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International Journal of Emergency... Jan 2024Black widows, one of the few spiders that can sting humans with poison, are members of the spider genus Latrodectus and are well-known for the extraordinary potency of...
Black widows, one of the few spiders that can sting humans with poison, are members of the spider genus Latrodectus and are well-known for the extraordinary potency of their neurotoxic venom. Latrodectism, a symptom marked by excruciating muscular pain, stomach pain, and diaphoresis after envenomation, is very typical. We described a black widow envenomation case that produced a significant reaction, including diaphoresis and excruciating pain throughout the left thigh that later spread to the lower leg, lower back, belly, and chest. Because of the patient's description of the spider that bit him and his typical clinical state, it was assumed that Latrodectus envenomation was the cause of his symptoms. The patient received 3 days of observation in the ED while receiving opioid analgesic pain management and muscle relaxant treatment with diazepam. The patient's pain and symptoms were satisfactorily managed, and he was sent home. This case report will help further research be done in the area where it was reported to see if there are cases with similar presentations misdiagnosed as other illnesses. Finally, immediate pain relief is the most critical goal for all patients.
PubMed: 38166617
DOI: 10.1186/s12245-023-00576-z -
Nature Structural & Molecular Biology Dec 2023α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression...
α5 subunit-containing γ-aminobutyric acid type A (GABA) receptors represent a promising drug target for neurological and neuropsychiatric disorders. Altered expression and function contributes to neurodevelopmental disorders such as Dup15q and Angelman syndromes, developmental epilepsy and autism. Effective drug action without side effects is dependent on both α5-subtype selectivity and the strength of the positive or negative allosteric modulation (PAM or NAM). Here we solve structures of drugs bound to the α5 subunit. These define the molecular basis of binding and α5 selectivity of the β-carboline, methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), type II benzodiazepine NAMs, and a series of isoxazole NAMs and PAMs. For the isoxazole series, each molecule appears as an 'upper' and 'lower' moiety in the pocket. Structural data and radioligand binding data reveal a positional displacement of the upper moiety containing the isoxazole between the NAMs and PAMs. Using a hybrid molecule we directly measure the functional contribution of the upper moiety to NAM versus PAM activity. Overall, these structures provide a framework by which to understand distinct modulator binding modes and their basis of α5-subtype selectivity, appreciate structure-activity relationships, and empower future structure-based drug design campaigns.
Topics: Receptors, GABA-A; gamma-Aminobutyric Acid; Isoxazoles
PubMed: 37903907
DOI: 10.1038/s41594-023-01133-1 -
PloS One 2023Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous...
BACKGROUND
Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants.
MATERIALS AND METHODS
The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ-30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001.
RESULTS
After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs.
CONCLUSIONS
PDE5i altered the ECoG recordings in the rats' motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.
Topics: Animals; Male; Rats; Anticonvulsants; Diazepam; Pentylenetetrazole; Phenobarbital; Phosphodiesterase 5 Inhibitors; Rats, Wistar; Seizures; Sildenafil Citrate; Tadalafil
PubMed: 38033148
DOI: 10.1371/journal.pone.0294754 -
Epilepsy Research Sep 2023Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Intravenous phenobarbital is frequently offered to patients with generalized convulsive status epilepticus (GCSE) in China, but its long-term benefits are unclear. We aimed to evaluate the long-term effects of intravenous phenobarbital on adult patients with GCSE.
METHODS
This randomized clinical trial with a 12-month follow-up was performed in Xuanwu Hospital, Capital Medical University (Beijing, China) between February 2011 and December 2021. After the failure of intravenous diazepam treatment, adult patients with GCSE were randomized to receive either intravenous phenobarbital or valproate. Neurological outcome within 12-month was dichotomized as good (modified Rankin scale, mRS 0-2) or poor (mRS 3-6). Cognitive function was measured by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) were tested for mood disorders.
RESULTS
We consecutively recruited 166 patients with GCSE. After excluding individuals with termination after intravenous diazepam (n = 61), and with other exclusion criteria (n = 7), 98 patients were included and 88.0% (66/75) of survivors achieved seizure freedom at 12-month. Forty-five patients (45.92%) had good outcomes at 3-month and 57 patients (58.16%) had good outcomes at 12-month. And 46.67% (35/75) of survivors showed mRS improvement at 12-month (phenobarbital group, n = 17 vs. valproate group, n = 18, P = 0.321). Despite there was no significant difference with respect to good outcomes at 3-month (54.0% vs. 37.5%, P = 0.101), the rate of good outcomes in phenobarbital group was higher than valproate group at 12-month (68.0% vs. 47.92%, P = 0.044). A total of 43 patients successfully participated cognitive and emotional tests. Mild cognitive impairment was found in 7.14% of phenobarbital group and 50.0% in valproate group (P = 0.026). In addition, there were no significant differences with respect to anxiety (36.36% vs. 38.10%) and depression (31.82% vs. 47.62%) between the phenobarbital and valproate groups.
CONCLUSIONS
Combined with long term conventional therapy, intravenous phenobarbital group had more good outcomes than intravenous valproate group in Chinese adult patients with GCSE up to 12-month follow-up. This finding may prompt the option of intravenous phenobarbital especially in patients with limited access to new antiseizure drugs.
Topics: Humans; Adult; Valproic Acid; Anticonvulsants; Follow-Up Studies; Treatment Outcome; Status Epilepticus; Phenobarbital; Diazepam
PubMed: 37467704
DOI: 10.1016/j.eplepsyres.2023.107187 -
Agri : Agri (Algoloji) Dernegi'nin... Oct 2023Pregabalin (PGB) is used in drug-resistant epilepsy. Also, it has analgesic effects in painful syndromes. Depression and anxiety are commonly seen in epilepsy and...
OBJECTIVES
Pregabalin (PGB) is used in drug-resistant epilepsy. Also, it has analgesic effects in painful syndromes. Depression and anxiety are commonly seen in epilepsy and neuropathic pain patients. PGB is often combined with anxiolytics and antidepressants. We aimed to investigate the antidepressant and anxiolytic effects of PGB and compare its effects with those of antidepressant and anxiolytic drugs and their combined use.
METHODS
Wistar Albino rats were used, and PGB (5, 10, 20, and 40 mg/kg), amitriptylin (AMT), fluoxetine (FLX), ketamine (KET), and diazepam (DZM), as well as combinations of PGB (20 mg/kg) with AMT, FLX, KET, and DZM, were administered. Elevated plus maze, forced swimming, and locomotor activity tests were performed.
RESULTS
In the elevated plus maze, PGB10, 20, 40, AMT, FLX, and DZM increased open arm time. The PGB20+FLX combination increased compared to PGB20. In forced swimming, PGB doses increased immobility time. AMT, FLX, DZM, and KET decreased compared to control and PGB doses. Other combinations of PGB20 reversed immobility time, except FLX. In locomotor activity, PGB20, AMT, KET, and DZM decreased distance.
CONCLUSION
PGB had a depressant effect in all doses and a dose-dependently anxiolytic effect. In combinations of PGB with AMT, KET, and DZM, it reversed their antidepressant effects. We assumed FLX could be preferred instead of AMT in patients using PGB. When PGB is used in combination, drug interactions should be considered. These results are also very remarkable in terms of pharmacoeconomics.
Topics: Rats; Humans; Animals; Anti-Anxiety Agents; Pregabalin; Rats, Wistar; Antidepressive Agents; Fluoxetine; Amitriptyline; Ketamine; Epilepsy
PubMed: 37886867
DOI: 10.14744/agri.2022.98474 -
Cureus Dec 2023As benign as its nature is, a febrile seizure (FS) can be one of the most frightening experiences for parents to witness. It is a seizure that occurs in infants and... (Review)
Review
As benign as its nature is, a febrile seizure (FS) can be one of the most frightening experiences for parents to witness. It is a seizure that occurs in infants and children aged six months to five years, accompanied by a fever (with a temperature of at least 100.4°F or 38.0°C by any method), without any infection in the central nervous system. FS is typically benign and tends to resolve on its own. Overall, the risk of recurrence after an FS is high, so there is still a sizable knowledge discrepancy that needs to be addressed for better understanding and management of the disease. Thus, the objective of this review is to evaluate current therapeutic modalities available for FS and summarize recent recommendations on the management of this condition. On June 25, 2023, a review was undertaken using the Medical Subject Headings Tool (MeSH), and the following keywords yielded 867 results: seizures, febrile/drug therapy [Mesh] and seizures, and febrile/therapy [Mesh]. A total of 21 relevant articles were chosen for the research. Seizures were classified as simple and complex FS (CFS) based on clinical features. CFS usually results in recurrence. Certain investigations like computed tomography (CT) scans, magnetic resonance imaging (MRIs), and electroencephalography (EEG) are helpful, along with laboratory investigations, to rule out other causes of FS. After reviewing the current literature, we have tried to conclude whether the current pharmacotherapy is effective in treating FS.
PubMed: 38249234
DOI: 10.7759/cureus.50947 -
Sao Paulo Medical Journal = Revista... 2023Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics...
BACKGROUND
Neuroleptic malignant syndrome (NMS) is a neurologic emergency potentially fatal. This rare side effect is most commonly associated with first-generation antipsychotics and less frequently with atypical or second-generation antipsychotics. The diagnosis relies on both clinical and laboratory criteria, with other organic and psychiatric conditions being ruled out.
CASE REPORT
A 39-year-old female patient, who is institutionalized and completely dependent, has a medical history of recurrent urinary infections and colonization by carbapenem-resistant Klebsiella pneumoniae. Her regular medication regimen included sertraline, valproic acid, quetiapine, risperidone, lorazepam, diazepam, haloperidol, baclofen, and fentanyl. The patient began experiencing dyspnea. Upon physical examination, she exhibited hypotension and a diminished vesicular murmur at the right base during pulmonary auscultation. Initially, after hospitalization, she developed high febrile peaks associated with hemodynamic instability, prompting the initiation of antibiotic treatment. Despite this, her fever persisted without an increase in blood inflammatory parameters, and she developed purulent sputum, necessitating antibiotherapy escalation. The seventh day of hospitalization showed no improvement in symptoms, suggesting NNMS as a differential diagnosis. All antipsychotic and sedative drugs, as well as antibiotherapy, were discontinued, after which the patient showed significant clinical improvement.
CONCLUSION
Antipsychotic agents are commonly employed to manage behavioral changes linked to various disorders. However, their severe side effects necessitate a high degree of vigilance, the cessation of all medications, and the implementation of supportive care measures. A prompt and accurate diagnosis of NMS is crucial to alleviating the severe, prolonged morbidity and potential mortality associated with this syndrome.
Topics: Female; Humans; Adult; Antipsychotic Agents; Haloperidol; Quetiapine Fumarate; Risperidone; Neuroleptic Malignant Syndrome
PubMed: 38055420
DOI: 10.1590/1516-3180.2022.0401.R1.13032023 -
Brain Research Oct 2023Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of... (Meta-Analysis)
Meta-Analysis
Active avoidance (AA) is an adaptive response to potentially harmful situations while maladapted avoidance that does not extinguish is one of the core symptoms of anxiety and post-traumatic stress disorder. However, the neural mechanisms of AA extinction and its relationship to anxiety remain unclear. We examined AA extinction during three extinction training sessions in two-way active avoidance paradigm and tested the effect of anxiolytic on AA extinction. Then we performed a meta-analysis of rodent studies, identified anxiolytic diazepam facilitates AA acquisition, and tested the same treatment in AA extinction. Diazepam-treated rats significantly reduced avoidance in the first two extinction training, compared with the saline-treated rats, and the reduction in avoidance remained in the third drug-free session. Then we explored extinction associated hippocampal and amygdala activity in saline-and diazepam-treated rats using c-Fos immunostaining following the last extinction session. The density of c-Fos positive cells was higher in dorsal CA3 of the diazepam group than in that of saline-treated animals, and was also higher in the central and basolateral amygdala regions of diazepam-treated rats than in that of saline-treated animals. Combined, these results suggest anxiolytics promotes AA extinction associated with dorsal CA3 and amygdala activity changes.
Topics: Rats; Animals; Diazepam; Anti-Anxiety Agents; Extinction, Psychological; Amygdala; Anxiety; Proto-Oncogene Proteins c-fos; Avoidance Learning
PubMed: 37429455
DOI: 10.1016/j.brainres.2023.148481 -
Metabolism: Clinical and Experimental Aug 2023Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk...
BACKGROUND
Homeostasis of autophagy under normal conditions and nutrient stress is maintained by adaptive activation of regulatory proteins. However, the protein-lipid crosstalk that modulates the switch from suppression to activation of autophagy initiation is largely unknown.
RESULTS
Here, we show that human diazepam-binding inhibitor (DBI), also known as acyl-CoA binding protein (ACBP), binds to phosphatidylethanolamine of the phagophore membrane under nutrient-rich growth conditions, leading to inhibition of LC3 lipidation and suppression of autophagy initiation. Specific residues, including the conserved tyrosine residues of DBI, interact with phosphatidylethanolamine to stabilize the later molecule in the acyl-CoA binding cavity of the protein. Under starvation, phosphorylation of serine-21 of DBI mediated by the AMP-activated protein kinase results in a drastic reduction in the affinity of the protein for phosphatidylethanolamine. The release of serine-21 phosphorylated DBI from the phagophore upon nutrient starvation restores the high LC3 lipidation flux and maturation of the phagophore to autophagosome.
CONCLUSION
DBI acts as a strategic barrier against overactivation of phagophore maturation under nutrient-rich conditions, while triggering autophagy under nutrient-deficient conditions.
Topics: Humans; Carrier Proteins; Phosphatidylethanolamines; Autophagy; Nutrients; Serine
PubMed: 36280213
DOI: 10.1016/j.metabol.2022.155338 -
Clinical Psychopharmacology and... Nov 2023Epilepsy is a disease characterized by the periodic occurrence of seizures. Seizures can be controlled by antiseizure medications, which can improve the lives of... (Review)
Review
Epilepsy is a disease characterized by the periodic occurrence of seizures. Seizures can be controlled by antiseizure medications, which can improve the lives of individuals with epilepsy when given proper treatment. Therefore, this study aimed to review the scientific literature on brain neuroplasticity after treatment with antiseizure drugs in different regions of the brain. According to the findings, that several antiseizure, such as lamotrigine, diazepam, levetiracetam, and valproic acid, in addition to controlling seizures, can also act on neuroplasticity in different brain regions. The study of this topic becomes important, as it will help to understand the neuroplastic mechanisms of these drugs, in addition to helping to improve the effectiveness of these drugs in controlling the disease.
PubMed: 37859439
DOI: 10.9758/cpn.23.1058