Central Nervous System Depressant Effects Research Articles

Suboxone (Buprenorphine/Naloxone) Toxicity in Pediatric Patients

Suboxone, a combination of buprenorphine and naloxone in sublingual tablet form, was recently approved in the United States for management of opioid dependence. Little information exists regarding the potential for opioid toxicity after Suboxone exposure in the pediatric population. We report a case of opioid toxicity after exposure to Suboxone in a pediatric patient and a review of other cases of pediatric Suboxone ingestion in the literature. A previously healthy 2-year-old boy was found with 1 tablet of Suboxone (8 mg buprenorphine/2 mg naloxone) in his mouth. Remnants of the partly dissolved tablet were immediately removed from the child's oropharynx. The child experienced 1 episode of spontaneous emesis and became drowsy en route to the emergency department 30 minutes after the exposure. The patient was observed in the emergency department; no interventions were necessary, and the child was discharged asymptomatic and stable 6 hours post ingestion. Suboxone, a combination of buprenorphine and naloxone, may produce opioid toxicity via sublingual absorption or ingestion by children. We present the case of a child with mild central nervous system depression after exposure to Suboxone. Pediatric case reports that demonstrate more significant central nervous system and respiratory depressant effects from Suboxone ingestion are emerging.

Repetitive generalized seizure-like activity during emergence from sevoflurane anesthesia

Sevoflurane-induced seizures are most often described during mask induction of anesthesia when high concentrations of the volatile agent are administered concomitant with alveolar hyperventilation. The occurrence of seizure-like activity during emergence from sevoflurane anesthesia has been rarely reported. We describe a patient who developed several episodes of generalized tonic-clonic seizure-like activity during and immediately after emergence from sevoflurane anesthesia and discuss the potential factors that contributed to this unusual complication. The patient was treated with intravenous propofol, midazolam, and phenytoin and required intensive care management before his neurologic status stabilized. The report emphasizes that sevoflurane is capable of producing excitatory central nervous system (CNS) phenomena in spite of causing primarily CNS depressant effects.

Sitting position does not alter minimum alveolar concentration for desflurane

Hypotension is a common complication of the sitting position during anesthesia, and is often counteracted by decreasing anesthetic depth, thereby exposing patients to the risk of being inadequately anesthetized. Baroreceptor unloading and the consequent sympathoexcitation, as during head up tilt, decreases pain threshold and arouses the central nervous system (CNS), whereas hypotension exerts a direct CNS depressant effect. We estimated the minimal alveolar concentration (MAC) of desflurane for immobility in patients undergoing surgery in the sitting position, in comparison to MAC desflurane for patients having a similar type of surgery in the supine position. The Dixon up-and-down method was used to evaluate the MAC for desflurane in patients undergoing cervical spine laminoplasty (n = 24) or discectomy (n = 24) in the sitting and supine positions, respectively. Logistic regression with co-variate adjustment was employed to examine if the two positions (sitting and supine) have different or share the same concentration vs response relationship for immobility. Monte Carlo simulation was used to calculate 95% confidence intervals (CI) for the MAC in each position, and to estimate the difference in MAC (delta MAC) between the sitting and supine positions. Modeling both sitting [6.54% (6.50-6.66, 95% CI)] and supine [6.70 (6.55-6.81)] patients as having different MAC concentrations did not significantly improve our simplified model, which treats the two patient groups as one [6.61 (6.52-6.70), delta -2 log likelihood = 2.735, P = 0.098]. Mean delta MAC (95% CI) was -0.14 (-0.30, 0.03). The sitting position does not change desflurane anesthetic requirements for immobility.

Enaminone Amides as Novel Orally Active GABAAReceptor Modulators

A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma-aminobutyric acidA (GABAA) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [35S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha1beta2gamma2L GABAA receptors. The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervous system depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-dark paradigm.

Combining Physostigmine with Meperidine for Sedation and Analgesia During Colonoscopy

Opiate or benzodiazepine drugs are often used during colonoscopy, but they are associated with respiratory depression and prolonged recovery. Physostigmine, a tertiary anticholinesterase agent, is known to enhance analgesia and to reverse the central nervous system depressant effects of these drugs. This study compared the effect of giving meperidine alone with the effect of giving meperidine in combination with physostigmine in patients who were undergoing complete colonoscopy. A total of 44 outpatients undergoing elective colonoscopy were randomly assigned to receive analgesia with either meperidine 0.5 mg/kg intravenously (group 1, n=24) or physostigmine 10 micrograms/kg intravenously, followed 5 minutes later by meperidine 0.5 mg/kg intravenously (group 2; n=20). The patients were assessed with regard to oxygen saturation, hemodynamic changes, pain perception and sedation scores, readiness to go home, and adverse effects. The group 1 patients' oxygen saturations consistently fell, both during the procedure and in the recovery period; in group 2, oxygen saturations remained stable throughout the procedure and recovery period (95.88%+/-0.99 vs. 98.15+/-0.99, P<0.001). Patients in group 2 reported lower pain perception scores during the procedure (measured using a visual analog scale) than patients in group 1 (1.46+/-0.31 vs. 1.75+/-0.41; F1,42=6.484, P<0.015) and were less sedated during recovery (F1,41=6.56, P<0.015). No significant differences were found between the two groups with regard to heart rate or arterial blood pressure. All patients in group 2 were ready to go home after 25 minutes in the recovery area; three patients in group 1 were not ready to leave at 25 minutes and left the facility after 60 minutes. Four patients suffered from minor side effects of physostigmine (sweating and nausea). Combining physostigmine with meperidine as preparatory treatment for patients undergoing colonoscopy prevents respiratory depression, improves analgesia, and shortens recovery time, with only mild side effects.

Metoclopramide-induced central nervous system depression in the chicken

BackgroundMetoclopramide is a dopamine D2-receptor antagonist used as an antiemetic and gastroprokinetic agent in man and animals. The drug causes sedation as a side effect in man. Such a sedative action of metoclopramide has not been documented in the chicken as the drug is not used clinically in this species. The present study examines the central nervous system depressant effects of metoclopramide in 7–14 days old broiler chicks.ResultsInjection of metoclopramide at 50, 100 and 200 mg/kg, subcutaneously (s.c.) induced sedation in the chicks in a dose dependent manner. The chicks manifested, within 3.6–19 minutes of metoclopramide injection, signs of sedation characterized by drooping of the head and wings, closed eyelids, reduced motility and decreased distress calls. The duration of sedation ranged between 37.2 to 163.4 minutes. Metoclopramide at 100 and 200 mg/kg induced, within 12.2 and 6.2 minutes, sleep (loss of righting reflex) for 43.8 and 158.6 minutes, respectively. The median effective doses of metoclopramide for induction of sedation and sleep in the chicks were 11 and 53 mg/kg, s.c., respectively. Lower doses of metoclopramide (5 and 10 mg/kg, s.c.) significantly decreased the open-field activity of the chicks and increased the durations of their tonic immobility. All treated-chicks recovered from the central nervous system depressant effect of metoclopramide without any observable adverse effects.ConclusionThe data suggest that metoclopramide induces central nervous system depression in chicks, and the drug could have potential clinical applications as a sedative-hypnotic agent in avian species not intended for human consumptions.

Effects of First- and Second-Generation Histamine-H1-Receptor Antagonists on the Pentobarbital-Induced Loss of the Righting Reflex in Streptozotocin-Induced Diabetic Mice

The second-generation histamine-H1-receptor antagonists, such as epinastine and cetirizine, are used as non-sedating antihistamines for treating allergic symptoms due to their poor ability to penetrate blood-brain barrier. Because it has been reported that the blood-brain barrier system is disturbed in diabetes, it is possible that second-generation histamine-H1-receptor antagonists may easily penetrate the blood-brain barrier and cause potent sedation in diabetics. In the present study, we investigated the effects of first-generation (diphenhydramine) and second-generation (epinastine and cetirizine) histamine-H1-receptor antagonists on the duration of pentobarbital-induced loss of the righting reflex (LORR) in non-diabetic and diabetic mice. Systemic treatment with diphenhydramine (3 – 30 mg/kg, s.c.), and intracerebroventricular treatment with epinastine (0.03 – 0.3 μg/mouse) and cetirizine (0.03 – 0.3 μg/mouse) dose-dependently and significantly increased the duration of pentobarbital-induced LORR in both nondiabetic and diabetic mice. Although systemic treatment with epinastine (3 – 30 mg/kg, s.c.) and cetirizine (3 – 30 mg/kg, s.c.) did not affect the duration of pentobarbital-induced LORR in nondiabetic mice, these treatments significantly prolonged it in diabetic mice. Our results suggest that the systemic administration of second-generation histamine-H1-receptor antagonists may produce a central nervous system depressant effect in diabetes.

The Sydney Medically Supervised Injecting Centre: reducing harm associated with heroin overdose

The Sydney Medically Supervised Injecting Centre (MSIC) commenced operation on a trial basis in May 2001. Operating within a clinical model, the Centre's primary objective is to reduce the morbidity and mortality associated with drug overdose. Staff include nurses authorized to administer naloxone to reverse the central nervous system depressant effects of heroin, according to clinical protocols developed and modified for the Centre's setting. Data were collected on clients’ drug overdose history, demographics, and recent drug and alcohol use at each subsequent visit. The MSIC registered 3747 injecting drug users and supervised 56 861 injecting episodes (61% to inject heroin, 30% to inject cocaine and 9% other drugs) in the first 18 months of operation. A total of 409 drug overdoses occurred (80% heroin, 15% cocaine and 5% other drugs) during this time. Among the heroin overdoses treated, 25% also required naloxone. Risk factors identified included history of heroin overdose, heroin as the main drug injected, engagement in sex work, frequent attendance at the MSIC, and otherwise injecting in a public place. Being in methadone maintenance treatment and a daily injector at registration were protective. Overall, It is likely that the early intervention provided by the supervised setting of the MSIC reduced the morbidity and mortality that would have otherwise been associated with these drug overdoses had they occurred elsewhere. Better understanding of risk factors for heroin overdose has the potential to also prevent heroin overdose in this and other settings.

Unmasking Anticholinergic Load: When 1 + 1= 3

AbstractThe cholinergic system is a major neuromodulatory neurotransmitter system, interacting with core regions of the brain and affecting learning and memory function. Cholinergic function is severely reduced in patients with pathologic conditions, such as Alzheimer's disease. Muscarinic receptors M1–M5 are located at the postsynaptic level of the central cholinergic synapse. Blockage of certain muscarinic receptors has been shown to affect cognitive functioning. The roles of the individual receptor subtypes has implications for pharmacotherapy; eg, nonselective antimuscarinic/anticholinergic medications may block muscarinic neurotransmission, causing deficits in recall and new learning, while M1-receptor agonists and M2-receptor antagonists may not interfere with cognitive functioning. Studies investigating central nervous system (CNS) depressant effects of drugs have shown that antimuscarinic agents have the potential to cause impairment of CNS functioning. CNS dysfunction may be manifested as changes in memory, disruption of sleep, hallucinations, confusion, and delirium.Anticholinergic load refers to the cumulative effect of taking multiple drugs with anticholinergic activity. The extent to which a particular drug affects the cholinergic system can be determined by its ability to cross the blood-brain barrier, the integrity of which decreases with age. Elderly individuals are also at high risk for increased anticholinergic load due to reductions in metabolism and elimination as well as pharmacokinetic drug interactions. In addition, elderly people are often prescribed several medications that have direct anticholinergic properties and take over-the-counter medications which may also carry substantial anticholinergic burden. The cumulative effect of these medications in vulnerable elderly patients may precipitate early cognitive declines or further exacerbate cognitive deficits in those already suffering from dementia. Risk of cognitive impairment in patients with overactive bladder can thus be reduced through use of M3-selective antagonists, such as darifenacin, and via alternatives to pharmacotherapy, such as behavioral modification, pelvic floor strengthening, and bladder-retraining exercises.

Effects of second-generation histamine H 1 receptor antagonists on the sleep–wakefulness cycle in rats

The present study was performed to examine the sedative effects of second-generation histamine H 1 receptor antagonist using power spectrum analysis in the rat. Similar to ketotifen, olopatadine caused a decrease in sleep latency at a dose of 50 mg/kg, while epinastine and cetirizine showed no significant effect even at a dose of 50 mg/kg. On the other hand, no significant difference was observed in the total times of wakefulness, non-rapid eye movement sleep and rapid eye movement sleep by any drugs used in the experiments. The number of sleep phases and interval between sleep phases were also unchanged by these drugs. Ketotifen and olopatadine inhibited [ 3H]mepyramine binding to rat brain homogenates in parallel with a decrease in sleep latency. No significant effect was observed with epinastine and cetirizine on [ 3H]mepyramine binding. These findings suggest that the differences in the central nervous system (CNS) depressant effect observed in second generation H 1 receptor antagonists may be due to their liability to penetrate into the CNS.

Neuropharmacological profile of hydroalcohol extract of Valeriana edulis ssp. procera roots in mice.

Valerian is the common name given to the crude drug consisting of the underground organs of the species Valeriana. Valeriana edulis ssp. procera Meyer is the Mexican valerian. The aim of the present work was to elucidate the neuropharmacological profile of a hydroalcohol extract of Valeriana edulis roots at doses of 100, 300 and 1000 mg/kg in several experimental models. A dose-dependent anticonvulsant and anxiolytic-like effect of V. edulis was demonstrated. In addition, the extract decreased rotarod performance and traction force and prolonged the pentobarbital-induced sleeping time at high doses. Concomitant administration of valerian extract and pentobarbital showed a synergistic effect on motor coordination and traction force in mice. The anxiolytic-like effect of V. edulis was compared with diazepam and with diphenhydramine and doxylamine, the latter in order to consider the H(1)-antihistamine effect as another possibility to explain, at least in part, the central nervous system depressant effect of valerian. These results also underlie the medical and industrial use of this species and allowed the conclusion that the extract of V. edulis has central nervous depressant properties similar to, but with some differences to V. of ficinalis, a very well known species.

Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels

Human TREK-1 and TRAAK (hTREK-1 and hTRAAK) are the recently cloned tandem pore-domain potassium channels that are highly expressed in the central nervous system (CNS). The roles of 2P domain K + channels in general anesthesia and neuroprotection have been proposed recently. We have investigated the ability of 2,2,2-trichloroethanol (an active metabolite of the general anesthetic chloral hydrate (CH)) to modulate the activity of hTREK-1 and hTRAAK channels expressed heterologously in Chinese hamster ovary cells by using whole-cell patch-clamp recording. Trichloroethanol potentiated hTREK-1 and hTRAAK channel activity in a reversible, concentration-dependent manner. The parent compound CH also augmented the activity of both the channels reversibly. CH activation of hTREK-1 was transient followed by a rapid inhibition, whereas hTRAAK activation was not followed by inhibition. Deletions of the carboxy terminal domain (Δ89, Δ100 and Δ119) of hTREK-1 did not abolish sensitivity to TCE (20 mM) suggesting that C-terminal tail is not essential for the activation of hTREK-1 by TCE. The hTREK-1 currents consisted of an instantaneous and a time-dependent component. The time-dependent current was reduced by trichloroethanol (20 mM). Our findings identify TREK-1 and TRAAK channels as molecular targets for trichloroethanol and suggest that activation of these channels might contribute to the CNS depressant effects of CH.

Pharmacological study of 'treenoponchomul'-an Ayurvedic diuretic preparation

The pharmacological effects of an Ayurvedic diuretic drug 'Treenoponchomul' (TPM) was investigated in animal model. The pharmacological actions of the test drug along with that of the components thereof, on the Central Nervous System (CNS) were studied. The drug under study TPM showed little effect on the CNS, the same can not be said about the components. The most prominent CNS depressant effect was observed with Saccharum officinarum Linn. (EE) in that it lowered the spontaneous motor activity as well the exploratory -behavior of the animals. An exploration retarding effect of moderate degree, was evident with Imperata cylindrica Beauv. (UU), and Phragmites maxima Blatter & McCann (NN). Although the test drug did not alter the normal locomotor and/ or exploratory behavior of the treated animals, it did significantly (p<0.01) lower the locomotion of the amphetamine induced hyperactive animals. TPM along with its components (especially Desmostachya bipinnata Stapf. Root, KU), significantly reduced the gastro-intestinal motility of the treated animals (p<0.01). The test drug and its components lowered the body weight of the treated animals, on being administered chronically (30 days), with EE being the only exception.

Portier, Richet, and the discovery of anaphylaxis: A centennial

Portier, Richet, and the discovery of anaphylaxis: A centennial

Nonhalogenated alkane anesthetics fail to potentiate agonist actions on two ligand-gated ion channels.

Although ether, alcohol, and halogenated alkane anesthetics potentiate agonist actions or increase the apparent agonist affinity of ligand-gated ion channels at clinically relevant concentrations, the effects of nonhalogenated alkane anesthetics on ligand-gated ion channels have not been studied. The current study assessed the abilities of two representative nonhalogenated alkane anesthetics (cyclopropane and butane) to potentiate agonist actions or increase the apparent agonist affinity of two representative ligand-gated ion channels: the nicotinic acetylcholine receptor and y-aminobutyric acid type A (GABA(A)) receptor. Nicotinic acetylcholine receptors were obtained from the electroplax organ of Torpedo nobiliana, and human GABA(A) receptors (alpha1beta2gamma2L) were expressed in human embryonic kidney 293 cells. The Torpedo nicotinic acetylcholine receptors apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the apparent rates of desensitization induced by a range of acetylcholine concentrations. The GABA(A) receptor's apparent agonist affinity in the presence and absence of anesthetic was assessed by measuring the peak currents induced by a range of GABA concentrations. Neither cyclopropane nor butane potentiated agonist actions or increased the apparent agonist affinity (reduced the apparent agonist dissociation constant) of the Torpedo nicotinic acetylcholine receptor or GABA(A) receptor. At clinically relevant concentrations, cyclopropane and butane reduced the apparent rate of Torpedo nicotinic acetylcholine receptor desensitization induced by low concentrations of agonist. Our results suggest that the in vivo central nervous system depressant effects of nonhalogenated alkane anesthetics do not result from their abilities to potentiate agonist actions on ligand-gated ion channels. Other targets or mechanisms more likely account for the anesthetic activities of nonhalogenated alkane anesthetics.

A pharmacological study of Cecropia obtusifolia Bertol aqueous extract

Cecropia obtusifolia (Cecropiaceae) is a species from tropical America and its leaves are used in traditional medicine for the treatment of diabetes and as an anti-inflammatory agent. In the present study, the analgesic, anti-inflammatory and central nervous system depressant effects of the aqueous extract from the leaves of C. obtusifolia were investigated in different experimental models, with the purpose of validating its ethnomedical uses. The results obtained with the extract from the leaves of C. obtusifolia reflect a low toxicity, a substantial central depressor effect and analgesic activity and significant motor incoordination and muscle relaxant activity. Concerning the analgesic activity, using the hot plate test, the extract did not produce any effect, however it showed a significant effect on the pain induced by chemical stimuli (acetic and formalin test); this suggests the peripheral analgesic effect of the extract. The extract also showed a topical and systemic anti-inflammatory effect. Thus this work could justify the popular use of C. obtusifolia in rheumatic and kidney inflammation pathologies and reveals that this plant is an interesting species

Anesthetic properties of 4-iodopropofol: implications for mechanisms of anesthesia.

Positive modulation of gamma-aminobutyric acid type A (GABAA) receptor function is recognized as an important component of the central nervous system depressant effects of many general anesthetics, including propofol. The role for GABAA receptors as an essential site in the anesthetic actions of propofol was recently challenged by a report that the propofol analog 4-iodopropofol (4-iodo-2,6-diisopropylphenol) potentiated and directly activated GABAA receptors, yet was devoid of sedative-anesthetic effects in rats after intraperitoneal injection. Given the important implications of these findings for theories of anesthesia, the authors compared the effects of 4-iodopropofol with those of propofol using established in vivo and in vitro assays of both GABAA receptor-dependent and -independent anesthetic actions. The effects of propofol and 4-iodopropofol were analyzed on heterologously expressed recombinant human GABAA alpha1beta2gamma2 receptors, evoked population spike amplitudes in rat hippocampal slices, and glutamate release from rat cerebrocortical synaptosomes in vitro. Anesthetic potency was determined by loss of righting reflex in Xenopus laevis tadpoles, in mice after intraperitoneal injection, and in rats after intravenous injection. Like propofol, 4-iodopropofol enhanced GABA-induced currents in recombinant GABAA receptors, inhibited synaptic transmission in rat hippocampal slices, and inhibited sodium channel-mediated glutamate release from synaptosomes, but with reduced potency. After intraperitoneal injection, 4-iodopropofol did not produce anesthesia in mice, but it was not detected in serum or brain. However, 4-iodopropofol did produce anesthesia in tadpoles (EC50 = 2.5 +/- 0.5 microM) and in rats after intravenous injection (ED50 = 49 +/- 6.2 mg/kg). Propofol and 4-iodopropofol produced similar actions on several previously identified cellular and molecular targets of general anesthetic action, and both compounds induced anesthesia in tadpoles and rats. The failure of 4-iodopropofol to induce anesthesia in rodents after intraperitoneal injection is attributed to a pharmacokinetic difference from propofol rather than to major pharmacodynamic differences.

Sustained isocapnic hypoxia suppresses the perception of the magnitude of inspiratory resistive loads

The sensation of increased respiratory resistance or effort is likely to be important for the initiation of alerting or arousal responses, particularly in sleep. Hypoxia, through its central nervous system-depressant effects, may decrease the perceived magnitude of respiratory loads. To examine this, we measured the effect of isocapnic hypoxia on the ability of 10 normal, awake males (mean age = 24.0 +/- 1.8 yr) to magnitude-scale five externally applied inspiratory resistive loads (mean values from 7.5 to 54.4 cmH(2)O. l(-1). s). Each subject scaled the loads during 37 min of isocapnic hypoxia (inspired O(2) fraction = 0.09, arterial O(2) saturation of approximately 80%) and during 37 min of normoxia, using the method of open magnitude numerical scaling. Results were normalized by modulus equalization to allow between-subject comparisons. With the use of peak inspiratory pressure (PIP) as the measure of load stimulus magnitude, the perception of load magnitude (Psi) increased linearly with load and, averaged for all loaded breaths, was significantly lower during hypoxia than during normoxia (20.1 +/- 0.9 and 23.9 +/- 1.3 arbitrary units, respectively; P = 0. 048). Psi declined with time during hypoxia (P = 0.007) but not during normoxia (P = 0.361). Our result is remarkable because PIP was higher at all times during hypoxia than during normoxia, and previous studies have shown that an elevation in PIP results in increased Psi. We conclude that sustained isocapnic hypoxia causes a progressive suppression of the perception of the magnitude of inspiratory resistive loads in normal subjects and could, therefore, impair alerting or arousal responses to respiratory loading.

Antinociceptive effects of the tubercles of Anredera leptostachys

The tubercles of Anredera leptostachys are used as an antinociceptive and anti-inflammatory in the popular medicine of the Caribbean basin. In the present work, the anti-nociceptive and central nervous system depressant (CNS) effects of the methanolic extract from the tubercles of A. leptostachys have been evaluated. The antinociceptive activity was assayed in several experimental models in mice: acetic acid, formalin and hot plate tests. The methanolic extract (250 and 500 mg/kg) significantly and in a dose-dependent manner reduced the nociception induced by the acetic acid ( P<0.001). In the hot plate test, the extract significantly increased the latency time of jump although it slightly increased the licking time. The naloxone partially reversed the antinociception of the extract in the hot plate test. In the formalin test, the methanolic extract also significantly reduced the painful stimulus but the effect was not dose-dependent. In the study of the CNS-depressant effects, the extract was found to produce a significant reduction of the exploratory capacity with both doses assayed ( P<0.001). The muscular relaxation only decreased with the higher doses assayed ( P<0.001). The escape instinct was also significantly reduced ( P<0.001) by the two doses of the extract and both were more effective than standard drugs morphine and diazepam.

Central nervous system depressant effect of Hoslundia opposita Vahl

Central nervous system depressant effect of Hoslundia opposita Vahl