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Test Drug (test + drug)
Selected AbstractsEnhanced Anticonvulsant Activity of Neuroactive Steroids in a Rat Model of Catamenial EpilepsyEPILEPSIA, Issue 3 2001Doodipala S. Reddy Summary: ,Purpose: Perimenstrual catamenial epilepsy may in part be due to withdrawal of the endogenous progesterone-derived neurosteroid allopregnanolone that potentiates ,-aminobutyric acidA (GABAA) receptor,mediated inhibition. Here we sought to determine whether the anticonvulsant potencies of neuroactive steroids, benzodiazepines, phenobarbital (PB), and valproate (VPA) are altered during the heightened seizure susceptibility accompanying neurosteroid withdrawal in a rat model of perimenstrual catamenial epilepsy. Methods: Test drugs were evaluated for their ability to alter the convulsant activity of pentylenetetrazol (PTZ) in young adult female rats, in pseudopregnant rats with prolonged exposure to high levels of progesterone (and its neurosteroid metabolites), and in pseudopregnant rats 24 h after acute withdrawal of neurosteroids by treatment with the 5,-reductase inhibitor finasteride. Test drugs were administered at doses equivalent to twice their ED50 values for protection against PTZ-induced clonic seizures in naive young adult female rats. Results: The anticonvulsant activity of allopregnanolone (5 mg/kg, s.c.), pregnanolone (5 mg/kg, s.c.), allotetrahydrodeoxycorticosterone (15 mg/kg, s.c.), and tetrahydrodeoxycorticosterone (10 mg/kg, s.c.) were enhanced by 34,127% after neurosteroid withdrawal. The anticonvulsant activity of PB (65 mg/kg, i.p.) was also enhanced by 24% in neurosteroid-withdrawn animals. In contrast, the anticonvulsant activity of diazepam (4 mg/kg, i.p.), bretazenil (0.106 mg/kg, i.p.), and VPA (560 mg/kg, i.p.) were reduced or unchanged in neurosteroid-withdrawn animals. Conclusions: The anticonvulsant activity of neuroactive steroids is potentiated after neurosteroid withdrawal, supporting the use of such agents in the treatment of perimenstrual catamenial epilepsy. [source] The Pharmacokinetics of Antiepileptic Drugs in Rats: Consequences for Maintaining Effective Drug Levels during Prolonged Drug Administration in Rat Models of EpilepsyEPILEPSIA, Issue 7 2007Wolfgang Löscher Summary:, Rodent models of chronic epilepsy with spontaneous recurrent seizures likely represent the closest parallel to the human condition. Such models may be best suited for therapy discovery for pharmacoresistant epilepsy and for antiepileptogenic or disease-modifying therapeutics. However, the use of such rodent models for therapy discovery creates problems with regard to maintaining effective drug levels throughout a prolonged testing period. This is particularly due to the fact that rodents such as rats and mice eliminate most drugs much more rapidly than humans. Thus, knowledge about elimination rate of a test drug in a laboratory species is essential for development of a treatment paradigm that allows maintaining adequate drug levels in the system over the period of treatment. Currently, the most popular models of epilepsy with spontaneous seizures are poststatus epilepticus models of temporal lobe epilepsy in rats. Such models are both used for studies on antiepileptogenesis and drug resistance. For validation of these models, current antiepileptic drugs (AEDs) have to be used. In this article, the elimination rates of these AEDs and their effective plasma levels in rats are reviewed as a guide for developing treatment protocols for chronic drug testing. The advantages and disadvantages of several technologies for drug delivery are discussed, and some examples for calculation of adequate treatment protocols are given. As shown in this review, because of the rapid elimination of most AEDs in rats, it is no trivial task to maintain effective steady-state AED levels in the plasma throughout the day over multiple days to ensure that there will be adequate levels in the system for the purpose of the experiment. However, the use of an adequate dosing regimen that is based on elimination rate is an absolute prerequisite when using rat models for discovery of new antiepileptogenic therapies or therapies for pharmacoresistant epilepsy, because otherwise such models may lead to erroneous conclusions about drug efficacy. [source] Valproate Suppresses Status Epilepticus Induced by 4-Aminopyridine in CA1 Hippocampus RegionEPILEPSIA, Issue 11 2003Eduardo D. Martín Summary:,Purpose: We investigated the effects of valproate (VPA) on an in vivo model of status epilepticus (SE) induced by intrahippocampal application of 4-aminopyridine (4-AP). Methods: To induce continuous epileptiform activity without a clinical component, 4-AP (100 mM) was slowly injected in the hippocampus of adult rats. Extracellular field potential from the CA1 region of the rat hippocampus was recorded to assess abnormal epileptiform activity. Once the SE seizures were induced by 4-AP, the test drug was injected. In some experiments to test the ability of a drug to prevent the induction of SE, the drug was administered before 4-AP injection. Results: Intrahippocampal injection of 4-AP induced continuous epileptic activity without a clinical component that lasted >60 min. The intravenous injection of 400,600 mg/kg VPA rapidly (,100 s) abolished the SE, and this effect persisted for ,4 h in our experimental model. The intravenous injection of 100,300 mg/kg VPA did not abolish previously induced SE, but prevented the appearance of SE when applied before the induction of SE. The intravenous injection of 80 mg/kg phenytoin or carbamazepine did not abolish or prevent SE. Conclusions: We conclude that 4-AP,induced SE was suppressed by VPA at 400,600 mg/kg, whereas minor doses (100,300 mg/kg) only prevent the 4-AP,induced SE. Present results suggest the revisiting of VPA as a useful drug for the treatment of SE. [source] Probability of acceptable intubation conditions with low dose rocuronium during light sevoflurane anaesthesia in childrenACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 8 2001M. Eikermann Background: To define the rocuronium doses which would provide 50%, 90%, and 95% probability of ,acceptable' intubation conditions during light sevoflurane anaesthesia, we studied 60 children aged 2,7 years in a prospective, randomised, assessor blinded study. Methods: After mask ventilation with 1 MAC sevoflurane/N2O for 17±1 (x̌±SD) min we administered rocuronium (either 0.15, 0.22, 0.3, 0.5, or 1.0 mg ,· ,kg,1) or placebo, and quantified the evoked force of the adductor pollicis muscle. Intubation conditions were assessed before and 2 min after injection of the test drug. Results: Intubation conditions were improved significantly with rocuronium and scored ,acceptable' in 70%, 90%, and 100% of the children after injection of rocuronium 0.15, 0.22, and 0.3 mg ,· ,kg,1, respectively. In parallel, twitch tension decreased to 53% (6,100), 26% (11,100), and 11% (0,19) of baseline (median (range)). Recovery of train-of-four ratio to 0.8 was achieved 13 (7,19), 16 (8,28), and 27 (23,44) min after injection of the respective rocuronium doses. Higher rocuronium doses did not further improve intubation conditions but only prolonged time of neuromuscular recovery. Logistic regression analysis revealed that rocuronium 0.11 (CI 0.05,0.16), 0.21 (0.14,0.28), and 0.25 (0.15,0.34) mg ,· ,kg,1 provides a 50%, 90%, and 95% probability of ,acceptable' intubation conditions in children during 1 MAC sevoflurane/N2O anaesthesia, respectively. Furthermore, we calculated that force depression of adductor pollicis muscle to 81% (CI 72,90), 58% (42,74), and 50% (29,71) of baseline is associated with 50%, 90%, and 95% probability of ,acceptable' intubation conditions. Conclusions: Submaximal depression of muscle force with low dose rocuronium improves intubation conditions in children during light sevoflurane anaesthesia while allowing rapid recovery of neuromuscular function. However, when using low dose rocuronium neuromuscular monitoring may be helpful to detect children with inadequate response to the relaxant so as to avoid an unsuccessful intubation attempt. [source] Influence of topical antifungal drugs on ciliary beat frequency of human nasal mucosa,THE LARYNGOSCOPE, Issue 7 2010An In Vitro Study Abstract Objectives/Hypothesis: Topical antifungal treatment is a subject of discussion in the treatment of chronic rhinosinusitis. The aim of this research was to study the effects of antifungal drugs on ciliary beat frequency (CBF) of human nasal mucosa under in vitro conditions. Study Design: Case series of in vitro experiments and in vitro study of cultured ciliated cells of human nasal mucosa. Methods: Human nasal mucosa was acquired during routine endoscopic sinus surgery. Cells were cultivated on object slides and exposed to different antifungal drugs in a newly developed test system. This system allowed continuous and reproducible exposure to different drugs at constant temperature, pH value, and osmolarity. The drugs were amphotericin B in two different concentrations and itraconazole. Results: Rinsing with higher concentrations of amphotericin B led to an immediate decrease of CBF, with a total stop after 15 minutes. A different result was seen in the group with lower concentrations; CBF decreased again quickly after rinsing with the test drug, but all of them recovered after rinsing with neutral solution. When using itraconazole a decline in CBF was observed again; one half of the samples returned to activity. Conclusions: Our in vitro results demonstrate a dose-dependent effect of the antifungal drugs amphotericin B and itraconazole on ciliary beat frequency of human nose epithelium. Laryngoscope, 2010 [source] | ||||||||||