Significant CNS Depressant Research Articles

Imidazole Incorporated Semicarbazone Derivatives as a New Class of Anticonvulsants: Design, Synthesis and In-Vivo Screening

A series of novel imidazole incorporated semicarbazones was synthesized using an appropriate synthetic route and characterized by spectral analysis (IR, 1H NMR, 13C NMR and Mass). The anticonvulsant activity of the synthesized compounds was determined using doses of 30, 100, and 300 mg kg-1 against maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) induced seizure and minimal neurotoxicity test. Six compounds exhibited protection in both models and 2-(1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene)-N-p-tolylsemicarbazone emerged as the most active compound of the series without any neurotoxicity and significant CNS depressant effect. Liver enzyme estimations (SGOT, SGPT, Alkaline phosphatase) of the compound also showed no significant change in the enzymes levels. Moreover, it caused 80% elevation of γ-amino butyric acid (GABA) levels in the whole mice brain, thus indicating that it could be a promising candidate in designing of a potent anticonvulsant drug.

Overdose of Atypical Antipsychotics

Historically, treatment for schizophrenia focused on sedation. The advent of the typical antipsychotics resulted in treatment aimed specifically at the underlying disease, but these agents were associated with numerous adverse effects, and were not particularly effective at treatment of the negative symptoms of schizophrenia. As a result, numerous atypical agents have been developed over the past 2 decades, including several agents within the past 5 years. Overdose of antipsychotics remains quite common in Western society. In 2010, poison control centres in the US received nearly 43,000 calls related to atypical antipsychotics alone. Due to underreporting, the true incidence of overdose with atypical antipsychotics is likely much greater. Following overdose of an atypical antipsychotic, the clinical effects observed, such as CNS depression, tachycardia and orthostasis are largely predictable based on the unique receptor binding profile of the agent. This article, which focuses on the atypical antipsychotics commonly used in the treatment of schizophrenia, discusses the features commonly encountered in overdose. Specifically, agents that result in QT prolongation and the corresponding potential for torsades de pointes, as well as unique features encountered with the various medications are discussed. The diagnosis of this overdose is largely based on history. Routine use of drug screens is unlikely to be beneficial. The primary goal of management is aggressive supportive care. Patients with significant CNS depression with associated loss of airway reflexes and respiratory failure need advanced airway management. Hypotension should be treated first with intravenous fluids, with the use of direct acting vasopressors reserved for persistent hypotension. Benzodiazepines should be used for seizures, with barbiturates used for refractory seizures. Intravenous magnesium can be administered for patients with a corrected QT interval exceeding 500 milliseconds.

Hospital mortality among poisoned patients presenting unconscious

Objectives. The hospital mortality from acute poisoning in the western world is approximately 0.6%. However, this figure is based on series of consecutive cases, including mild intoxications. The aim of this paper was to investigate the mortality among poisoned patients with CNS depression on admission. Design. This report is based on two case series. One observational study of 352 prospectively included cases of poisoning with a Glasgow coma scale (GCS) score ≤ 10 at presentation during the 2-year-period 2003–2005, and one retrospective review of all poisonings admitted to a hospital in Stockholm 2009–2011. Results. The observational study showed a hospital mortality rate of 2.8%. Nine of the 10 fatalities had a GCS score below 7 on admission. The more recent retrospective review consisted of 1314 cases of poisoning of whom 419 (32%) had a GCS score ≤ 10 on admission. The hospital mortality among these 419 cases was 2.4%. All 10 deaths in this cohort had a GCS score below 7 at presentation. The subgroup of patients pooled from both case series with a GCS score of 3–6 (n = 444) had a mortality rate of 4.3%. Conclusions. Based on the findings in this report, and on a literature search, about 30% of hospitalized poisonings have a significant CNS depression on admission. Based on our experience, cases of poisoning with a GCS score of 7–10 on admission do not seem to have a worse prognosis than poisonings in general. However, cases of poisoning presenting with deeper coma (GCS score 3–6) have a mortality rate approximately seven times higher than the overall hospital mortality from acute poisoning.

Synthesis and Pharmacological Studies for New Benzotriazole and Dibenzodiazepine Derivatives as Antipsychotic Agents

New benzotriazoles (5-8) or dibenzodiazepine derivatives (11-18) were synthesized starting from 3-[(2-amino- 4,5-disubstitutedphenyl)amino]-5,5-disubstitutedcyclohex-2-enones (1-4) through internal coupling of their diazonium salts or internal Mannich reaction in the presence of aromatic aldehydes. Pharmacological evaluation of benzotriazole and dibenzodiazepine derivatives for their clozapine-like properties revealed that dibenzodiazepine 11 bearing 4-bromophenyl group exhibited the same antipsychotic activity as the reference drug clozapine while the activity of benzotriazole 7 was 25% lesser than that of clozapine. Moreover, compounds 7 and 11 did not show significant CNS depressant activity as well as no or slight neurotoxicity on contrast to clozapine when tested in mice using forced swim, rotarod and horizontal screen tests.

Evaluation of CNS depressant activity of different plant parts ofNyctanthes arbortristislinn.

The present study was carried out with the water-soluble portion of the ethanol extracts of flowers, barks, seeds and leaves of Nyctanthes arbortristis Linn. to confirm their CNS depressant activity. The ethanol extracts of the plant parts were obtained by soxhlet extraction. After performing the gross behavioral study, the CNS depressant activity was evaluated by observing the prolongation of sleeping time induced by pentobarbital sodium in mice. Attempts have been made to explore the possible mechanism behind this activity by determining their effect on brain monoamine neurotransmitters like dopamine and serotonin. The gross behavioral study showed that ethanol extracts of the leaves, flowers and seeds possess significant CNS depressant activity. The leaves, flowers, seeds and barks (600 mg/kg) showed significant and dose-dependent prolongation of onset and duration of sleep and so found to cause decrease dopamine and increase serotonin level. From which it can be concluded that the CNS depressant activity of the ethanol extracts of seeds, leaves and flowers may be due to the decrease in dopamine and increase in serotonin level.

Antipsychotic Poisoning in Young Children

The aim of this review was to determine the spectrum and severity of effects of unintentional antipsychotic poisoning in children. A computerised literature search of MEDLINE (1966 to February 2005) and EMBASE (1980 to February 2005) was undertaken. The Internet was searched using URL: www.google.com. The proceedings of the North American Congress of Clinical Toxicology (NACCT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) were hand searched. All cases of unintentional antipsychotic (all classes) poisoning in children aged 0-6 years were included. The data extracted included the age, weight, antipsychotic, dose, clinical effects, treatment and outcomes. The toxic dose was estimated as the lowest dose causing objective adverse effects.Sixty-eight reports were identified. Few contained all of the required information. Most of the case series included multiple antipsychotics with limited information on individual drugs or all ages with limited paediatric information. For most antipsychotics the ingestion of one tablet caused symptoms that were sometimes severe and usually lasted from 1 to 3 days. Extrapyramidal symptoms (EPS) were often delayed for up to 12-24 hours. Chlorpromazine caused CNS depression, hypotension and miosis; EPS and cardiac effects were rare, and the toxic dose was estimated to be 15 mg/kg. Haloperidol caused drowsiness (rarely coma) and over one-half of patients had neuromuscular effects (mainly EPS), with a toxic dose estimated at 0.15 mg/kg. Thioridazine caused CNS depression and potentially cardiac effects, with a toxic dose of 1.4 mg/kg. Atypical antipsychotics caused significant CNS depression (except risperidone); EPS were less common. Toxic doses were clozapine 2.5 mg/kg, olanzapine 0.5 mg/kg and aripiprazole 3 mg/kg. EPS responded to anticholinergic drug treatment. In summary, unintentional antipsychotic ingestion in children can cause severe effects that last 1-3 days, often with one tablet. Children potentially ingesting a toxic dose or who are symptomatic should be considered for assessment in hospital. Most cases resolve with good supportive care. Toxic doses are only estimates that are based on limited data and should be used with caution until prospective studies are undertaken.

Metabolism of a novel hypnotic, N3-phenacyluridine, and hypnotic and sedative activities of its enantiomer metabolites in mouse

1. The metabolism of N3-phenacyluridine (3-phenacyl-1- beta-D-ribofuranosyluracil), a potent hypnotic nucleoside derivative, was studied in mouse. 2. Of the radioactivity, 65% was excreted in urine within 48 h after intraperitoneal (i.p.) administration of [3H] N3-phenacyluridine. The urinary metabolites N3-phenacyluracil and N3-alpha-hydroxy-beta-phenethyluridine were extracted, isolated and analyzed by mass spectrometry. 3. Racemates of N3-alpha-hydroxy-beta-phenethyluridine were synthesized and both isomers were separated as N3-(S)-(+)-alpha-hydroxy-beta-phenethyluridine and N3-(R)-(-)-alpha hydroxy-beta-phenethyluridine by hplc (CHIRALCEL-OJ column) with retentions of 13.8 and 17.9 min respectively. The reduction process took place with high stereo-selectivity, which gave an alcohol product in the urine with the same retention (17.9 min) as one of the synthetic isomers separated by hplc. 4. One of urinary metabolites was identified as N3-(S)-(+)-alpha-hydroxy-beta-phenethyluridine. N3-phenacyluridine was predominantly converted to an alcoholic metabolite of (S)-(+)-configuration. 5. N3-phenacyluracil and uridine were also identified as minor metabolites. 6. The pharmacological effects of the metabolites and related compounds were also evaluated in mouse. N3-(S)-(+)-alpha-hydroxy-beta-phenethyluridine, but not N 3-(R)-(-)-alpha hydroxy-beta-phenethyluridine, possessed hypnotic activity and potentiated pentobarbitalinduced sleeping time with a similar potency to the parent compound, N3-phenacyluridine. N3-alpha-hydroxy-beta-phenethyluridine (racemate) had almost two thirds of the hypnotic activity of N3-(S)-(+)- alpha-hydroxy-beta-phenethyluridine. No other metabolites exhibited hypnotic activities. 7. The present study indicates that N3-(S)-(+)-alpha-hydroxy-beta-phenethyluridine, a major metabolite of N3-phenacyluridine, is an active metabolite and contributes a significant CNS depressant effect.

The Poisoned Child: Evolving Concepts in Care

More than 1 million children in the United States ingest poisons each year. The vast majority of these exposures result in no harm to the child. The task of the emergency physician is to discern which children are at risk and treat those children with appropriately aggressive therapy while minimizing intervention for the rest. In pediatric exposure cases, the toxin is usually identified. A careful toxic differential diagnosis will lead to a list of likely poisons in symptomatic patients without an identified exposure. The cornerstone of treatment remains the evaluation of the ingestion episode, careful assessment of the patient, and the application of basic supportive medical care. In the ED, when it has been determined that gastrointestinal decontamination is indicated on the basis of the substance and quantity ingested, activated charcoal is the decontamination agent of choice if the substance ingested is absorbed by activated charcoal. Gastric emptying should be restricted to those circumstances when the substance ingested is not bound to activated charcoal or the rare event when a child presents to the ED within 1 hour of ingestion with significant CNS depression. Whole bowel irrigation is a recently described technique to enhance the passage of drugs already beyond the pylorus. The indications for its use are poorly defined. Laboratory tests are generally overordered after pediatric ingestions. Appropriate use of the laboratory includes an assessment of basic serum chemistry studies in symptomatic patients, confirmation of suspected toxins, and the determination of the need for specific antidotal therapy. General "drug screens" are expensive and rarely contribute to patient care. Use of specific therapies, including antidotes and enhanced elimination techniques, should be limited to those cases when expectation that a defined benefit outweighs the risk of the procedure is reasonable. The indications for the use of these interventions in children may be different from those for adults.

Anticonvulsant effects of extracts of the West African black pepper, Piper guineense

A water extract of the West African black pepper Piper guineense L. was tested for activity against audiogenic seizures in DBA/2 mice, and against seizures induced in T.O. mice by N- methyl- dl-aspartate (NMDLA), pentylenetetrazole (PTZ) and maximal electroshock. Single intraperitoneal doses of the extract produced significant protection of DBA/2 mice against audiogenic seizures. The highest of three doses tested produced 100% and 58% protection at 6 h and 18 h after treatment, respectively. The extract also protected T.O. mice against convulsions induced by NMDLA and maximal electroshock but it had no significant effect on PTZ-induced convulsions. The doses of the extract tested did not cause significant impairment of performance of T.O. mice on a rotarod test. The results indicate that the extract of P. guineense has prolonged anticonvulsant activity at doses which do not cause significant CNS depression.

Prophylaxis of amygdala kindling-induced epileptogenesis: Comparison of a GABA uptake inhibitor and diazepam

The prophylactic effect of an inhibitor of synaptosomal GABA uptake, SK&F 89976-A (N-[4,4-diphenyl-3-butenyl]-nipecotic acid), on the development of amygdala kindled seizures was studied in adult female rats. For comparative purposes, the action of diazepam was also investigated. Dosages of SK&F 89976-A and diazepam which were previously shown to be the ED 50 for seizure inhibition in fully kindled rats (15 mg/kg and 2 mg/kg i.p., respectively) were administered daily 30 min prior to amygdala stimulation in naive, unkindled rats. Both drugs inhibited the evolution of full kindled seizure activity and markedly suppressed kindling-associated increases in the duration of behavioral and electrographic seizures. Control rats developed fully kindled stage 5 seizures after 8.9 ± 1.1 amygdala stimulations but drug-treated rats did not progress beyond an early stage of kindled seizures as long as the animals were treated with the drugs (22 days). Diazepam produced significant CNS depressant effects throughout the course of administration but SK&F 89976-A prevented kindling with no depressant side effects. The ability of SK&F 89976-A and diazepam to inhibit the development of full amygdala kindled seizures may be related to enhancement of central inhibitory GABAergic systems.

Lack of CNS depression from large doses of trimethaphan in sheep.

It is not uncommon to observe prolonged CNS depression for several hours following controlled hypotension and halothane anesthesia for neurosurgery. The present study evaluates possible contribution of large doses of trimethaphan to CNS depression. Four adult sheep were placed on transapical left ventricular bypass (TALVB) withdrawing blood from the apex of the left ventricle through a roller pump, Pall Ultipor filter, and returning the blood to a carotid artery. In the awake and unanesthetized animals, 1 to 2 gm of trimethaphan were administered IV during each experiment while maintaining mean arterial pressure at 60 to 75 torr. Two sheep stood up and knelt down without obvious correlation with dose of trimethaphan administered at the time; two remained standing and continued eating during the trimethaphan infusion. Cardiovascular recovery from these large doses of trimethaphan was within 15 to 30 minutes after the conclusion of drug infusion. The data strongly suggest that large doses of trimethaphan have no significant CNS depression in the awake and unanesthetized sheep.

Neonatal Bromide Intoxication : Prenatal Ingestion of a Large Quantity of Bromides With Transplacental Accumulation in the Fetus

A 27-year-old woman who was 34 weeks pregnant was admitted in a semicomatose state. Five days later she gave birth to an infant who demonstrated significant CNS depression. Elevated blood levels confirmed bromide intoxication in both the mother and infant secondary to chronic maternal bromide ingestion (Nervine). Simultaneous determinations revealed a higher initial serum bromide level in the infant compared to that of the mother in spite of a subsequent more rapid rate of disappearance in the neonate. It is suggested that the drug history obtained from the pregnant woman include nonprescription medications containing bromides. This possibility should also be included in the differential diagnosis in infants exhibiting evidence of CNS depression, particularly those born to mothers classified as neurotic or psychotic.

Propylene glycol as a drug solvent in pharmacologic studies

Pharmacologic activity of propylene glycol (PG) was evaluated, using several procedures commonly employed in drug screening. Acute pretreatment of mice with 2.08 g/kg of PG (equivalent to administration of 0.01 ml/g of a 20% solution) produced a significant elevation in initial clonic seizure threshold to iv infusion of pentylenetetrazol, not apparent with this dose when a single CD99 dose of convulsant was used. Parallel results were obtained at higher doses of PG vs. strychnine convulsions. Potentiation of hexobarbital sleeping time was observed at doses of PG below the TD50 of 5.77 g/kg. Higher doses decreased spontaneous motor activity. Subchronic administration of PG did not alter hexobarbital sleeping time subsequently determined, but did diminish diphenylhydantoin anti-MES (maximal electroshock seizure) activity. Thus, at cosolvent concentrations which might be employed in animal experiments, PG exhibits weak but significant CNS depressant activity as well as strychnine, pentylenetetrazol, tremorine, and oxotremorine antagonist action. There-fore, use of PG as an “inert” cosolvent in pharmacologic studies cannot be recommended when the ip route is employed.

Evaluation of analgesic and neuropharmacological properties of the aerial part of <i>Tinospora cordifolia</i> Miers. in mice

Tinospora cordifolia Miers. is used in the Ayurvedic system of medicine for the treatment of jaundice, diabetes, and rheumatoid arthritis, and is also used as memory enhancer. But still there is no report of analgesic and neuropharmacological activities of the plant. For this reason, the present study was designed to evaluate analgesic and neuropharmacological activities of methanol extract of the aerial parts of Tinospora cordifolia. Analgesic activity of the crude extract at the dose of 200 and 400 mg/kg b.w. was evaluated for its central and peripheral pharmacological actions using hotplate and tail flick tests and acetic acid-induced writhing test respectively in mice. The extract produced a significant (p < 0.05-0.001) increase in pain threshold in hotplate and tail flick tests in a dose dependent manner. In acetic acid-induced writhing test the extract at both doses produced significant (p < 0.001) inhibition of writhing reaction but maximum inhibition (65.01%) of writhing was found at 400 mg/kg dose compared to the reference drug Diclofenac-Na at the dose of 10 mg/kg b.w. (77.07%). Neuropharmacological activity of the extract was also evaluated using rodent behabioural models; hole cross to evaluate motor activity, open field to evaluate exploratory behaviour and thiopental sodium-induced sleeping time to evaluate sedative potential of the extract. The extract significantly (p < 0.05-0.001) decreased motor activity and exploratory behavior of mice in hole cross and open field test respectively. The extract also produced rapid onset and maximized the duration of sleeping time when administered with thiopental sodium. Results of this study suggest that the aerial part of T. cordifolia possesses significant analgesic and CNS depressant activity. Key words: Tinospora cordifolia; Menispermaceae; Analgesic; Neuropharmacological.DOI: 10.3329/sjps.v2i2.5822Stamford Journal of Pharmaceutical Sciences Vol.2(2) 2009: 31-37

Clinical Comparison of Pharmacologic Emetics in Children

A simple method has been developed for the determination of the efficacy of pharmacologic emetic agents in children based on measuring the efficiency of stomach content return. The following conclusions can be reached from the study: (a) apomorphine can be safely administered by paramedical personnel, (b) it is not associated with significant CNS depression or protracted vomiting as has previously been feared, (c) it is faster acting than syrup of ipecac, and (d) it is equally effective in removing test material from the stomach as syrup of ipecac. However, it is apparent from this investigation that neither agent is truly effective or predictable in removing stomach contents, hence a search should be made for a more efficacious means of treating acute ingestions. Until more effective methods are found, it is recommended that syrup of ipecac be used as a first-aid measure in the home, and apomorphine be used in the emergency room.