in lungs of experimental animals when baclofen muscle relaxant was administered, namely circulatory disturbances at all levels of the microvasculature (venular and capillary congestion, hemorrhages in the interalveolar septums, alveoli, sludge), emphysema, sites of which punctuated with atelectases and dystelectases. The complex of pathological changes in the lungs had a certain dynamics and reached its highest severity by the 24th hour. Bax expression was strong, while Bcl-2 expression was moderate in the immunohistochemical (IHC) study of bronchical epithelium and alveolar type 1 cells, Bax and Bcl-2 expression in neutrophils was moderate in rats of the 1st group. The expression of Bax and Bcl-2 was strong in the bronchial epithelium and alveolar type 1 cells, the expression of Bax in neutrophils was moderate, and BCL-2 - strong in animals of the 2nd group. The expression of Bax in bronchial epithelium and alveolar type 1 cells was moderate, expression of Bcl-2 in bronchial epithelium and alveolar type 1 cells - strong, expression of Bax in neutrophils - weak and expression of Bcl-2 - strong among the rats of the 3rd group. The complex of pathological changes in lungs had a certain dynamic. Data on the histological changes in lungs in combination with the results of the chemical study, can be used to diagnose the poisoning by baclofen and to establish the time since the drug was administered. The results obtained during the IHC study suggest the involvement of apoptosis in the development of lesion of bronchial epithelium and alveolar type 1 cells. In addition, the expression of Bcl-2 in epithelial cells may play a role in the process of their regeneration.

Intrathecal baclofen therapy: a 30-year experience

The first pump for intrathecal administration of baclofen was implanted in 1984. Over thirty years, intrathecal prolonged infusion of muscle relaxants has occupied a worthy niche among all methods for correction of non-focal drug-resistant disabling muscle spasticity. However, this method has not become routine despite high awareness of specialists in Russia and abroad, as well as undeniable advantages for restoring the daily activity, improving the walking pattern and providing care and quality of life in people with limited mobility. This is due to scrupulous analysis of adverse events and accurate attitude towards its use. A review of national and foreign literature was performed. Prolonged intrathecal baclofen therapy is perspective for long-term treatment of severe spasticity interfering with quality of life and self-care if oral muscle relaxants are contraindicated or ineffective. This procedure is effective for impaired articulation, chewing and spastic pain syndrome. One can reduce the incidence of side effects via correct dosage of the drug, and tolerance to therapy can be reduced by timely elimination of problems with catheter.

Long-term results on the suppression of secondary brain injury by early administered low-dose baclofen in a traumatic brain injury mouse model

Secondary injury from traumatic brain injury (TBI) perpetuates cerebral damages through varied ways. Attenuating neuroinflammation, which is a key feature of TBI, is important for long-term prognosis of its patients. Baclofen, a muscle relaxant, has shown promise in reducing excessive inflammation in other neurologic disorders. However, its effectiveness in TBI remains ambiguous. Thus, our study aimed to investigate whether early administration of baclofen could elicit potential therapeutic effects by diminishing exaggerated neuroinflammation in TBI mice. In this study, 80 C57BL/6 mice were used, of which 69 mice received controlled cortical impact. The mice were divided into six groups (11–16 mice each). Baclofen, administered at dose of 0.05, 0.2 and 1 mg/kg, was injected intraperitoneally a day after TBI for 3 consecutive weeks. 3 weeks after completing the treatments, the mice were assessed histologically. The results showed that mice treated with baclofen exhibited a significantly lower volume of lesion tissue than TBI mice with normal saline. Baclofen also reduced activated glial cells with neurotoxic immune molecules and inhibited apoptotic cells. Significant recovery was observed and sustained for 6 weeks at the 0.2 mg/kg dose in the modified neurological severity score. Furthermore, memory impairment was recovered with low-doses of baclofen in the Y-maze. Our findings demonstrate that early administration of low dose baclofen can regulate neuroinflammation, prevent cell death, and improve TBI motor and cognitive abnormalities.

Overtime Histological Changes in the Lungs after Intoxication with Baclofen Alone or in Combination with Ethanol (Experimental Study)

The aim of the study was to evaluate the overtime histological changes in the lungs after intoxication with baclofen alone or in combination with ethanol.Materials and methods. The experiment was carried out on 35 male Wistar rats weighing 290-350 g and aged 20 weeks. The animals were split into 7 equal groups (n=5); test drugs were administered via nasogastric tube: rats from Groups 1, 3 and 5 were treated with baclofen at 85 mg/kg; rats from Groups 2, 4 and 6 received similar dose of baclofen and 40% alcohol by volume at a dose of 7 ml/kg; control group rats were not administered with any drugs. Animals of all groups were removed from the experiment by cervical dislocation under anesthesia (chlorolase) after 3 hours (Groups 1, 2), 4.5 hours (Groups 3, 4) and after 24 hours (Groups 5, 6, and the controls). Lung tissue samples were examined by light microscopy. The nonparametric Kraskel-Wallis test was used for multiple comparisons between the groups, and nonparametric Mann–Whitney test with Bonferroni correction was used for pairwise comparison.Results. Light microscopy showed no pathological changes in the lungs of the Control group animals. Baclofen alone, or in combination with ethanol caused significant circulatory disorders (venular and capillary fullness, hemorrhages in the interalveolar septa (IAS) and alveoli, sludge phenomenon), emphysema, atelectasis and distelectasis, and pulmonary edema. IAS thickness in rats from all experimental groups was different from that in animals from the Control group, all differences confirmed by the Kruskel-Wallis test: H=748, p=0.00001.In Group 1 animals IAS was 44.2% thinner (p=0.00052) vs the control Group, while in all remaining experimental groups it was, on the contrary, thicker: in Group 2 – 57.6% increase in thickness (p=0.000038), in Group 3 – 99 % (p=0.00001), in Group 4 – 2.2-fold increase (p= 0.00001), in Group 5 – 2.1-fold (p= 0.00001), in Group 6 – 2.5-fold increase (p= 0.00001). Most significant increase in IAS thickness (6-fold, p=0.00001) occurred within the period from 3 to 4.5 hours after administration of baclofen, while within the period from 4.5 to 24 hours no statistically significant increase occurred (p=0.99). Co-administration of baclofen and ethanol caused 2.8-fold (p=0.00001) increase in IAS thickness after 3 hours as compared to the effects of baclofen only. IAS thickness at 4.5 hours after baclofen and ethanol co-administration increased by additional 41.8% as compared to thickness at 3 hours (p=0.00001). IAS became 11.8% thicker at 24 hours vs 4.5 hours (p=0.87). At 24 hours IAS was 21.7% (p= 0.0011) thicker after baclofen and ethanol co-administration vs baclofen alone. The alveoli size increased by 69.4% (p=0.00001) in Group 1 animals vs the Control group, by 14.3% (p=0.43) - in Group 2, by 55% (p=0.00004) - in Group 3, by 26.3% (p=0.002) - in Group 4, by 45% (p=0.0003) - in Group 5 (baclofen, 24 h), by 43.3% (p=0.0004) – in Group 6 (baclofen and ethanol, 24 h). Co-administration of baclofen and ethanol initially caused a slight increase in alveoli size, bur 3 hours later there was a visible shrinkage in the diameter of alveoli by 32.5% (p= 0.003) vs baclofen mono, 4.5 hours later – by 18.5% (p= 0.062), and 24 hours later – by 1.2% (p= 0.99), that is, the differences were leveled.Conclusion. The combined effects of baclofen and ethanol induce more severe alterations in pulmonary tissue compared to baclofen alone. The pathological changes in the lungs reached their maximum by 24 hours, which confirmed by morphometric assessment. Morphological changes in pulmonary tissue alongside with established chemical properties of the two agents can be used to diagnose cases of intoxication either with baclofen alone or in combination with ethanol.

Hierarchical Bayesian pharmacometrics analysis of Baclofen for alcohol use disorder

Alcohol use disorder (AUD), also called alcohol dependence, is a major public health problem, affecting almost of the world’s population. Baclofen, as a selective receptor agonist, has emerged as a promising drug for the treatment of AUD. However, the inter-trial, inter-individual and residual variability in drug concentration over time in a population of patients with AUD is unknown. In this study, we use a hierarchical Bayesian workflow to estimate the parameters of a pharmacokinetic (PK) population model from Baclofen administration to patients with AUD. By monitoring various convergence diagnostics, the probabilistic methodology is first validated on synthetic longitudinal datasets and then applied to infer the PK model parameters based on the clinical data that were retrospectively collected from outpatients treated with oral Baclofen. We show that state-of-the-art advances in automatic Bayesian inference using self-tuning Hamiltonian Monte Carlo (HMC) algorithms provide accurate and decisive predictions on Baclofen plasma concentration at both individual and group levels. Importantly, leveraging the information in prior provides faster computation, better convergence diagnostics, and substantially higher out-of-sample prediction accuracy. Moreover, the root mean squared error as a measure of within-sample predictive accuracy can be misleading for model evaluation, whereas the fully Bayesian information criteria correctly select the true data generating parameters. This study points out the capability of non-parametric Bayesian estimation using adaptive HMC sampling methods for easy and reliable estimation in clinical settings to optimize dosing regimens and efficiently treat AUD.

IMMUNOCHEMICAL ANALYSIS OF BCL-2 AND BAX EXPRESSION IN BRONCHIAL EPITHELIUM IN RATS IN ACUTE BACLOFEN POISONING

Baclofen (also sold under trade names Lioresal, Baclosan) belongs to a group of drugs called antispasmodics. This drug is available in oral and intrathecal forms. Baclofen has a pronounced psychotropic effect and is often a subject to abuse, especially among young people. The aim of the study was to detect apoptosis in the bronchial epithelium in rats. The study was performed on 20 male Wistar rats (weight: 290-350 g., age: 20 weeks). The animals were divided into 4 groups. The group of controls included 5 intact rats, each of three experimental groups included 5 rats treated with baclofen at a dose of 85 mg/kg and euthanized by the displacement of the cervical vertebrae after 3, 4,5, and 24 hours, respectively. In the bronchial epithelium of the controls bax was weakly expressed, which shows a low level of apoptosis. 3 and 4,5 hours after baclofen administration bax was strongly expressed and 24 hours after baclofen administration bax was moderately expressed. In the bronchial epithelium of the controls bcl-2 was weakly expressed; 3 hours after baclofen administration bcl-2 was moderately expressed; 4,5 hours and 24 hours after baclofen administration bcl-2 was strongly expressed. The results from the present study suggest the involvement of apoptosis in the development in the lesion of bronchial epithelium. Furthermore, bax and bcl-2 expression in the regenerating epithelial cells may play a role in the recovery of this lesion. Keywords: baclofen, poisoning, immunohistichemistry (IHC), apoptosis, bcl-2, bax.

THE DYNAMICS OF HISTOMORPHOLOGICAL CHANGES IN ACUTE BACLOFEN POISONING

Aim: to assess the dynamics of histolological changes in the lung under acute baclofen poisoning. Materials and methods: The study was performed on 20 male Wistar rats weighing 200-215 g and aged 20 weeks. The animals were divided into four groups (5 animals in each) – controls, group 1 (baclofen, 3h.), group 2 (baclofen, 4,5 h.) and group 3 (baclofen, 24 h.). Results: The thickness of intraalveolar septi in group 1 (baclofen, 3 h.) was considerably lower than in the group of controls. 4,5 hours after baclofen administration the thickness of intraalveolar septa was significantly higher than in group 1 (baclofen, 3 h.) and in the group of controls. 24 hours after baclofen administration the thickness of intraalveolar septa was significantly higher than in group 1 (baclofen, 3 h.) and in the group of controls. The diameter of the alveoli was considerably higher in all study groups than in the group of controls. The diameter of the alveoli 3 hours after baclofen administration was higher than 4,5 and 24 hours after baclofen administration, but the difference was not significant. Conclusion: In baclofen poisoning, a certain complex of general pathological processes in lungs develops. It includes circulatory disorders, increased vascular permeability, infiltration of intraaveolar septa. The quantitive assessment of the changes can be used to assess the severity of general pathological process in acute baclofen poisonings and to determine the exact time of the poisoning.

Management of Central Hyperthermia in Traumatic Brain Injury Using Baclofen

Central hyperthermia in cases of traumatic brain injury (TBI) is often misdiagnosed or underdiagnosed due to inadequate data. The current diagnosis is one of exclusion. Existing treatment as per guidelines is symptomatic and supportive. Continuous fever after TBI may delay therapy, worsen functional outcome and prolong hospital stay. We discuss a case of a 33-year-old gentleman with TBI with recurring fever spikes during inpatient rehabilitation, non-responsive to antipyretics and antibiotics. A diagnosis of central hyperthermia was reached after eliminating other possible causes. Based on a prior case report, baclofen was tried successfully to manage central hyperthermia. In our patient, a complete cessation of fever was noted within 2 days of initiation of baclofen. To test the effect and minimise the possibility of coincidental dissipation of fever, baclofen was temporarily withdrawn. The corresponding decrease in temperatures and days of baclofen administration followed by recurrence with cessation, are depicted graphically. Once baclofen was resumed, he remained afebrile for the remainder of his inpatient period. This case brings to light the possible efficacy of low-dose baclofen in the management of fever of central origin. It also highlights the importance of considering the possibility of fever of central origin in the subacute stage after TBI. Standardisation of baclofen use with well-designed clinical trials is the proposed next step.

681 Postoperative Muscle Relaxant Use Associated With Increased Risk of Delirium Following Lumbar Spinal Fusion

INTRODUCTION: Muscle relaxants including cyclobenzaprine and baclofen are frequently utilized in pain management following spine surgery as part of enhanced recovery after surgery (ERAS) protocols. These medications are associated with anticholinergic and central nervous system side effects and are used with caution in outpatient treatment for those at high-risk of delirium, especially the elderly. Literature investigating their association with delirium in the postoperative setting has not been described. METHODS: Patients over age 65 undergoing elective posterior lumbar fusion between 2017 and 2021 at the senior author’s institution were retrospectively reviewed. Variables collected included patient demographics as well as whether subjects received postoperative administration of baclofen and/or cyclobenzaprine on postoperative day 1 as part of a multimodal analgesia regimen. Doubly-robust inverse probability weighting (IPW) with cox-regression was used to evaluate the incidence of postoperative delirium between groups. RESULTS: Five-hundred and thirty-one patients were included in the analysis. Incidence of delirium in those who received postoperative muscle relaxants was 17.6% (44/250) compared to 11.4% (32/281) in the control group who did not (p = 0.001). Doubly-robust IPW analysis found patients who received muscle relaxants were at a 2.07 (95% CI: 1.18-3.63) times increased risk of delirium compared to controls (p = 0.015). Postoperative time to delirium onset was similar between groups (3.0 vs 3.1 days; p = 0.916) while the average duration of delirium was significantly longer in those who received postoperative muscle relaxants (2.5 vs 1.6 days; p = 0.008). CONCLUSIONS: Postoperative muscle relaxant use was associated with a higher risk of delirium in elderly adults following lumbar spinal fusion. Although muscle relaxants may assist with postoperative pain control as part of ERAS protocols while minimizing opioid administration, their side effect profile should be considered in patients at high risk of postoperative delirium.

THE QUANTITATIVE CHARACTERISTICS OF HISTOPATHOLOGICAL CHANGES IN LUNGS IN ACUTE BACLOFEN POISONING

The aim of the study was to quantify the changes in the lungs in acute baclofen poisoning in an animal experiment. Materials and Methods: The study was performed on 20 male Wistar rats weighing 290–350 g and aged 20 weeks. The animals were divided into 4 groups. The reference group of controls included 5 intact rats. The animals of three experimental groups included 5 rats each were treated with baclofen at a dose of 85 mg/kg. The tested rats were euthanized by displacement of cervical vertebrae at 3, 4,5 and 24 hours, respectively. Lung tissue samples were examined by light microscopy using a video system at ×400 magnification. Results: The area of the intraalveolar septi 4,5 hours after baclofen administration was significantly higher than in the reference group of controls. 3 and 4,5 hours after baclofen administration an increase in the area of alveloli was observed, but the increase was insignificant and the area of alveoli returned to the initial size by the 24th hour. 3 and 4,5 hours after baclofen administration a slight decrease in the area of pulmonary parenchima was observed, which also returned to its initial size in 24 hours. The total area of pulmonary microvessels 4,5 hours after baclofen administration was significantly higher than in the control group and 3 hours after baclofen administration. The area of pulmonary microvessels 24 hours after baclofen administration was significantly higher than in the group of controls, 3 or 4,5 hours after baclofen administration. The area of edema increased and was significantly higher 24 hours after baclofen administration. In baclofen poisoning, a certain complex of general pathological processes in lungs develops. There is a circulatory disorder, increased vascular permeability, infiltration of intraaveolar septis. Conclusion: The quantitative assessment of the changes can be used to evaluate severity of general pathological process in acute baclofen poisonings and to determine the exact time of the poisonings.

Damage to neurons of the cerebral cortex in acute poisoning with baclofen and its combination with ethanol

BACKGROUND: The number of poisoning with a muscle relaxant baclofen has increased recently. The brain is one of the target organs in baclofen poisoning.&#x0D; AIM: To identify and quantify cerebral cortex neuron damage in baclofen and baclofen ethanol poisoning.&#x0D; MATERIAL AND METHODS: A histological study of rat cerebral cortex was performed. The controls (n = 5) received neither baclofen nor ethanol. Groups 1 and 3 received baclofen (85 mg/kg), whereas groups 2 and 4 received baclofen (85 mg/kg) and ethanol (7 ml/kg). Groups 1 and 3 were euthanized 4 h after the drug administration, whereas groups 2 and 4 were euthanized after 24 h. Histological sections were stained with hematoxylin and eosin and by the Nissl method and examined by light microscopy (400). The number of damaged neurons was calculated. Statistical processing was performed by the nonparametric MannWhitney method.&#x0D; RESULTS: Neurons with reversible and irreversible changes in the controls accounted for 13% and 9%, respectively. At 4 h after baclofen administration, neurons with reversible and irreversible changes accounted for 22% and 21%; 4 h after baclofen and ethanol administration, 24% and 29%; 24 h after baclofen administration, 25% and 37%, respectively. Baclofen and ethanol administration caused an increase in the share of neurons with reversible (27%) and irreversible (41%) changes. The differences between group 3 and the control group were significant, and the difference was significant when group 4 was compared with the control group and group 3.&#x0D; CONCLUSION: Understanding the processes in the brain during baclofen and baclofen ethanol administration will allow the provision of medical care to this category of patients more effectively. The signs of brain neuron damage, along with the results of forensic chemical analysis, can be used to establish the immediate cause of death.

Intrathecal Baclofen for Spasticity: Is There an Effect on Bladder Function? Report of Three Cases and Review of the Literature.

traumatic brain injury (TBI) is very often associated with spasticity. Medical interventions may include medications such as baclofen, a Gamma-Aminobutyric Acid (GABA) -receptor agonist of poor lipid solubility. Intrathecal baclofen (ITB) administration is a contemporary treatment option which minimizes adverse effects in contrast with the oral form of the drug. Regarding low urinary tract dysfunction, TBI, as a suprapontine lesion, results in neurogenic detrusor overactivity. Frequency, urgency and urge incontinence are the predominant signs and symptoms of this condition. Our study aims to report the potential changes in bladder function in patients with spasticity, due to TBI, after the implantation of the baclofen pump and the control of spasticity. We report three cases of TBI whose spasticity responded well to ITB. We evaluated our medical reports regarding bladder function retrospectively, before and after baclofen pump implantation. We compared the data of bladder diaries and urodynamic parameters. Bladder function was improved in all patients. Regarding bladder diaries; the number of incontinence and micturition episodes was decreased and the volume per void was slightly increased. Regarding urodynamic parameters; bladder capacity and reflex volume increased, Pdetmax decreased, PVR was the same and DLPP was slightly decreased. Although the baclofen pump is implanted to treat spasticity, detrusor activity may be also affected. Therefore, patients' urologic profiles should also be reevaluated after ITB. Further prospective studies are required to investigate the effect of ITB on bladder function in the clinical field and also at the basic science level.

Acute baclofen administration promotes functional recovery after spinal cord injury

BACKGROUND CONTEXTTraumatic spinal cord injury (SCI) leads to severe motor and sensory functional impairments that affect personal and social behaviors. Medical advancements have improved supportive therapeutic measures for SCI patients, but no effective neuroregenerative therapeutic options exist to date. Deficits in motor function are the most visible consequence of SCI. However, other complications, as spasticity, produce a significant impact on SCI patient's welfare. Baclofen, a GABA agonist, is the most effective drug for spasticity treatment. Interestingly, emerging data reveals that baclofen can also play a role on neuroprotection and regeneration after SCI. PURPOSEThe goal of this study was to understand the potential of baclofen as a treatment to promote recovery after SCI. STUDY DESIGNWe used a pre-clinical SCI mouse model with the administration of baclofen 1 mg/Kg at different time-points after injury. METHODSBehavior analysis (locomotor and bladder function) were performed during nine weeks of the in vivo experiment. Afterwards, spinal cords were collected and processed for histological and molecular analysis. RESULTSOur data showed that baclofen leads to locomotor improvements in mice when its administered acutely after SCI. Moreover, baclofen administration also led to improved bladder function control in all experimental groups. Interestingly, acute baclofen administration modulates microglia activation state and levels of circulating chemokines and cytokines, suggesting a putative role of baclofen in the modulation of the immune response. CONCLUSIONSAlthough further studies must be performed to understand the mechanisms that underlie the functional improvements produced by baclofen, our data shed light into the pharmacological potential of baclofen to promote recovery after SCI. CLINICAL RELEVANCEOur outcomes revealed that baclofen, a well-known drug used for spasticity management, improves the motor performance after SCI in a pre-clinical animal model. Our data opens new avenues for pharmacological strategies design to promote SCI recovery.

Systemic administration of racemic baclofen reduces both acquisition and maintenance of alcohol consumption in male and female mice.

Baclofen is a GABAB receptor agonist with proposed use as a treatment for alcohol use disorder (AUD). In preclinical studies, racemic baclofen decreases alcohol consumption in both mice and rats; however, there is a significant disparity in the efficacy of the drug across species. We previously demonstrated that baclofen is enantioselective, with the racemic enantiomer successfully reducing binge-like alcohol consumption during Drinking-in-the-Dark (DID) in C57BL/6J (B6) mice, as well as 24-h consumption during two-bottle choice (2BC) preference drinking in replicate 1 High Alcohol Preferring (HAP) mice. Here we extend these findings by investigating the effects of racemic baclofen on the acquisition and maintenance of alcohol consumption, locomotor activity, and saccharin drinking in two different mouse genotypes and drinking paradigms. Adult male and female B6 mice were allowed free access to 20% (v/v) alcohol for 2h daily in a 14-day DID procedure. Adult male and female replicate 2 HAP (HAP2) mice were allowed 24-h access to 10% (v/v) alcohol versus tap water in a 2BC procedure for 14 days. Systemic injections of baclofen (0.0 or 3.0mg/kg) were given 3h into the dark cycle on days 1-5 in alcohol acquisition experiments and days 6-10 in alcohol maintenance experiments. We found that racemic baclofen significantly reduces acquisition of DID and 2BC alcohol drinking in male and female B6 and HAP2 mice, whereas it only significantly reduces the maintenance of DID alcohol intake in B6 mice. Racemic baclofen did not alter home cage locomotor activity but did alter saccharin intake, suggesting it may have nonspecific effects. The current data add to literature suggesting that smaller doses of racemic baclofen may be an effective treatment of AUD. Future work should focus on the longitudinal efficacy of racemic baclofen in high-drinking mouse genotypes to further investigate whether it is effective for those with a genetic predisposition to AUD.

Motor-evoked potentials after focal electrical stimulation predict drug-induced convulsion potentials in rats

Drug-induced convulsions—often caused by the inhibition of GABA receptors and stimulation of glutamate receptors—are difficult to predict in animals. In this study, we attempted to detect the proconvulsant potential using motor-evoked potentials (MEPs) after focal electrical stimulation or upon using a functional observational battery (FOB). Pentylenetetrazole, kainic acid, and pilocarpine were used as convulsion-inducing drugs, and baclofen was used as a negative control. First, each compound was administered to male rats, and the FOB tests were performed. All drugs induced behavioral changes, but no commonality was found. Single electrical stimulation train MEPs were recorded under anesthesia for 60 min (at 5 min intervals) after administration of each drug. A dose-dependent increase in MEPs was observed for each convulsion-inducing drug. Moreover, paired electrical stimulation (conditioned and test) of the cerebral motor cortex was conducted with a 1–15 ms interstimulus interval (ISI), 10 min after administration of the drug. All convulsion-inducing drugs inhibited the short-interval intracortical inhibition (ISI: 3 ms), which may be associated with GABA. Intracortical facilitation (ISI: 11 ms), related to glutamate, was not enhanced by any drug but was inhibited by pilocarpine. Dose correlation was not found in short-interval intracortical inhibition or intracortical facilitation in any drugs. No changes in MEPs were observed after baclofen administration. These results suggest that it is possible to evaluate the convulsion potential and associated mechanisms using MEP, independent of the behavioral changes. The early identification of convulsion potential using this model will lead to more efficient drug development.

Results of Intrathecal Baclofen Treatment in Sixteen Spasticity Patients According to Four Different Measurement Scales:A Retrospective Analysis.

IntroductionSpasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes. It occurs as a result of overstimulation of the stretch reflex and is a component of the upper motor neuron syndrome. Intrathecal Baclofen (ITB) pump administration in patients with a diagnosis of spasticity may be a suitable option for reducing the complaints of the patients and increasing their quality of life. The aim of this study is to analyze clinically and statistically the diagnosis, treatment criteria, and post-treatment results of patients with spasticity who were treated in our clinic.Materials and MethodSixteen patients who were diagnosed with spasticity and placed on an intrathecal Baclofen pump between January 2015 and December 2020 were included in this study. An intrathecal Baclofen trial was first applied to patients who were candidates for the Baclofen pump. The spasticity levels of the patients who decided to have an intrathecal Baclofen pump were scored according to the modified Ashworth scale (MAS) and Penn spasm frequency scale (PSFS). In addition, the scaling of the patients' own conditions according to the visual analogue scale (VAS) and ambulation status according to the modified functional ambulation classification (MFAC) were recorded. All these evaluations were repeated in the preoperative, early postoperative, and follow-up periods.ResultsThe sex distribution of the patients included in the study was equal to eight women and eight men. The age distribution was between 18 and 76. The average age was 40.62 (standard deviation ±17.79). The average preoperative modified Ashworth scale score was 3.73, and the average Penn spasm frequency scale score of the patients was 3.67. The average preoperative modified functional ambulation classification score was 1.87, and the average visual analogue scale score was 6.67. At the end of the second postoperative week, the average modified Ashworth scale score was 1.80 and the average Penn spasm frequency scale score was 1.67. The modified functional ambulation classification score was 2.60 and the visual analogue scale score was 4.58. The average follow-up period of the patients was 64 months. At the end of the follow-up periods, the average late-period modified Ashworth scale score was 1.87, and the Penn spasm frequency scale score was 1.67. The average modified functional ambulation classification score was 3.00, and the average visual analogue scale score was 4.50. Statistically, there was a significant difference between preoperative and postoperative results in both modified Ashworth scale and Penn spasm frequency scale scores (P<0.05). Modified functional ambulation classification preoperative and postoperative comparison results (P<0.05) and visual analogue scale results (P<0.05) were also statistically significant. No significant difference was found between the early postoperative period and the late postoperative period in all measurements (P=1.00).ConclusionIntrathecal Baclofen administration is one of the many treatment options for spasticity. In this way, it has been shown that greater Baclofen efficacy is achieved and its side effects are reduced. It should always be remembered that the process of this treatment is teamwork that requires the participation of more than one specialty branch. Physical therapists, neurologists, pediatricians, and neurosurgeons should be included in this teamwork.