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1.
Int J Mol Sci ; 25(13)2024 Jun 26.
Article in English | MEDLINE | ID: mdl-39000086

ABSTRACT

Currently, pharmacotherapy provides successful seizure control in around 70% of patients with epilepsy; however, around 30% of cases are still resistant to available treatment. Therefore, effective anti-epileptic therapy still remains a challenge. In our study, we utilized two mouse lines selected for low (LA) and high (HA) endogenous opioid system activity to investigate the relationship between down- or upregulation of the opioid system and susceptibility to seizures. Pentylenetetrazole (PTZ) is a compound commonly used for kindling of generalized tonic-clonic convulsions in animal models. Our experiments revealed that in the LA mice, PTZ produced seizures of greater intensity and shorter latency than in HA mice. This observation suggests that proper opioid system tone is crucial for preventing the onset of generalized tonic-clonic seizures. Moreover, a combination of an opioid receptor antagonist-naloxone-and a GABA receptor agonist-diazepam (DZP)-facilitates a significant DZP-sparing effect. This is particularly important for the pharmacotherapy of neurological patients, since benzodiazepines display high addiction risk. In conclusion, our study shows a meaningful, protective role of the endogenous opioid system in the prevention of epileptic seizures and that disturbances in that balance may facilitate seizure occurrence.


Subject(s)
Pentylenetetrazole , Seizures , Animals , Pentylenetetrazole/toxicity , Mice , Seizures/metabolism , Seizures/drug therapy , Seizures/chemically induced , Male , Naloxone/pharmacology , Disease Models, Animal , Diazepam/pharmacology , Disease Susceptibility , Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Narcotic Antagonists/pharmacology
2.
J Nippon Med Sch ; 91(3): 347-350, 2024.
Article in English | MEDLINE | ID: mdl-38972748

ABSTRACT

Symptoms of catatonia include silence, motionlessness, and postural retention. Although it is important to detect and treat catatonia early, before it becomes severe, postoperative cases have inherent risks that hinder diagnosis and treatment. A 60-year-old man with schizophrenia underwent endoscopic/thoracoscopic esophagectomy and was extubated in the operating room. In the intensive care unit (ICU), he had stiffness in the neck, ankles, and knees, catalepsy during passive knee flexion, mild disturbance of consciousness, mild creatine kinase elevation, and respiratory depression. Intravenous diazepam was administered for diagnosis, and the patient's rapid improvement indicated catatonia. He was intubated and started on lorazepam; tapering produced no recurrence of symptoms. The patient was extubated and transferred to the general ward on postoperative Day 2. Because this patient was extubated in the operating room and was managed postoperatively in the ICU with a full-time doctor, his symptoms were easily recognized and early diagnosis was possible. Thus, we were able to administer drug therapy quickly and adequately and perform forward management that accounted for postoperative risks, thereby achieving a favorable outcome.


Subject(s)
Catatonia , Early Diagnosis , Lorazepam , Humans , Male , Middle Aged , Catatonia/diagnosis , Catatonia/drug therapy , Lorazepam/administration & dosage , Lorazepam/therapeutic use , Esophagectomy , Treatment Outcome , Diazepam/administration & dosage , Schizophrenia/diagnosis , Schizophrenia/drug therapy , Postoperative Complications/diagnosis
3.
Nat Rev Dis Primers ; 10(1): 49, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39025858

ABSTRACT

Catatonia is a neuropsychiatric disorder characterized by motor, affective and cognitive-behavioural signs, which lasts from hours to days. Intensive research over the past two decades has led to catatonia being recognized as an independent diagnosis in the International Classification of Diseases, 11th Revision (ICD-11) since 2022. Catatonia is found in 5-18% of inpatients on psychiatric units and 3.3% of inpatients on medical units. However, in an unknown number of patients, catatonia remains unrecognized and these patients are at risk of life-threatening complications. Hence, recognizing the symptoms of catatonia early is crucial to initiate appropriate treatment to achieve a favourable outcome. Benzodiazepines such as lorazepam and diazepam, electroconvulsive therapy, and N-methyl-D-aspartate antagonists such as amantadine and memantine, are the cornerstones of catatonia therapy. In addition, dopamine-modulating second-generation antipsychotics (for example, clozapine and aripiprazole) are effective in some patient populations. Early and appropriate treatment combined with new screening assessments has the potential to reduce the high morbidity and mortality associated with catatonia in psychiatric and non-psychiatric settings.


Subject(s)
Benzodiazepines , Catatonia , Electroconvulsive Therapy , Catatonia/diagnosis , Catatonia/therapy , Catatonia/physiopathology , Catatonia/etiology , Humans , Electroconvulsive Therapy/methods , Benzodiazepines/therapeutic use , Lorazepam/therapeutic use , Antipsychotic Agents/therapeutic use , Amantadine/therapeutic use , Memantine/therapeutic use , Diazepam/therapeutic use
4.
Addict Biol ; 29(7): e13425, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39051484

ABSTRACT

Benzodiazepine (BZD) dependence poses a significant challenge in mental health, prompting the exploration of treatments like repetitive transcranial magnetic stimulation (rTMS). This research aims to assess the impact of rTMS on alleviating symptoms of BZD dependence. A randomized control trial was employed to study 40 BZD-dependent inpatients. Their symptoms were quantified using the Hamilton Anxiety Rating Scale (HAMA), Montgomery-Åsberg Depression Rating Scale (MADRS) and Pittsburgh Sleep Quality Index (PSQI). Participants were divided into a conventional treatment group (daily diazepam with gradual tapering) with supportive psychotherapy and another group receiving the same treatment supplemented with rTMS (five weekly sessions for 2 weeks). Significant improvements were observed in both groups over baseline in MADRS, HAMA and PSQI scores at the 2nd, 4th, 8th and 12th week assessments (p < 0.05). The group receiving rTMS in addition to conventional treatment exhibited superior improvements in all measures at the 8th and 12th weeks. The addition of rTMS to conventional treatment methods for BZD dependence significantly betters the recovery in terms of depression, anxiety and sleep quality, highlighting the role of rTMS as an effective adjunct therapy.


Subject(s)
Depression , Sleep Wake Disorders , Transcranial Magnetic Stimulation , Humans , Transcranial Magnetic Stimulation/methods , Male , Adult , Female , Sleep Wake Disorders/therapy , Depression/therapy , Benzodiazepines/therapeutic use , Substance-Related Disorders/therapy , Anxiety/therapy , Middle Aged , Treatment Outcome , Young Adult , Psychiatric Status Rating Scales , Diazepam/pharmacology
5.
Behav Pharmacol ; 35(6): 351-365, 2024 Sep 01.
Article in English | MEDLINE | ID: mdl-39051902

ABSTRACT

Diazepam administration has been shown to influence the release of histamine in various brain areas involved in motor behavior. Therefore, the present study explored the plausible regulatory role of the central histaminergic system in diazepam-induced deficits in motor performance in mice using the rota-rod and beam walking tests. In this study, several doses of diazepam (0.5, 1, 2, and 3 mg/kg, i.p.) were assessed in mice for changes in motor performance on the rota-rod and beam walking test. In addition, the brain histamine levels were determined after diazepam administration, and the diazepam-induced motor deficits were assessed in mice, pretreated centrally (intracerebroventricular) with histaminergic agents such as histamine (0.1, 10 µg), histamine precursor (L-histidine: 0.1, 2.5 µg), histamine neuronal releaser/H 3 receptor antagonist (thioperamide: 0.5, 10 µg), H 1 and H 2 receptor agonist [2-(3-trifluoromethylphenyl) histamine (FMPH: 0.1, 6.5 µg; amthamine: 0.1, 5 µg)/antagonist (H 1 : cetirizine 0.1 µg) and (H 2 : ranitidine: 50 µg)]. Results indicate that mice treated with diazepam at doses 1, 2 mg/kg, i.p. significantly increased the brain histamine levels. Moreover, in mice pretreated with histaminergic transmission-enhancing agents, the diazepam (2 mg/kg, i.p.)-induced motor incoordination was significantly reversed. Contrastingly, diazepam (1 mg/kg, i.p.) in its subeffective dose produced significant motor deficits in mice preintracerebroventricular injected with histamine H 1 and H 2 receptor antagonists on both the employed tests. Therefore, it is postulated that endogenous histamine operates via H 1 and H 2 receptor activation to alleviate the motor-impairing effects of diazepam.


Subject(s)
Diazepam , Histamine , Animals , Diazepam/pharmacology , Mice , Histamine/pharmacology , Histamine/metabolism , Male , Dose-Response Relationship, Drug , Motor Activity/drug effects , Walking , Histamine Agonists/pharmacology , Rotarod Performance Test , Brain/drug effects , Brain/metabolism , Histamine Agents/pharmacology , Histamine Antagonists/pharmacology , Histidine/pharmacology
6.
Neurologia (Engl Ed) ; 39(5): 426-431, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38830721

ABSTRACT

INTRODUCTION: Status epilepticus is an important cause of pediatric neurological emergency. Immediate treatment is essential to prevent definitive neurological damage. Several antiepileptic drugs are available for the management of status epilepticus. METHODS: Retrospective study of patients admitted at the emergency department of a tertiary hospital for 5 years (2014-2019). We analyzed the compliance to the treatment guidelines for pediatric status epilepticus. RESULTS: One hundred and seventeen admissions were identified, 23.9% of these were febrile status epilepticus. Among the other cases, the most frequent cause was genetic (22.2%). The majority were convulsive status epilepticus (93.1%), 58.7% of which were generalized tonic-clonic seizures. Benzodiazepines were the most used first and second line drug (98.2% and 94.8%). The most frequent third drug used was diazepam (56.4%) followed by phenytoin (18.2%). An infra-therapeutic antiepileptic drug dose was given in 48.7% of cases. 49.6% presented with a prolonged status epilepticus and 6.8% needed intensive care. Incorrect sequence of drugs and infra-therapeutic doses were associated with prolonged status (p<0.001 and p<0.05) and an increased number of antiepileptic drugs used (p<0.001 and p<0.05). CONCLUSIONS: Benzodiazepines were the most frequently first and second line drugs used for status epilepticus management. Surprisingly, the most frequently third line drugs used were also benzodiazepines. These findings were partially explained by the misuse of infra-therapeutic doses of these drugs. Noncompliance with the implemented guidelines was associated with unfavorable outcomes.


Subject(s)
Anticonvulsants , Emergency Service, Hospital , Status Epilepticus , Humans , Status Epilepticus/drug therapy , Anticonvulsants/therapeutic use , Retrospective Studies , Female , Male , Child , Child, Preschool , Infant , Benzodiazepines/therapeutic use , Guideline Adherence , Adolescent , Diazepam/therapeutic use
7.
PLoS One ; 19(6): e0305409, 2024.
Article in English | MEDLINE | ID: mdl-38875245

ABSTRACT

BACKGROUND AND OBJECTIVE: Pulmonary fibrosis caused by lung injury is accompanied by varying degrees of inflammation, and diazepam can reduce the levels of inflammatory factors. Therefore, the purpose of this study was to determine whether diazepam can inhibit inflammation and ameliorate pulmonary fibrosis by regulating the let-7a-5p/myeloid differentiation factor 88 (MYD88) axis. METHODS: Lipopolysaccharide (LPS) was used to induce cell pyroptosis in an animal model of pulmonary fibrosis. After treatment with diazepam, changes in cell proliferation and apoptosis were observed, and the occurrence of inflammation and pulmonary fibrosis in the mice was detected. RESULTS: The results showed that LPS can successfully induce cell pyroptosis and inflammatory responses and cause lung fibrosis in mice. Diazepam inhibits the expression of pyroptosis-related factors and inflammatory factors; moreover, it attenuates the occurrence of pulmonary fibrosis in mice. Mechanistically, diazepam can upregulate the expression of let-7a-5p, inhibit the expression of MYD88, and reduce inflammation and inhibit pulmonary fibrosis by regulating the let-7a-5p/MYD88 axis. CONCLUSION: Our findings indicated that diazepam can inhibit LPS-induced pyroptosis and inflammatory responses and alleviate pulmonary fibrosis in mice by regulating the let-7a-5p/MYD88 axis.


Subject(s)
Diazepam , Inflammation , Lipopolysaccharides , MicroRNAs , Myeloid Differentiation Factor 88 , Pulmonary Fibrosis , Pyroptosis , Animals , Pyroptosis/drug effects , Mice , Diazepam/pharmacology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/metabolism , Myeloid Differentiation Factor 88/metabolism , Myeloid Differentiation Factor 88/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Inflammation/drug therapy , Inflammation/pathology , Inflammation/metabolism , Male , Mice, Inbred C57BL , Disease Models, Animal , Signal Transduction/drug effects
8.
Biomed Pharmacother ; 176: 116939, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38870629

ABSTRACT

BACKGROUND: Sclareol (SCL), a labdane diterpene compound found in Salvia sclarea L., exhibited therapeutic effects. This study investigated the potential interaction between SCL and diazepam (DZP) in modulating sedation in the thiopental sodium-induced sleeping animal model, supported by in-silico molecular docking analysis. METHODS: The control, sclareol (5, 10 and 20 mg/kg), and the reference drugs [diazepam: 3 mg/kg and Caffeine (CAF): 10 mg/kg] were used in male albino mice. Then, sodium thiopental (40 mg/kg, i.p.) was administrated to induce sleep. The latent period, percentage of sleep incidence and modulation of latency were measured. Further, homology modeling of human γ-aminobutyric acid (GABA) was conducted examine the binding mode of GABA interaction with SCL, DZP, and CAF compounds RESULTS: SCL (low dose) slightly increased the sleep latency, while the higher dose significantly prolonged sleep latency. DZP, a GABAA receptor agonist, exhibited strong sleep-inducing properties, reducing sleep latency, and increasing sleeping time. Caffeine (CAF) administration prolonged sleep latency and reduced sleeping time, consistent with its stimulant effects. The combination treatments involving SCL, DZP, and CAF showed mixed effects on sleep parameters. The molecular docking revealed good binding affinities of SCL, DZP, and CAF for GABAA receptor subunits A2 and A5. CONCLUSIONS: Our findings highlighted the complex interplay between SCL, DZP, and CAF in regulating sleep behaviors and provided insights into potential combination therapies for sleep disorders.


Subject(s)
Diazepam , Hypnotics and Sedatives , Molecular Docking Simulation , Sleep , Thiopental , Animals , Male , Hypnotics and Sedatives/pharmacology , Mice , Diazepam/pharmacology , Sleep/drug effects , Thiopental/pharmacology , Diterpenes/pharmacology , Caffeine/pharmacology , Computer Simulation , Receptors, GABA-A/metabolism , Humans , Dose-Response Relationship, Drug , Sleep Latency/drug effects
9.
Neuropharmacology ; 257: 110035, 2024 Oct 01.
Article in English | MEDLINE | ID: mdl-38876310

ABSTRACT

We previously showed that the PDE4 inhibitor apremilast reduces ethanol consumption in mice by protein kinase A (PKA) and GABAergic mechanisms. Preventing PKA phosphorylation of GABAA ß3 subunits partially blocked apremilast-mediated decreases in drinking. Here, we produced Gabrb1-S409A mice to render GABAA ß1 subunits resistant to PKA-mediated phosphorylation. Mass spectrometry confirmed the presence of the S409A mutation and lack of changes in ß1 subunit expression or phosphorylation at other residues. ß1-S409A male and female mice did not differ from wild-type C57BL/6J mice in expression of Gabrb1, Gabrb2, or Gabrb3 subunits or in behavioral characteristics. Apremilast prolonged recovery from ethanol ataxia to a greater extent in Gabrb1-S409A mice but prolonged recovery from zolpidem and propofol to a similar extent in both genotypes. Apremilast shortened recovery from diazepam ataxia in wild-type but prolonged recovery in Gabrb1-S409A mice. In wild-type mice, the PKA inhibitor H89 prevented apremilast modulation of ataxia by ethanol and diazepam, but not by zolpidem. In Gabrb1-S409A mice, inhibiting PKA or EPAC2 (exchange protein directly activated by cAMP) partially reversed apremilast potentiation of ethanol, diazepam, and zolpidem ataxia. Apremilast prevented acute tolerance to ethanol ataxia in both genotypes, but there were no genotype differences in ethanol consumption before or after apremilast. In contrast to results in Gabrb3-S408A/S409A mice, PKA phosphorylation of ß1-containing GABAA receptors is not required for apremilast's effects on acute tolerance or on ethanol consumption but is required for its ability to decrease diazepam intoxication. Besides PKA we identified EPAC2 as an additional cAMP-dependent mechanism by which apremilast regulates responses to GABAergic drugs.


Subject(s)
Cyclic AMP-Dependent Protein Kinases , Ethanol , Mice, Inbred C57BL , Phosphodiesterase 4 Inhibitors , Receptors, GABA-A , Thalidomide , Animals , Thalidomide/pharmacology , Thalidomide/analogs & derivatives , Cyclic AMP-Dependent Protein Kinases/metabolism , Phosphodiesterase 4 Inhibitors/pharmacology , Male , Female , Ethanol/pharmacology , Mice , Receptors, GABA-A/genetics , Receptors, GABA-A/metabolism , Receptors, GABA-A/drug effects , Gene Knock-In Techniques , Phosphorylation/drug effects , Ataxia/genetics , Alcohol Drinking/drug therapy , Alcohol Drinking/genetics , Mice, Transgenic , Diazepam/pharmacology
10.
Epilepsia Open ; 9(4): 1575-1581, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38872261

ABSTRACT

Diazepam is a cornerstone immediate-use antiseizure rescue therapy that may extend the duration between seizure clusters in people living with epilepsy. However, our mechanistic understanding of intermittent rescue therapy on disease progression is limited by the lack of suitable preclinical models. Specifically, the pharmacokinetics of diazepam varies widely between humans and laboratory animals. Here, we developed a novel repeat rescue therapy dosing paradigm in rats to maintain prolonged therapeutic concentrations seen in humans. Rats received three diazepam doses separated by 1 h (0.75, 1.5, or 3 mg/kg, intraperitoneal); plasma and brains were collected at 10 min and 1, 3, or 6 h following the last dose. Plasma and brain concentrations followed a dose-dependent increase with peak concentrations following the repeat 3 mg/kg paradigm (180 ng/mL) being equivalent to plasma levels observed in human studies with diazepam nasal spray. Increased brain-to-plasma ratios in this paradigm indicate that diazepam accumulation in the brain may be long-acting at the site of action. Overall, our repeat diazepam dosing paradigm mimics drug concentrations and accumulation seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology in rodent models of epilepsy. PLAIN LANGUAGE SUMMARY: There is more to learn about how diazepam works in the brains of people who use it only when they have two or more seizures in 24 h (this is called a seizure cluster). Ethical studies in animals can be used to learn more about medicines in the body. In this study, we showed that three doses of diazepam in rats give about the same amount of the drug as one dose for a person. We can now test rats with epilepsy to see how the drug might work in people who take it when needed for seizure clusters.


Subject(s)
Anticonvulsants , Brain , Diazepam , Disease Models, Animal , Dose-Response Relationship, Drug , Epilepsy , Seizures , Animals , Diazepam/administration & dosage , Diazepam/pharmacokinetics , Anticonvulsants/pharmacokinetics , Anticonvulsants/administration & dosage , Anticonvulsants/therapeutic use , Rats , Seizures/drug therapy , Epilepsy/drug therapy , Male , Brain/metabolism , Brain/drug effects , Rats, Sprague-Dawley
11.
Bull Exp Biol Med ; 176(5): 585-590, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38724813

ABSTRACT

Leukocyte elastase is a marker of inflammation. Previously, a relationship was found between the severity of mental disorders in patients and elastase-like activity of blood plasma. The effect of various neurotropic drugs on leukocyte elastase activity was analyzed in an in vitro experiment. We revealed an inhibitory effect of the benzodiazepine tranquilizers diazepam and bromodihydrochlorophenylbenzodiazepine and immunomodulators aminodihydrophthalazinedione and diclofenac on the plasma elastase-like activity of healthy donors and pure human neutrophil elastase. The antipsychotics chlorpromazine and alimemazine, as well as the nootropic vinpocetine increased elastase-like activity in a dose-dependent manner. The activating effect of chlorpromazine and vinpocetine, but not alimemazine, was reproduced in neutrophil elastase. We hypothesized that these drugs can affect the development of inflammatory reactions in the complex therapy of mental disorders.


Subject(s)
Antipsychotic Agents , Chlorpromazine , Diazepam , Leukocyte Elastase , Humans , Leukocyte Elastase/metabolism , Chlorpromazine/pharmacology , Diazepam/pharmacology , Antipsychotic Agents/pharmacology , Diclofenac/pharmacology , Nootropic Agents/pharmacology , Tranquilizing Agents/pharmacology , Immunologic Factors/pharmacology , Vinca Alkaloids
12.
Biomed Pharmacother ; 176: 116771, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38795639

ABSTRACT

Anxiety-like conditions can interfere with daily activities as the adaptive mechanism fails to cope with stress. These conditions are often linked with increased oxidative stress, and abrupt neurotransmission and electroencephalography (EEG) wave pattern. Geraniol, a monoterpenoid, has antioxidant and anti-inflammatory activities, as well as brain-calming effects. Therefore, in this study, geraniol was tested for the potential anxiolytic effects in a rat model of anxiety. The rats were exposed to an electric foot shock (1 mA for 1 s) to develop anxiety-like symptoms. Treatment was carried out using geraniol (10 and 30 mg/kg) and the standard diazepam drug. The behavior of the rats was analyzed using the open field test, light-dark test, and social interaction test. Afterward, the rats were decapitated to collect samples for neurochemical and biochemical analyses. The cortical-EEG wave pattern was also obtained. The study revealed that the electric foot shock induced anxiety-like symptoms, increased oxidative stress, and altered hippocampal neurotransmitter levels. The power of low-beta and high-beta was amplified with the increased coupling of delta-beta waves in anxiety group. However, the treatment with geraniol and diazepam normalized cortical-EEG wave pattern and hippocampal serotonin and catecholamines profile which was also reflected by reduced anxious behavior and normalized antioxidant levels. The study reports an anxiolytic potential of geraniol, which can be further explored in future.


Subject(s)
Acyclic Monoterpenes , Anti-Anxiety Agents , Anxiety , Behavior, Animal , Electroencephalography , Hippocampus , Oxidative Stress , Rats, Wistar , Synaptic Transmission , Animals , Acyclic Monoterpenes/pharmacology , Oxidative Stress/drug effects , Anxiety/drug therapy , Male , Hippocampus/drug effects , Hippocampus/metabolism , Anti-Anxiety Agents/pharmacology , Rats , Synaptic Transmission/drug effects , Behavior, Animal/drug effects , Electroshock , Antioxidants/pharmacology , Terpenes/pharmacology , Diazepam/pharmacology , Disease Models, Animal , Brain Waves/drug effects
13.
Drug Res (Stuttg) ; 74(5): 220-226, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38729181

ABSTRACT

Combinations of medications are frequently employed when their effects are similar. Beyond aiding in the reduction of medication dosages, this approach may yield additional positive outcomes. Studies have shown that zinc can mitigate anxiety-related behavior in laboratory animals. This study aimed to investigate the potential stabilizing effects of zinc chloride and diazepam in Wistar albino rats.Five groups, each comprising six animals. Test groups included two combinations of zinc chloride and diazepam, each with two different doses of diazepam (1 and 2 mg/kg) and 10 mg/kg of zinc chloride. Four established anxiety models-the Elevated Plus Maze (EPM), the hole board, the light and dark box, and the mirror chamber-were employed to assess the anxiolytic effects. The combination of zinc chloride and diazepam proved to be more effective than the individual doses of zinc chloride and diazepam, indicating enhanced anxiolytic effects.


Subject(s)
Anti-Anxiety Agents , Anxiety , Behavior, Animal , Chlorides , Diazepam , Drug Synergism , Rats, Wistar , Zinc Compounds , Animals , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/administration & dosage , Diazepam/pharmacology , Zinc Compounds/pharmacology , Zinc Compounds/administration & dosage , Rats , Anxiety/drug therapy , Male , Behavior, Animal/drug effects , Maze Learning/drug effects , Disease Models, Animal , Drug Therapy, Combination , Dose-Response Relationship, Drug
14.
Toxicol Lett ; 397: 103-116, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38703967

ABSTRACT

Animal research continues to serve a critical role in the testing and development of medical countermeasures. The Göttingen minipig, developed for laboratory research, may provide many benefits for addressing research questions within chemical defense. Targeted development of the Göttingen minipig model could reduce reliance upon non-human primates, and improve study design, statistical power, and throughput to advance medical countermeasures for regulatory approval and fielding. In this vein, we completed foundational pharmacokinetics and physiological safety studies of intramuscularly administered atropine sulfate, pralidoxime chloride (2-PAM), and diazepam across a broad range of doses (1-6 autoinjector equivalent) using adult male Göttingen minipigs (n=11; n=4-8/study) surgically implanted with vascular access ports and telemetric devices to monitor cardiovascular, respiratory, arterial pressure, and temperature signals. Pharmacokinetic data were orderly and the concentration maximum mirrored available human data at comparably scaled doses clearly for atropine, moderately for 2-PAM, and poorly for diazepam. Time to peak concentration approximated 2, 7, and 20 min for atropine, 2-PAM, and diazepam, respectively, and the elimination half-life of these drugs approximated 2 hr (atropine), 3 hr (2-PAM), and 8 hr (diazepam). Atropine sulfate dose-dependently increased the magnitude and duration of tachycardia and decreased the PR and ST intervals (consistent with findings obtained from other species). Mild hypothermia was observed at the highest diazepam dose. Göttingen minipigs appear to provide a ready and appropriate large animal alternative to non-human primates, and further development and evaluation of novel nerve agent medical countermeasures and treatment strategies in this model are justified.


Subject(s)
Atropine , Diazepam , Swine, Miniature , Animals , Swine , Male , Diazepam/pharmacokinetics , Diazepam/pharmacology , Atropine/pharmacokinetics , Atropine/pharmacology , Nerve Agents/pharmacokinetics , Nerve Agents/toxicity , Dose-Response Relationship, Drug , Injections, Intramuscular , Half-Life , Heart Rate/drug effects , Telemetry , Models, Animal , Pralidoxime Compounds
15.
Neurol Res ; 46(8): 752-762, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38719201

ABSTRACT

BACKGROUND: Anxiety is an adaptive response to potentially threatening conditions. Excessive and uncontrolled anxiety responses become nonadaptive and cause anxiety disorders. To better understand the anxiety-modulating effects of Mg sulfate, behavioral test batteries in the assessment of anxiety and learning and memory functions were performed simultaneously over a time period. This study also examines the effects of Mg sulfate compared to diazepam, an anxiolytic drug with amnestic effects on anxiety-like behavior, as well as possible oxidative-nitrosative stress and hippocampal changes in male rats exposed to predator odor. METHODS: Young adult Sprague-Dawley male rats were used. The rats were assessed using a comprehensive neurobehavioral test battery consisting of novel object recognition, open field, and successive alleys tasks. Anxiety was induced by cat odor, and diazepam and Mg were used as study drugs. Of the frontal cortex and hippocampus, the state of total oxidant and antioxidant and NO levels and histological examination of hippocampal CA1, CA2, CA3, and DG regions were performed. RESULTS: Diazepam- and Mg-treated rats showed an improvement in anxiety-related behavior to predator odors. Furthermore, Mg treatment alleviated some of the increasing oxidative stress in the frontal cortex and hippocampus of rats, while diazepam treatment in particular enhanced hippocampal oxidant and antioxidant activity. In addition, brain NO increase induced by animal odor exposure or diazepam treatment was ameliorated by Mg administration. CONCLUSIONS: Overall, our work suggests that Mg had a partial anxiolytic effect on anxiety-like behaviors, although not as much as diazepam, and this effect varied depending on the dose. Mg treatment might counteract increased oxidative stress and elevated NO levels in the brain.


Subject(s)
Anti-Anxiety Agents , Anxiety , Diazepam , Disease Models, Animal , Magnesium Sulfate , Rats, Sprague-Dawley , Animals , Male , Anxiety/drug therapy , Diazepam/pharmacology , Anti-Anxiety Agents/pharmacology , Anti-Anxiety Agents/therapeutic use , Magnesium Sulfate/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Oxidative Stress/drug effects , Rats , Memory/drug effects , Nitric Oxide/metabolism , Odorants
16.
Pharmacol Biochem Behav ; 241: 173792, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38806117

ABSTRACT

Formosan wood mice (Apodemus semotus) are endemic rodents in Taiwan. Recently Formosan wood mice exhibit similar locomotor behaviors in the laboratory environment as in the field environment has shown. Contemporaneously, Formosan wood mice have higher moving distances of and central dopaminergic (DAergic) activities than C57BL/6 mice in behavioral test. This study tried to compare the behavioral responses between male Formosan wood mice and male C57BL/6 mice in the light-dark exploration tests. We also measured the levels of DA and 3,4-dihydroxyphenylacetic acid (DOPAC), the primary metabolite of DA, to assess the dopaminergic activity of the medial prefrontal cortex, striatum, and nucleus accumbens. Our data show that Formosan wood mice revealed higher exploration and central DAergic activities than did C57BL/6 mice in the light-dark exploration tests, and diazepam (an anxiolytics) treatment reduced the exploratory activity and central dopaminergic activities in Formosan wood mice, but not in C57BL/6 mice. After repeated exposure to light-dark exploration tests, the latency to dark zone was increased, and the duration in light zone as well as the central DAergic activity were decreased in C57BL/6 mice. This study provides comparative findings; Formosan wood mice showed the higher exploratory activities than C57BL/6 mice did, and their central DAergic activities were related to the behavioral responses in these two mice. This could potentially shed light on the reasons behind the prevalence of higher exploration and central dopaminergic activities. Using Formosan wood mice as a model to study human diseases related to hyperactivity adds significant value to the potential research.


Subject(s)
Behavior, Animal , Dopamine , Exploratory Behavior , Mice, Inbred C57BL , Murinae , Animals , Male , Mice , Dopamine/metabolism , Exploratory Behavior/drug effects , Behavior, Animal/drug effects , 3,4-Dihydroxyphenylacetic Acid/metabolism , Diazepam/pharmacology , Anti-Anxiety Agents/pharmacology , Nucleus Accumbens/metabolism , Nucleus Accumbens/drug effects , Prefrontal Cortex/metabolism , Prefrontal Cortex/drug effects , Corpus Striatum/metabolism , Corpus Striatum/drug effects , Motor Activity/drug effects
17.
BMC Anesthesiol ; 24(1): 193, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811866

ABSTRACT

OBJECTIVES: This study evaluated the effectiveness, psychological effects, and sleep quality using intramuscular diazepam infusion compared with placebo in patients with herpes zoster (HZ)-related pain. METHODS: The patients were randomized to either the diazepam or control group. The diazepam group received an intramuscular injection of diazepam for 3 consecutive days, while the control group received an intramuscular injection of 0.9% normal saline. The primary outcome was pain relief on posttreatment day 4, as measured using the Visual Analog Scale (VAS). Moreover, anxiety and depression were evaluated using the Generalized Anxiety Disorder-7 (GAD7) and Patient Health Questionnaire-9 (PHQ9), respectively. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: In total, 78 patients were enrolled in the trial. The mean differences in VAS scores between the two groups were 0.62 (P = 0.049) on posttreatment day 3 and 0.66 (P = 0.037) on posttreatment day 4. The effective rates of pain management in the diazepam group ranged from 10.26 to 66.67%, which were higher than those in the control group on posttreatment days 3 and 4 (P < 0.05). The mean difference in PSQI scores between the diazepam and control groups was 1.36 (P = 0.034) on posttreatment day 7. No differences were found in the incidence of analgesia-adverse 1reactions between the diazepam and placebo groups. CONCLUSIONS: The intramuscular injection of diazepam for 3 consecutive days provides effective pain management and improves the quality of life. Our study suggests that diazepam is more effective than the placebo in patients with HZ-related pain. TRIAL REGISTRATION: The study was prospectively registered at https://www.isrctn.com/trialist(Registration date: 24/01/2018; Trial ID: ISRCTN12682696).


Subject(s)
Diazepam , Herpes Zoster , Humans , Male , Female , Double-Blind Method , Injections, Intramuscular , Aged , Herpes Zoster/complications , Herpes Zoster/drug therapy , Diazepam/administration & dosage , Pain Measurement/methods , Middle Aged , Sleep Quality , Anxiety/drug therapy , Pain/drug therapy
18.
BMJ Open ; 14(4): e080109, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38569687

ABSTRACT

OBJECTIVES: Long-term benzodiazepine use is common despite known risks. In the original Eliminating Medications Through Patient Ownership of End Results (EMPOWER) Study set in Canada, patient education led to increased rates of benzodiazepine cessation. We aimed to determine the effectiveness of implementing an adapted EMPOWER quality improvement (QI) initiative in a US-based healthcare system. DESIGN: We used a pre-post design with a non-randomised control group. SETTING: A network of primary care clinics. PARTICIPANTS: Patients with ≥60 days' supply of benzodiazepines in 6 months and ≥1 risk factor (≥65 years of age, a concurrent high-risk medication prescribed or a diazepam equivalent daily dose ≥10) were eligible. INTERVENTION: In March 2022, we engaged 22 primary care physicians (PCPs), and 308 of their patients were mailed an educational brochure, physician letter and flyer detailing benzodiazepine risks; the control group included 4 PCPs and 291 of their patients. PRIMARY AND SECONDARY MEASURES: The primary measure was benzodiazepine cessation by 9 months. We used logistic regression and a generalised estimating equations approach to control for clustering by PCP, adjusting for demographics, frailty, number of risk factors, and diagnoses of arthritis, depression, diabetes, falls, and pain. RESULTS: Patients in the intervention and control groups were comparable across most covariates; however, a greater proportion of intervention patients had pain-related diagnoses and depression. By 9 months, 26% of intervention patients (81 of 308) had discontinued benzodiazepines, compared with 17% (49 of 291) of control patients. Intervention patients had 1.73 greater odds of benzodiazepine discontinuation compared with controls (95% CI: 1.09, 2.75, p=0.02). The unadjusted number needed to treat was 10.5 (95% CI: 6.30, 34.92) and the absolute risk reduction was 0.095 (95% CI: 0.03 to 0.16). CONCLUSIONS: Results from this non-randomised QI initiative indicate that patient education programmes using the EMPOWER brochures have the potential to promote cessation of benzodiazepines in primary care.


Subject(s)
Benzodiazepines , Deprescriptions , Humans , Benzodiazepines/therapeutic use , Control Groups , Patient Education as Topic , Diazepam , Delivery of Health Care , Pain/drug therapy
19.
Neurol Res ; 46(8): 717-726, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38679045

ABSTRACT

Introduction: The close relationship between inflammatory processes and epileptic seizures is already known, although the exact pathophysiological mechanism is unclear. In this study, the anticonvulsant capacity of piroxicam, an anti-inflammatory drug, was evaluated. A rat pentylenetetrazole kindling model was used.Methods: Male Wistar rats, 8-9 weeks old, received piroxicam (0.15 and 0.30 mg/kg), diazepam (2 mg/kg) or saline for 14 days, and PTZ, on alternate days. Intraperitoneal was chosen as the route of administration. The intensity of epileptic seizures was assessed using a modified Racine scale. The open field test and object recognition analysis were performed at the beginning of the study to ensure the safety of the drugs used. At the end of the protocol, the animals were euthanized to measure the levels of inflammatory (TNF-a and IL-6) and anti-inflammatory (IL-10) cytokines in the cortex, hippocampus, and serum.Results:There were no changes in the open field test and object recognition analysis. Piroxicam was found to decrease Racine scale scores at both concentrations. The reported values for IL-6 levels remained steady in all structures, whereas the TNF-alpha level in the cortex was higher in animals treated with piroxicam than in the saline and diazepam subjects. Finally, animals treated with the anti-inflammatory drug presented reduced IL-10 levels in the cortex and hippocampus.onclusions: Using inflammation as a guiding principle, the anticonvulsant effect of PIRO could be associated with the hippocampal circuits, since this structure showed no increase in inflammatory cytokines.


Subject(s)
Anticonvulsants , Disease Models, Animal , Kindling, Neurologic , Piroxicam , Rats, Wistar , Animals , Piroxicam/pharmacology , Male , Kindling, Neurologic/drug effects , Anticonvulsants/pharmacology , Rats , Pentylenetetrazole , Seizures/drug therapy , Cytokines/metabolism , Diazepam/pharmacology , Hippocampus/drug effects , Hippocampus/metabolism , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Dose-Response Relationship, Drug , Epilepsy/drug therapy
20.
Eur J Pharmacol ; 972: 176561, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38580182

ABSTRACT

Neuronal depression in the thalamus underlies anesthetic-induced loss of consciousness, while the precise sub-thalamus nuclei and molecular targets involved remain to be elucidated. The present study investigated the role of extrasynaptic GABAA receptors in the central medial thalamic nucleus (CM) in anesthesia induced by gaboxadol (THIP) and diazepam (DZP) in rats. Local lesion of the CM led to a decrease in the duration of loss of righting reflex induced by THIP and DZP. CM microinjection of THIP but not DZP induced anesthesia. The absence of righting reflex in THIP-treated rats was consistent with the increase of low frequency oscillations in the delta band in the medial prefrontal cortex. CM microinjection of GABAA receptor antagonist SR95531 significantly attenuated the anesthesia induced by systemically-administered THIP, but not DZP. Moreover, the rats with declined expression of GABAA receptor δ-subunit in the CM were less responsive to THIP or DZP. These findings explained a novel mechanism of THIP-induced loss of consciousness and highlighted the role of CM extrasynaptic GABAA receptors in mediating anesthesia.


Subject(s)
Anesthesia , Isoxazoles , Receptors, GABA-A , Animals , Receptors, GABA-A/metabolism , Male , Rats , Isoxazoles/pharmacology , Diazepam/pharmacology , Rats, Sprague-Dawley , Mediodorsal Thalamic Nucleus/drug effects , Mediodorsal Thalamic Nucleus/metabolism , Mediodorsal Thalamic Nucleus/physiology , Reflex, Righting/drug effects , Synapses/drug effects , Synapses/metabolism , Thalamus/drug effects , Thalamus/metabolism
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