Efficacy and safety of remimazolam tosilate versus propofol in patients undergoing day surgery: a prospective randomized controlled trial.

BACKGROUND: Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery. METHODS: 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded. RESULTS: Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P < 0.001). The three groups had comparable postoperative recovery quality and inflammatory and cognitive state changes (P > 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P < 0.001) and phenylephrine (P = 0.015) were needed in the RT group. Furthermore, serum triglyceride levels were lower (P < 0.001) and injection pain was much less frequent in the RT with or without flumazenil groups compared with the propofol group (5.3% vs. 0% vs. 18.4%). CONCLUSION: RT permits rapid induction and comparable recovery profile compared with propofol in general anesthesia for day surgery, but has a prolonged recovery time without flumazenil. The safety profile of RT was superior to propofol in terms of hypotension and injection pain. TRIAL REGISTRATION: The study was registered at Chinese Clinical Trial Registry http://www.chictr.org.cn/ (Registration date: 19/7/2021; Trial ID: ChiCTR2100048904).

[Efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency]. / Éffektivnost' i bezopasnost' preparata noofen v terapii sindroma khronicheskoi ustalosti u bol'nykh s tserebrovaskuliarnoi nedostatochnost'iu.

AIM: To assess the efficacy and safety of noophen in the treatment of chronic fatigue syndrome in patients with cerebrovascular insufficiency. MATERIAL AND METHODS: Fifty-three patients with cerebrovascular disease, who complain about persistent fatigue, were randomized into two groups. Patients of the main group (n=33) received standard therapy and noophen, patients of the control group (n=20) received only standard therapy. Treatment efficacy was assessed using MFI-20, HADS-A, LSEQ. In addition, cognitive functioning was evaluated using Schulte test. RESULTS AND CONCLUSION: Treatment with noophen resulted in the marked decrease in the total intensity of fatigue measured with MFI-20. The decrease in fatigue intensity by 30-50% was observed in 3/4 of patients of the main group. Noophen reduced all components of fatigue syndrome, including a mental component, and improved motivation. The reduction of the mental fatigue component was combined with the improvement of cognitive functioning assessed with Schulte test. Therefore, the effect of noophen on motivation and mental fatigue component can promote cognitive training in patients with cerebrovascular insufficiency.

[Treatment of trigeminal neuralgia: an update and future prospects of percutaneous techniques]. / Tratamiento de la neuralgia del trigemino: actualizacion y perspectivas futuras de las tecnicas percutaneas.

INTRODUCTION: Trigeminal neuralgia is one of the most severe facial pain syndromes. The annual incidence varies between 4-13% and has a significant effect on patients' quality of life. When the pain cannot be controlled by pharmacological treatment, several different surgical options can be considered. The choice of technique will be based on observational studies and its application depends on the experience of each centre. AIMS: To assess the effectiveness and level of evidence of pharmacological and surgical treatment in trigeminal neuralgia, and to analyse the current role of percutaneous techniques in the treatment of this pathology. DEVELOPMENT: The initial treatment of trigeminal neuralgia is pharmacological and carbamazepine is the only drug with a sufficiently high level of evidence. The percutaneous surgical techniques are effective and easy to apply, but the tendency for relapses to appear means there is a preference for vascular microdecompression. Yet, there are no reports of comparative studies that determine the superiority of a technique with a good level of evidence. The three most commonly used percutaneous techniques, balloon compression, glycerol rhizotomy and thermocoagulation by radiofrequency, were reviewed. This last technique is the one that has undergone the greatest development in recent years, with the emergence of neurophysiological techniques that make it possible to optimise results. CONCLUSIONS: The selection of a surgical technique for use in trigeminal neuralgia does not have much backing from randomised clinical trials. The new procedures in the application of radiofrequency can improve the treatment prospects of this pathology.

TITLE: Tratamiento de la neuralgia del trigemino: actualizacion y perspectivas futuras de las tecnicas percutaneas.Introduccion. La neuralgia del trigemino es uno de los sindromes de dolor facial mas graves. La incidencia anual varia entre el 4-13% y altera de forma significativa la calidad de vida de los afectados. Cuando el dolor no puede controlarse con tratamiento farmacologico, existen diferentes opciones quirurgicas. La seleccion de la tecnica esta basada en estudios observacionales y su aplicacion depende de la experiencia de cada centro. Objetivos. Evaluar la efectividad y el nivel de evidencia del tratamiento farmacologico y quirurgico en la neuralgia del trigemino, y analizar el papel actual de las tecnicas percutaneas en el tratamiento de esta patologia. Desarrollo. El tratamiento inicial de la neuralgia del trigemino es el farmacologico y la carbamacepina es el unico farmaco con suficiente nivel de evidencia. Las tecnicas quirurgicas percutaneas son efectivas y de facil aplicacion, pero la tendencia a la recidiva conduce a la preferencia por la microdescompresion vascular. Sin embargo, no hay estudios comparativos que determinen la superioridad de alguna tecnica con buen nivel de evidencia. Se han revisado las tres tecnicas percutaneas mas utilizadas, la compresion con balon, la rizotomia con glicerol y la termocoagulacion por radiofrecuencia. Esta ultima es la que ha presentado mayor desarrollo en los ultimos años, con la aparicion de tecnicas neurofisiologicas que pueden optimizar los resultados. Conclusiones. La seleccion de una tecnica quirurgica en la neuralgia del trigemino no esta bien apoyada por ensayos clinicos aleatorizados. Los nuevos procedimientos en la aplicacion de la radiofrecuencia pueden mejorar las perspectivas del tratamiento de esta patologia.

SGE-102: a novel therapy for refractory status epilepticus.

Refractory status epilepticus (SE) has a mortality rate of up to 35%. Current treatment protocols for the treatment of SE begin with benzodiazepines and then proceed to conventional anticonvulsants. If seizures continue, SE is considered refractory (RSE) and treatment with anesthetic agents in undertaken. Twenty-four h to 48 h after initiation of anesthesia with midazolam, pentobarbital or thiopental, or propofol, an attempt is made to wean the anesthetic. If this fails and seizures recur, SE is considered highly refractory (HRSE) and repeated attempts are undertaken. No randomized trial data are available to guide the choice of anesthetic agent in either RSE or HRSE status. Medication resistance in established SE is thought to result, in part, from internalization of synaptic γ-aminobutyric acid (GABA) receptors, making them unavailable for modulation. Neurosteroids act on both synaptic and extrasynaptic GABAA receptors, which are not internalized, and are therefore hypothesized to have a role in the treatment of RSE. SGE-102 is a neurosteroid metabolite of progesterone with demonstrated anticonvulsant properties in animal seizure models. A randomized double-blind placebo-controlled adjunctive trial of SGE will include subjects randomized at the time that initial treatment with anesthesia is initiated. Subjects will receive midazolam and either SGE-102 or placebo. Midazolam will be tapered and discontinued between hours 24 and 48. SGE-102 or placebo will be continued through hour 120. The primary end point will be the difference in proportion of subjects from each arm who remain seizure free through hour 120. Secondary end points will include the proportion of subjects who are seizure free at hour 168, 2 days after discontinuation of the experimental agent. The study will be powered to have a 90% chance of detecting a clinically meaningful reduction in seizure recurrence at 120 h. Comprehensive safety and pharmacokinetic data will also be obtained during the course of the trial.

[Chronic postsurgical pain]. / Douleurs chroniques postchirurgicales.

OBJECTIVES: Update reviewing of chronic postsurgical pain. DATA SOURCES: The following review is based on the English and French literature published in PubMed database between January 1998 and 2013. The research articles were made with following keywords alone or in combination: "chronic pain", "surgery", "postsurgical pain". These keywords were combined with "epidemiology", "incidence", "predictive factors" and "prevention". Study selection Publications were deemed relevant if they contained information about CPSP after 8 weeks post surgery. Animal publications were not included. Only randomized controlled studies were taken into consideration for the pharmacological prevention. DATA EXTRACTION: Data extracted were related to epidemiology, impact, predictive factors and prevention of CPSP. DATA SYNTHESIS: Epidemiology of CPSP is more recognized as it is experienced by 10-50% of individuals after classical operations. CPSP can be severe in about 5 to 10% of these patients. CPSP is a major public health problem still rarely diagnosed and treated. Twenty percent of patients consulting in a pain clinic have a CPSP. The frequency of neuropathic pain is important but the difference in the proportion to CPSP falls between 6-68% and depend on the type of surgery. Clinical risk factors and physiopathology of CPSP are subject of wide development. Human studies allowed better understanding of the neurophysiological as well psychological aspect of the development of CPSP. Finally, the possibility of pharmacological prevention of CPSP seems to have increased in the past years. Nevertheless, there are still many questions that need to be answers about the problem. We should clearly define the optimal characteristics of clinical and experimental studies as this will allow the better understanding of the prevention of CPSP. Anesthesiologists play a crucial role in this development. They are involved in all of the stages of the operative care of patients and play a decisive role in the evaluation of the risk, the development of a preventive strategy, and in the early detection and treatment of CPSP.

GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.

Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

Long-term behavioral, electrophysiological, and neurochemical monitoring of the safety of an experimental antiepileptic implant, the muscimol-delivering Subdural Pharmacotherapy Device in monkeys.

OBJECT: The authors evaluated the extent to which the Subdural Pharmacotherapy Device (SPD), chronically implanted over the frontal cortex to perform periodic, localized muscimol-delivery/CSF removal cycles, affects overall behavior, motor performance, electroencephalography (EEG) activity, and blood and CSF neurochemistry in macaque monkeys. METHODS: Two monkeys were used to adjust methodology and 4 monkeys were subjected to comprehensive testing. Prior to surgery, the animals' behavior in a large test chamber was monitored, and the motor skills required to remove food pellets from food ports located on the walls of the chamber were determined. The monkeys underwent implantation of the subdural and extracranial SPD units. The subdural unit, a silicone strip integrating EEG electrodes and fluid-exchange ports, was positioned over the right frontal cortex. The control unit included a battery-powered, microprocessor-regulated dual minipump and radiofrequency module secured to the cranium. After implantation, the SPD automatically performed periodic saline or muscimol (1.0 mM) deliveries at 12-hour intervals, alternating with local CSF removals at 6-hour intervals. The antiepileptic efficacy of this muscimol concentration was verified by demonstrating its ability to prevent focal acetylcholine-induced seizures. During SPD treatment, the monkeys' behavior and motor performance were again monitored, and the power spectrum of their radiofrequency-transmitted EEG recordings was analyzed. Serum and CSF muscimol levels were measured with high-performance liquid chromatography electrochemical detection, and CSF protein levels were measured with turbidimetry. RESULTS: The SPD was well tolerated in all monkeys for up to 11 months. The behavioral study revealed that during both saline and muscimol SPD treatment, the monkeys could achieve the maximum motor performance of 40 food-pellet removals per session, as before surgery. The EEG study showed that local EEG power spectra were not affected by muscimol treatment with SPD. The neurochemical study demonstrated that the administration of 1.0 mM muscimol into the neocortical subarachnoid space led to no detectable levels of this compound in the blood and cisternal CSF, as measured 1-125 minutes after delivery. Total protein levels were within the normal range in the cisternal CSF, but protein levels in the cortical-site CSF were significantly higher than normal: 361 ± 81.6 mg/dl. Abrupt discontinuation of 3-month, periodic, subdural muscimol treatments induced withdrawal seizures, which could be completely prevented by gradually tapering off the subdural muscimol concentration from 1.0 mM to 0.12-0.03 mM over a period of 2 weeks. The monkeys' general health and weight were maintained. Infection occurred only in one monkey 9 months after surgery. CONCLUSIONS: Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.

Intercepting neoplastic progression in lung malignancies via the beta adrenergic (ß-AR) pathway: implications for anti-cancer drug targets.

The understanding of signaling cascades involved in the induction, promotion, and progression of cancer, although advanced in recent years, is still incomplete. Tracing the imbalance of the impaired, physiologically-essential cellular signaling that drives the neoplastic process is a complex issue. This review discusses the role of the regulator of the fight or flight response, the beta-adrenergic signaling cascade, as a mediator of cancer growth and progression in in vitro and in vivo cancer models. We review a series of experiments from our own laboratory and those of others examining the contribution of this signaling network to lung and other human malignancies and thereby identifying potential targets for chemotherapeutic interventions. The stimulation of the ß-adrenergic receptor by lifestyle and environmental factors, as well as a preexisting risk for neoplasm, activates downstream effector molecules (adenylyl cyclase/cAMP/PKA/CREB) concomitant to the transactivation of related pathways (EGFR) that lead to pro-oncogenic signaling; this ß-adrenergic pathway thereby encourages cancer growth by evasion of apoptosis, invasion, angiogenesis, and metastasis. GABAergic signaling acts as an antagonist to the ß-adrenergic cascade by intercepting adenylyl cyclase activation, and thereby neutralizing the pro-oncogenic effects of ß-adrenergic stimulation. The regulation of cancer cell growth by neurobiological signals expands the possibilities for pharmacological interventions in cancer therapy.

20-OH-ecdysone prevents hot flushes in ovariectomized rats.

Hot flushes are due to the lack of estrogens and are the most characteristic climacteric complaints. Hormone replacement therapy was the standard treatment but now its use is limited because of side effects. Need therefore arises to search for non-estrogenic alternatives. The molting hormone 20-beta-hydroxyecdysone (Ecd) is produced by several plants including spinach and has no estrogenic or androgenic properties but enhances GABAergic effects in neurons. Since GABAergic compounds can ameliorate hot flushes, we investigated the effects of Ecd on subcutaneous body temperature of intact and ovariectomized (ovx) rats. The subcutaneous body temperature was recorded at 5-min intervals over a period of 3 hours. Rats were then ovx, and skin temperatures were recorded after an acute intravenous (5 mg) and during subchronic and chronic oral application of Ecd (73 mg/animal/day). For additional control purposes, a group of ovx rats received food containing estradiol-17 ß (E2). Skin temperature in individual ovx animals fluctuated largely with peaks (hot flushes) occurring every 20-40 minutes. Following the i.v. treatment with Ecd, skin temperature dropped by more than 1 °C, an effect much larger than in the controls. One and two weeks later, hot flushes were only seen in ovx controls but not in intact, E2-, or Ecd-treated animals. As a consequence, E2 and Ecd intake significantly (p < 0.05) reduced the mean temperature in ovx rats during the various time points of the study. These results suggest that Ecd is efficient to prevent hot flushes in ovx rats.

GABA-receptor agonist, propofol inhibits invasion of colon carcinoma cells.

Propofol (2,6-diisopropylphenol), one of the most commonly used intravenous anaesthetic agents during cancer resection surgery, has been reported to have the ability of influencing the invasion of human cancer cells. In the present study, using the human colon carcinoma cell line LOVO, we demonstrated that propofol stimulation significantly decreased the expression of MMP-2 and -9 and subsequently decreased the invasive activity of the cancer cells. Because MAPK signaling is one of the key regulators of MMP expression, we further evaluated MAPK signaling after stimulation with propofol. It was found that propofol stimulation inhibited the phosphorylation of MAPKs, including ERK1/2, JNK, and p38. Deactivation of ERK1/2 phosphorylation was sustained for up to 12h, while deactivation of phosphorylation of JNK and p38 returned to the endogenous level by 30 min. It was noteworthy that the ras/raf/MEK/ERK pathway inhibitor PD98059 attenuated the down-regulation of propofol-induced MMP-9 expression of LOVO cells. We also demonstrated that the propofol-induced decrease in invasive ability via ERK1/2 down-regulation was mediated mainly through the GABA-A receptor. These results indicate that propofol stimulation inhibits cancer cell invasion and that the effect is partly due to ERK1/2-dependent down-regulation of MMPs.

Novos sedativos hipnóticos / The newer sedative-hypnotics

Nas últimas décadas houve um esforço para o desenvolvimento de hipnóticos mais seguros e eficazes. Zolpidem, zaleplona, zopiclona, eszopiclona (drogas-z) e indiplona são moduladores do receptor GABA-A, os quais agem de forma seletiva na subunidade α1, exibindo, desta forma, mecanismos similares de ação, embora evidências recentes sugiram que a eszopiclona não seja tão seletiva para a subunidade α1 quanto o zolpidem. Ramelteon e tasimelteon são novos agentes crono-hipnóticos seletivos para os receptores de melatonina MT1 e MT2. Por outro lado, nos últimos anos, o consumo de drogas antidepressivas sedativas tem aumentado significativamente no tratamento da insônia. Como droga experimental, a eplivanserina tem sido testada como um potente agonista inverso do subtipo 5-HT2A da serotonina, com um uso potencial na dificuldade da manutenção do sono. Outro agente farmacológico para o tratamento da insônia é o almorexant, o qual apresenta um novo mecanismo de ação envolvendo antagonismo do sistema hipocretinérgico, desta forma levando à indução do sono. Finalmente, também discutiremos o potencial papel de outras drogas gabaérgicas no tratamento da insônia.

There has been a search for more effective and safe hypnotic drugs in the last decades. Zolpidem, zaleplon, zopiclone, eszopiclone (the z-drugs) and indiplon are GABA-A modulators which bind selectively α1 subunits, thus, exhibiting similar mechanisms of action, although recent evidence suggests that eszopiclone is not as selective for α1 subunit as zolpidem is. Ramelteon and tasimelteon are new chrono-hypnotic agents, selective for melatonin MT1 and MT2 receptors. On the other hand, the consumption of sedative antidepressant drugs is significantly increasing for the treatment of insomnia, in the last years. As an experimental drug, eplivanserin is being tested as a potent antagonist of serotonin 2-A receptors (ASTAR) with a potential use in sleep maintenance difficulty. Another recent pharmacological agent for insomnia is almorexant, which new mechanism of action involves antagonism of hypocretinergic system, thus inducing sleep. Finally we also discuss the potential role of other gabaergic drugs for insomnia.

Persistent non-cancer pain management in the older adult.

Pain is a prevalent symptom affecting as many as 50% of community-dwelling older adults. Pain affects quality of life, functional status, cognition, mood, sleep, and well-being. A multimodal approach to pain management consists of both non-pharmacologic and pharmacologic interventions. Prescribing analgesics is safe and effective in older persons if done judiciously by starting low and titrating slowly while monitoring closely for potential side effects.

Infections related to intrathecal baclofen therapy in children and adults: frequency and risk factors.

OBJECT: The purpose of this study was to determine the frequency of infection and to identify risk factors for infection in connection with the implantation of an intrathecal baclofen (ITB) pump. METHODS: This retrospective study included all pediatric and adult patients who received ITB at Rikshospitalet during the years 1999-2005. A database was created that included the following variables: patient age, sex, weight, diagnosis, surgical procedure performed, presence of a percutaneous endoscopic gastrostomy (PEG) tube, urinary as well as fecal incontinence, anesthetist's classification of patient status (American Society of Anesthesiologists grade), timing of antibiotics administration, surgeon, assisting nurse, and surgical procedure time. Moreover, the mode of intrathecal screening trial (transcutaneous vs subcutaneous catheter insertion) and any complications were registered. The authors differentiated between deep and superficial infection, and they registered the causative agent. RESULTS: A total of 163 patients received ITB; of these, 91 were pediatric patients (median age 10 years), and 72 were adults (median age 44 years). A total of 408 surgical procedures were performed. No infections occurred in direct relation to the screening trials. When a pump was implanted subsequent to a screening trial with transcutaneous catheter insertion, the rate of infection was 9% in the pediatric patients. The corresponding infection rate for pumps implanted after a screening trial with a subcutaneous distal catheter (Albright method) was 12%. This difference was not significant. There was a significantly higher incidence of deep infections following pump implantation in the pediatric group (p = 0.028) than in the adult group. The presence of a PEG tube increased the incidence of infection (p = 0.008) and may be one of the main reasons for a higher frequency of infections in children. When the patient suffered urinary and/or fecal incontinence, there was a higher chance of infection (p = 0.021). The surgical time was significantly longer in the pediatric group than in adults; however, the length of the surgical procedure had no impact on the occurrence of infection. The most common causative agent was Staphylococcus aureus; this microbe was responsible for 69% of deep infections. Also, 69% of deep infections occurred within 1 month after surgery. CONCLUSIONS: The rate of infection is significantly higher in children undergoing ITB pump implantation than it is in adults. Screening trials applying the Albright method fail to reduce the frequency of infection subsequent to pump implantation. The presence of a PEG tube has the greatest significance as a predictor of infection.

GABAA receptors in nucleus accumbens shell mediate the hyperphagia and weight gain following haloperidol treatment in rats.

AIMS: Weight gain is a common outcome of antipsychotics therapy in schizophrenic patients. However, the underlying neuronal mechanisms are unclear. The present study was undertaken to investigate the role of GABA(A) receptors within the framework of nucleus accumbens shell (AcbSh) in haloperidol-induced hyperphagia and body weight gain in sated rats. MAIN METHODS: In acute studies, GABA(A) receptor agonists muscimol, diazepam or antagonist bicuculline were administered by AcbSh route, alone or in combination with haloperidol (intraperitoneal/ip). Immediately after these treatments, preweighed food was offered to the animals at commencement of dark phase. Cumulative food intake was measured at 2 and 6 h post-injection time-points. Furthermore, effects of subacute haloperidol treatment, alone or in combination with muscimol, diazepam or bicuculline, on food intake and body weight were investigated. KEY FINDINGS: While acute treatment with haloperidol, muscimol or diazepam dose dependently stimulated the food intake, bicuculline suppressed the same. Prior administration of muscimol (20 ng/rat, intra-AcbSh) and diazepam (5 microg/rat, intra-AcbSh) significantly potentiated, whereas bicuculline (40 ng/rat, intra-AcbSh) negated the hyperphagic effect of acute haloperidol (0.005 or 0.01 mg/kg/rat, ip). Subacute administration of haloperidol (0.01 mg/kg/rat/day, ip) for 15 days produced increase in food intake and body weight. Although, concomitant administration of muscimol (20 ng/rat/day, intra-AcbSh) or diazepam (5 microg/rat/day, intra-AcbSh) markedly enhanced, bicuculline (40 ng/rat/day, intra-AcbSh) prevented the subacute haloperidol-induced hyperphagia and weight gain. SIGNIFICANCE: The results of present study suggest that increased food intake and body weight following haloperidol treatment in rats, may be mediated via AcbSh GABA(A) receptors.

Intrathecal baclofen therapy for neurological disorders: a sound knowledge base but many challenges remain.

Continuous infusion of intrathecal baclofen (ITB) via a subcutaneously implanted pump has developed over the last 20 years as a powerful tool in the management of spasticity in various adult and paediatric neurological conditions. Acting more focally on spinal GABA receptors, ITB causes fewer systemic side effects than orally administered baclofen. The result is facilitation of daily caring, and symptomatic relief from painful spasm. With increasing experience of ITB use, novel applications and indications are emerging. These include the management of dystonia and chronic neuropathic pain. However, despite some recent authoritative reviews, there is still uncertainty about optimal use and evaluation of this therapy. Many challenges remain. How can efficacy of therapy best be assessed both at primary testing and after pump implantation? What is the precise mechanism of baclofen action in different brain and spinal disorders associated with spasticity and dystonia? Does placement of the spinal catheter tip influence efficacy? What is the cranio-caudal gradient of CSF baclofen levels at given pump flow rates and does this matter? What CSF baclofen levels are efficacious in various conditions? Why do some patients with the same primary condition require large differences in ITB dose? What are the relative merits of programmable versus constant infusion rate pumps? What are the implications of setting up multidisciplinary teams for long term follow up? This review evaluates these questions and highlights other areas for further investigation.

Additive neuroprotection of GABA A and GABA B receptor agonists in cerebral ischemic injury via PI-3K/Akt pathway inhibiting the ASK1-JNK cascade.

Co-activation of GABA A and GABA B receptors results in neuroprotection during in vitro ischemia. However, it is unclear whether this mode of action is responsible for its neuroprotective effects in animal models of ischemia in vivo, and the precise mechanisms are also unknown. This study compared the neuroprotective efficacies of muscimol, a GABA A receptor agonist, and a GABA B receptor agonist baclofen in rat brain ischemia. The additive neuroprotection could be obtained in the hippocampal CA1 pyramidal cells prominently when muscimol and baclofen were co-applied. In particular, our study showed that co-activation of GABA A and GABA B receptors could strongly increase Akt activation and inhibit ASK1 activation by phosphorylation of serine 83 of ASK1. PI-3K inhibitor LY294002 reversed the increasing Akt activation and ASK1 (S83) phosphorylation. Moreover, MKK4/MKK7-JNK signaling activation was inhibited during ischemia/reperfusion (I/R) by co-treatment of muscimol with baclofen. JNK substrate, Bcl-2 and c-jun phosphorylation were also attenuated. Our results indicated that co-activation of GABA A receptor and GABA B receptor exerted neuroprotective effect via PI-3K/Akt pathway, which could inhibit the ASK1-c-Jun N-terminal protein kinase (JNK) cascade.