Motor Side Effects Research Articles

Negative Symptoms Management in Schizophrenia

Clinicians often overlook the presence of negative symptoms in treating schizophrenia. The burden borne by patients, families, and society is quite heavy. These symptoms not only have high costs, but also affect the functional prognosis in independence and socializing. There is a need for adequate therapy of negative symptoms of schizophrenia which can improve the patient’s quality of life. Negative symptoms are characterized by blunt affect, alogia, avolition, anhedonia, and asociality. Knowing the difference between the primary and secondary types of negative symptoms of schizophrenia can bring big impact on the therapy. The primary type of negative symptoms is an integral part of schizophrenia, while the secondary one is caused by external conditions of schizophrenia, such as depression. Management of negative symptoms of schizophrenia includes psychopharmaceuticals and non-psychopharmaceuticals. Atypical antipsychotics remain the drug of choice due to their affinity not only to D2 receptor, but also to serotonin, glutamate, histamine, α adrenergic, and muscarinic receptors. In addition, the higher dissociation rate of D2 receptors of atypical antipsychotics allow for minimal motor side effect. Cariprazine has been approved by The Food and Drug Associaton and The European Medicines Agency to treat primary and persistent negative symptoms due to its minimal side effect. Non-pharmacological therapies such as Cognitive Behavioral Therapy (CBT) and Motivation and Engagement Training (MOVE) can optimize the treatment efficacy. These therapies will enhance the cognitive improvement, adaptation, and social skill development of the patients.

A Comparative Study of Clonidine and Dexmedetomidine with 0.5% Levobupivacaine in ultrasound-guided Axillary Brachial Plexus Block for Upper Limb Surgeries

Background: Clonidine and Dexmedetomidine as an additive to Levobupivacaine in ultrasound-guided axillary brachial plexus block are not studied well. Hence, this study was designed to compare the efficacy of the Clonidine and Dexmedetomidine, used as an adjunct to Levobupivacaine in ultrasound-guided axillary brachial plexus block in upper limb elective surgery.Materials and Methods: Eighty patients of the American Society of Anesthesiologists Grade I/II undergoing upper limb elective surgery were divided into two equal age/gender-matched groups. Group-LD received ultrasound-guided axillary brachial plexus block using injection 0.5% Levobupivacaine 20 ml+dexmedetomidine (1 μg/Kg), and group LC received ultrasound-guided axillary brachial plexus block using injection 0.5% Levobupivacaine 20 ml + Clonidine (1.5 μg/Kg). The onset and duration of sensory and motor block, hemodynamics, and side effects were recorded. Results: The time for onset of sensory block and motor block in group LD was significantly faster than group LC (4.53±1.07 and 7.88±1.29 min vs. 5.90±0.81 and 8.85±1.81min, p<0.0001). The duration of motor block in group LD was significantly longer than group LC (Sensory and motor block: 662.50 ± 50.95 and 625.50 ± 51.95min, vs 567.75 ± 62.33 and 560.62 ± 67.19 min. p< 0.0001). The sedation score was highly significant at 30 min (p<0.0001) and was significant at 60 min (p<0.05), postoperatively. Conclusion: The addition of Dexmedetomidine (1μg/Kg) as an adjuvant to Levobupivacaine (0.5%) for upper limb surgeries by axillary brachial plexus block had provided the rapid onset of sensory block and motor block and enhanced duration of sensory and motor block with arousable sedation without any adverse effects compared to clonidine (1.5μg/Kg).

Multi-objective data-driven optimization for improving deep brain stimulation in Parkinson’s disease

Objective. Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease (PD) but its success depends on a time-consuming process of trial-and-error to identify the optimal stimulation settings for each individual patient. Data-driven optimization algorithms have been proposed to efficiently find the stimulation setting that maximizes a quantitative biomarker of symptom relief. However, these algorithms cannot efficiently take into account stimulation settings that may control symptoms but also cause side effects. Here we demonstrate how multi-objective data-driven optimization can be used to find the optimal trade-off between maximizing symptom relief and minimizing side effects. Approach. Cortical and motor evoked potential data collected from PD patients during intraoperative stimulation of the subthalamic nucleus were used to construct a framework for designing and prototyping data-driven multi-objective optimization algorithms. Using this framework, we explored how these techniques can be applied clinically, and characterized the design features critical for solving this optimization problem. Our two optimization objectives were to maximize cortical evoked potentials, a putative biomarker of therapeutic benefit, and to minimize motor potentials, a biomarker of motor side effects. Main Results. Using this in silico design framework, we demonstrated how the optimal trade-off between two objectives can substantially reduce the stimulation parameter space by 61 ± 19%. The best algorithm for identifying the optimal trade-off between the two objectives was a Bayesian optimization approach with an area under the receiver operating characteristic curve of up to 0.94 ± 0.02, which was possible with the use of a surrogate model and a well-tuned acquisition function to efficiently select which stimulation settings to sample. Significance. These findings show that multi-objective optimization is a promising approach for identifying the optimal trade-off between symptom relief and side effects in DBS. Moreover, these approaches can be readily extended to newly discovered biomarkers, adapted to DBS for disorders beyond PD, and can scale with the development of more complex DBS devices.

Therapeutic management of obesity induced by antipsychotic drugs

The introduction of second-generation antipsychotic drugs (SGAs) has contributed to a more effective treatment of mental diseases and patients’ improved quality of life. Their particular superiority to first-generation antipsychotics (FGAs) includes better outcomes in treating "negative" symptoms, impact on mood and lower risk of motor side effects (1). Their increasing use, going beyond psychotic disorders, has highlighted the problem of medication-induced weight gain and obesity in patients. Obesity leads to increased cardiovascular morbidity and mortality, decreased quality of life, and poor adherence. This narrative review discusses the impact of various SGA on weight gain and related adherence to medication, as well as available pharmacological and non-pharmacological interventions to counteract these effects. Most SGA commonly cause weight gain but the risk appears to be highest with olanzapine and clozapine. The best preventative strategies are tailored antipsychotic drugs and close monitoring of body weight and other metabolic parameters. Switching from one SGA to another less likely to cause metabolic disturbances is an option but carries a risk of relapse. Non-pharmacological interventions in the form of dietary counseling, exercise programs, cognitive and behavioral strategies appear to be equally effective in both individual and group forms. Both non-pharmacological prophylaxis and intervention strategies showed little effect on weight. Of the additional weight loss medications, metformin appears to be the compound with the best documented efficacy. There is no evidence of benefit from the routine prescription of additional weight loss medications. Drawing conclusions is hampered by the high heterogeneity of research methodology, as well as the participation of other factors such as lifestyle, genetic and disease-related factors.

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Adenosine and Kynurenic Acid Interactions: Possible Relevance for Schizophrenia Treatment?

Intrathecal chloroprocaine or hyperbaric prilocaine for ambulatory knee surgery? A prospective randomized study

PurposeThe aim of this study was to compare intrathecal 1% chloroprocaine with 2% hyperbaric prilocaine in the setting of ambulatory knee arthroscopy. We hypothesized that complete resolution of the sensory block was faster with chloroprocaine.MethodsEighty patients scheduled for knee arthroscopy were included in this prospective randomized double-blind study. Spinal anesthesia was performed with either chloroprocaine (50 mg) or hyperbaric prilocaine (50 mg). Characteristics of sensory and motor blocks and side effects were recorded.ResultsMean time to full sensory block recovery was shorter with chloroprocaine (169 (56.1) min vs 248 (59.4)). The characteristics of the sensory blocks were similar at the T12 dermatome level between the two groups. Differences appeared at T10: the percentage of patients with a sensory block was higher, onset quicker and duration longer with hyperbaric prilocaine. The number of patients with a sensory block at T4 dermatome level in both groups was minimal. Times to full motor recovery were identical in both groups (85 (70–99) vs 86 (76–111) min). Time to spontaneous voiding was shorter with chloroprocaine (203 (57.6) min vs 287.3 (47.2) min). Incidence of side effects was low in both groups.ConclusionsWhen considering the characteristics of the sensory block, the use of chloroprocaine may allow an earlier discharge of patients. Cephalic extension was to a higher dermatomal level and the sensory block at T10 level was of prolonged duration with hyperbaric prilocaine, suggesting that the choice between the two drugs should also be performed based on the level of the sensory block requested by the surgery.This study is registered in the US National Clinical Trials Registry, registration number: NCT030389, the first of February 2017, Retrospectively registered.

A COMPARATIVE STUDY OF INTRATHECAL BUPIVACAINEHEAVY (0.5%) WITH BUPIVACAINE HEAVY (0.5%) PLUS DEXMEDETOMIDINE FOR LOWER ABDOMINAL SURGERIES

Introduction: Several adjuncts like adrenaline, opioids and alpha-2 adrenergic agonists are being used with local anaesthetics intrathecally for prolongation of intra-operative and post-operative analgesia and to reduce the side-effects of high doses of local anaesthetics.&#x0D; Aim: The present study was done to evaluate the onset and duration of sensory and motor block, hemodynamic effects, post-operative analgesia and adverse effects of Dexmedetomidine given intrathecally with hyperbaric 0.5% Bupivacaine.&#x0D; Materials and methods: Sixty inpatients of ASA class I and II scheduled for various lower abdominal surgeries under Sub-Arachnoid Block were randomly divided into two groups of 30 each namely C (Control), D(Dexmedetomidine) . All received 12.5mg hyperbaric bupivacaine plus 0.5 ml Normal Saline in Group C (Control),10µg Dexmedetomidine (diluted in preservative free Normal saline of 0.5ml) in Group D(Dexmedetomidine) . The onset time to reach peak sensory and motor level, the regression time for sensory and motor block, hemodynamic changes and side-effects were noted.&#x0D; Results: The duration of sensory and motor block, rescue analgesia was significantly prolonged in Dexmedetomidine group when compared to that of Control group.&#x0D; Conclusion: Dexmedetomidine 10 µg seems to be a better neuraxial adjuvant to hyperbaric Bupivacaine.&#x0D; Keywords: Bupivacaine; Dexmedetomidine; intrathecal.

Effects of pedunculopontine nucleus cholinergic lesion on gait and dyskinesia in hemiparkinsonian rats.

Pedunculopontine nucleus (PPN) cholinergic neurons are implicated in freezing of gait in Parkinson's disease (PD) and motor stereotypy in normal animals, but the causal role of these neurons on specific gait parameters and treatment-induced dyskinesia remains speculative. Therefore, we examined whether selective cholinergic lesion of the rostral PPN affects PD motor and gait deficits, L-DOPA-induced dyskinesia and motor improvement, and DA-agonist-induced dyskinesia. Sprague-Dawley rats were assigned to one unilaterally lesioned group: Sham lesion, PPN cholinergic lesion with diphtheria urotensin II fusion toxin, medial forebrain bundle dopamine lesion with 6-hydroxydopamine, or dual acetylcholine and dopamine lesion. We used gait analysis and forepaw adjusting steps to examine PD gait and motor deficits. Forepaw adjusting steps were also used to assess motor improvement with L-DOPA treatment. The abnormal involuntary movements scale measured L-DOPA and dopamine D1- and D2-receptor agonist-induced dyskinesia. Lesions, verified via tyrosine hydroxylase and choline acetyltransferase immunohistochemistry reduced an average of 95% of nigral dopamine neurons and 80% of PPN cholinergic neurons, respectively. Rats receiving acetylcholine and dual lesion demonstrated enhanced freezing, and acetylcholine lesioned rats exhibited increased print area and stand index. Dopamine and dual lesion produced similar forepaw adjusting steps task on and off L-DOPA. Relative to DA lesioned rats, dual lesioned rats displayed reduced L-DOPA and DA agonist-induced dyskinesia at specific time points. Our results indicate that PPN cholinergic neurons affect gait parameters related to postural stability. Therefore, therapeutically targeting PPN cholinergic neurons could reduce intractable postural instability in PD without affecting motor benefits or side effects of L-DOPA treatment.

Dexmedetomidine infusion on subarachnoid block with bupivacaine in inguinal herniorrhaphies - A prospective study

Background: Dexmedetomidine (D) is alpha-2 agonist that acts as an anaesthetic and analgesic substitute. The goal of this study was to see how intravenous (I.V.) dexmedetomidine affected the length of sensory and motor block, postoperative analgesia, sedation degree, and side effects. Aims: To assess the effect of Dexmedetomidine infusion on the duration of analgesia with spinal Bupivacaine for adult patients undergoing herniorrhaphy and to assess side effects. Materials and methods: Prospective study was done under the for a period of 11 months. In 80 adults aged 20 to 60 years scheduled for herniorrhaphies were allocated into two study groups, named B and BD using computer generated randomization. The enrolled patients were divided into 2 groups each 40 patients to receive either 0.5 µg/kg dexmedetomidine intravenous bolus over 10 min (Group BD) or saline infusion (Group B) prior to subarachnoid block with 0.5% hyperbaric bupivacaine 12.5 mg Results: Numerical pain rating scale scores were significantly lower in group BD. Total analgesic requirement was significantly less in group BD. Time to request for first analgesic dose was longer in group BD as compared to group B. The duration of analgesia was longest in patients received intravenous dexmedetomidine along with spinal bupivacaine. Hemodynamic parameters and incidence of side effects were similar in both the groups. Conclusion: Premedication with single dose of intravenous dexmedetomidine 0.5 µg/kg prior to subarachnoid blockade with 0.5% hyperbaric bupivacaine hastens the onset and increases duration of sensory and motor block, with maintenance of stable hemodynamics and arousable sedation in Inguinal Herniorrhaphies.

Agmatine requires GluN2B-containing NMDA receptors to inhibit the development of neuropathic pain.

A decarboxylated form of L-arginine, agmatine, preferentially antagonizes NMDArs containing Glun2B subunits within the spinal cord and lacks motor side effects commonly associated with non-subunit-selective NMDAr antagonism, namely sedation and motor impairment. Spinally delivered agmatine has been previously shown to reduce the development of tactile hypersensitivity arising from spinal nerve ligation. The present study interrogated the dependence of agmatine’s alleviation of neuropathic pain (spared nerve injury (SNI) model) on GluN2B-containing NMDArs. SNI-induced hypersensitivity was induced in mice with significant reduction of levels of spinal GluN2B subunit of the NMDAr and their floxed controls. Agmatine reduced development of SNI-induced tactile hypersensitivity in controls but had no effect in subjects with reduced levels of GluN2B subunits. Ifenprodil, a known GluN2B-subunit-selective antagonist, similarly reduced tactile hypersensitivity in controls but not in the GluN2B-deficient mice. In contrast, MK-801, an NMDA receptor channel blocker, reduced hypersensitivity in both control and GluN2B-deficient mice, consistent with a pharmacological pattern expected from a NMDAr antagonist that does not have preference for GluN2B subtypes. Additionally, we observed that spinally delivered agmatine, ifenprodil and MK-801 inhibited nociceptive behaviors following intrathecal delivery of NMDA in control mice. By contrast, in GluN2B-deficient mice, MK-801 reduced NMDA-evoked nociceptive behaviors, but agmatine had a blunted effect and ifenprodil had no effect. These results demonstrate that agmatine requires the GluN2B subunit of the NMDA receptor for inhibitory pharmacological actions in pre-clinical models of NMDA receptor-dependent hypersensitivity.

Effects of JL13, a pyridobenzoxazepine compound, in dopaminergic and glutamatergic models of antipsychotic activity.

The pyridobenzoxazepine compound, 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13), has been developed as a potential antipsychotic drug. We tested the hypothesis that JL13 is efficacious in both dopaminergic and glutamatergic animal models of schizophrenia. We investigated JL13 for its efficacy to prevent cocaine- and ketamine-induced hyperlocomotion and MK-801-induced deficits in prepulse inhibition (PPI) of the startle reflex. Male Swiss mice received injections of JL13 (0.1-10 mg/kg) and were tested in the open field for basal locomotion. In separate experiments, the animals received injections of JL13 (0.1-3 mg/kg) followed by cocaine (10 mg/kg), ketamine (60 mg/kg), or MK-801 (0.5 mg/kg) and were tested in the open field for hyperlocomotion. In addition, it was also tested if JL13 prevented MK-801-induced disruption of PPI. Only the highest dose of JL13 impaired spontaneous locomotion, suggesting its favorable profile regarding motor side effects. At doses that did not impair basal motor activity, JL13 prevented cocaine-, ketamine-, and MK-801-induced hyperlocomotion. Moreover, JL13 prevented MK-801-induced disruption of PPI. Extending previous findings, this study shows that JL13 exerts antipsychotic-like activity in both dopaminergic and glutamatergic models. This compound has a favorable pharmacological profile, similar to second-generation antipsychotics.

Continuous versus extended antipsychotic dosing in schizophrenia: Less is more

Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects.

A safety evaluation of aripiprazole in the treatment of schizophrenia

ABSTRACT Introduction Aripiprazole is a third generation antipsychotic approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia. Aripiprazole is available as oral and long-acting injectable (LAI) depot formulations, with a unique mechanism of action comprising partial D2 and serotonin 5-HT1A agonism and antagonism at serotonin 5-HT2A receptors. Areas covered We review short-and-long-term clinical trials, meta-analyses of clinical trials and product information pertaining to the safety and efficacy of aripiprazole in adults with schizophrenia. Formulations of aripiprazole reviewed include oral aripiprazole, Aripiprazole monohydrate LAI (Abilify Maintena©) and Aripiprazole lauroxil LAI (Aristada©). Clinical studies and product information were collected from PubMed, Psychinfo, Embase, and other web sources. Expert opinion Aripiprazole is a generally well-tolerated third-generation antipsychotic with low rates of motor side effects and metabolic adverse effects that occur commonly with several alternative antipsychotics. Akathisia and tremor appear to occur at higher rates with aripiprazole compared to placebo but are still generally uncommon with incidences of 10–11% or less. Uniquely, aripiprazole treatment is associated with reduced serum prolactin levels and QTc interval. A variety of LAI options with dosing intervals as infrequent as every 8 weeks provide a compelling reason to select aripiprazole in patients with limited oral treatment adherence.

The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson's Disease.

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.

The mammalian target of rapamycin (mTOR) kinase mediates haloperidol-induced cataleptic behavior

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.

Premorbid Social Functioning and Affective Symptoms Predict Subjective Outcome Among Outpatients With Schizophrenia.

Improving the subjective outcome of patients is an important target in the treatment of schizophrenia. Accordingly, the aim of the present study was to examine the association of factors deemed relevant in this context, i.e., premorbid functioning, residual symptoms, and side effects of antipsychotic medication, with subjective outcome. To this end, 70 clinically stable outpatients with schizophrenia were included into a cross-sectional study. Premorbid functioning, psychopathology, and side effects were assessed by using the Premorbid Adjustment Scale, the Positive and Negative Syndrome Scale, and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale, respectively. Subjective outcome was measured in terms of life satisfaction (Life Satisfaction Questionnaire), self-esteem (Index of Self-Esteem), and needs for care (Berliner Bedürfnisinventar). Both premorbid social functioning and affective symptoms predicted life satisfaction, self-esteem, and patients’ basic needs, whereas positive and negative symptoms predicted needs in the health, social, and functional domains. Concerning side effects, parkinsonism and akathisia showed a significant negative correlation with self-esteem. These findings highlight the complex nature of subjective outcome in patients suffering from schizophrenia. Evidently, premorbid social functioning plays a prominent role in the experienced subjective outcome during the course of the illness. Furthermore, these preliminary findings underscore that constant efforts are essential to treat residual symptoms of the disorder and to avoid extrapyramidal motor side effects of antipsychotic medication. Longitudinal studies are needed to investigate this latter point in more detail.

Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects.

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.

Metoclopramide-Induced Neuroleptic Malignant Syndrome: A Review Study

Context: Neuroleptic malignant syndrome (NMS) has been introduced as a rare but lethal and idiosyncratic reaction to neuroleptics/antipsychotics. The most obvious risk of this syndrome is the use of neuroleptics, especially high-potency ones. Metoclopramide is also known as an anti-nausea medication administered before surgery to manage digestive problems. Evidence Acquisition: Formerly, it had been assumed that metoclopramide was a type of chlorobenzamide that was not in the phenothiazine group but free of extrapyramidal side effects (EPSs). The sequential reports of complications indicate that metoclopramide can cause EPSs and drug-induced motor side effects. A total number of 5044 articles were obtained after the initial search. Then, two researchers independently screened out their titles, and abstracts and 20 articles were finally selected based on the inclusion criteria. Results: Of the 20 articles reporting metoclopramide-induced NMS, treatments had been successful in 16 (80%) cases, but it had led to death in four (20%) patients. There were 11 and 8 male and female patients, respectively, and gender was not mentioned for a patient in one article. The age range of the patients was from six months to 84 years, and the mean age was 50.92 years. Conclusions: Although NMS following metoclopramide intake is reported very rarely, it should be considered for any psychiatric symptoms with unexpected mental changes, muscle rigidity, and fever after being treated with metoclopramide. The neuroleptic malignant syndrome can occur following multiple doses or just one dose of metoclopramide. Also, metoclopramide use in patients affected with kidney failure is accompanied by a higher risk of NMS. A previous history of NMS, a recent episode of catatonia, and severe agitation are all taken into account as risk factors in this domain.

Spinal Anesthesia with a Low Dose of Hyperbaric Bupivacaine plus Fentanyl versus Hyperbaric Bupivacaine for Transurethral Resection of Prostate surgery: Hemodynamic Effects, Duration of Analgesia and Motor Block

Background: Spinal anesthesia is the most prevalent anesthetic method used for transurethral resection of the prostate (TURP) surgery. Lower motor block and fewer side effects can be achieved by lower doses of anesthesia. Aim: The present study aimed to compare the effects of Spinal anesthesia with a low dose of hyperbaric bupivacaine plus fentanyl with hyperbaric bupivacaine for TURP surgery on hemodynamic effects, duration of analgesia, and Motor block. Method: This randomized-controlled study was conducted on 62 patients undergoing TURP surgery within 2017-18. BF group received 0.5% hyperbaric bupivacaine(1mg) 0.2 ml+fentanyl (20µg) 0.4 ml+5% dextrose 1.4ml, while B group received 0.5% hyperbaric bupivacaine (10mg)2ml. Bromage scale and Visual Analog Scale of pain and Nausea were used. The obtained data were analyzed in SPSS software version (20). Results: Groups were homogenous in terms of demographic characteristics. The time to reach the sensory level of T10 was significantly longer in the BF group, compared to the B group (P<0.001). The motor block score was less in the BF group than the B group. The mean total recovery time of the sensory block to L5 in the BF group was significantly lower than that of the BF group (P<0.001). The mean score of nausea severity during surgery was significantly lower in the BF group, compared to the B group (P=0.02). The hemodynamic stability was higher in the BF group. Implications for Practice: A combination of 1mg bupivacaine with 20μg fentanyl could be used for anesthesia in TURP surgery as an effective method to provide sufficient analgesic effects, as well as lower motor block and side effects.

Les psychoses épileptiques interictales

Interictal psychosis (IIP) refers to psychosis that occurs in clear consciousness in persons with epilepsy (PWE) with temporal onset not during or immediately following a seizure. The pooled prevalence estimate of psychosis in PWE is 5.6%. PWE and schizophrenia have very high mortality, and more than one in four persons with both disorders die between the age of 25 and 50years. IIP can manifest in brief or chronic forms. The chronic forms of IIP may closely resemble schizophrenia. However, some authors have described the typical presence of persecutory and religious delusions, sudden mood swings and the preservation of affect, as well as rarity of negative symptoms and catatonic states, but these differences remain controversial. Typically, IIP starts after many years of active temporal lobe epilepsy. Several epilepsy-related variables are considered pathogenically relevant in IIP including epilepsy type and seizure characteristics. Risk factors for developing IIP are family history of psychosis, learning disability, early age of onset of epilepsy, unilateral or bilateral hippocampal sclerosis, history of status epilepticus, history of febrile seizures, and poorly controlled temporal lobe epilepsy. In patients with epilepsy and psychosis, structural imaging studies have shown several relevant changes leading to conflicting findings. Altered neuronal plasticity and excitability have been described in epilepsy and psychotic disorders. Neuropathological data suggest that IIP are not the result of classic epileptic pathology of the temporal lobe. Forced normalization (FN) and alternating psychosis refer to patients with poorly controlled epilepsy (focal or generalized) who have had psychotic episodes associated with remission of their seizures and disappearance of epileptiform activity on their EEGs. FN mainly occurs in temporal lobe epilepsy when patients have frequent seizures that are abruptly terminated triggered by an antiepileptic drug, vagus nerve stimulation or epilepsy surgery. Treatment is based on withdrawal of the responsible drug, and by transient use of antipsychotics for acute symptomatic control on a case-by-case basis. FN is an entity whose pathophysiology remains uncertain. Antiepileptic drugs (AEDs) may sometimes induce psychotic symptoms and psychosis could be a direct effect of the AEDs. IIP has been reported more frequently following the initiation of zonisamide, topiramate, and levetiracetam when compared with other antiepileptic drugs. However, AEDs do not appear to be the only determinant of IIP. The management of IIP requires a multidisciplinary approach with early involvement of a liaison psychiatrist associated with a neurologist. IIP are underdiagnosed and mistreated. Existing recommendations are extrapolated from those established for the treatment of schizophrenia with some additional guidance from expert opinions. A two-step procedure, not necessarily consecutive, is suggested. The first step requires reevaluation of the antiepileptic treatment. The second step requires initiation of atypical neuroleptics. Antipsychotic drugs should be selected with consideration of the balance between pharmacological profiles, efficacy, and adverse effects. Regarding pharmacokinetic interactions, AEDs with inducing properties reduce the blood levels of all antipsychotics. It is important to consider implications of combining neuroleptics and AEDs with a similar spectrum of side effects. Regarding the duration of treatment, IIP episodes are more likely to be recurrent than in primary schizophrenia. In practice, atypical neuroleptics with few motor side effects such as risperidone can be used as first choice, given the low propensity for drug–drug interactions and the low seizure risk, with the added suggestion to start low and go slow. Clozapine could be prescribed in selected cases.