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Wolfgang Löscher - One of the best experts on this subject based on the ideXlab platform.
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anticonvulsant and proconvulsant effects of tramadol its enantiomers and its m1 metabolite in the rat kindling model of epilepsy
British Journal of Pharmacology, 2000Co-Authors: Heidrun Potschka, Elmar Friderichs, Wolfgang LöscherAbstract:The centrally acting analgesic tramadol has recently been reported to cause Seizures at re-commended dosages in patients, whereas animal experiments had indicated that Seizures only occur in high, toxic doses. Tramadol has a dual mechanism of action that includes weak agonistic effects at the mu-opioid receptor as well as inhibition of monoamine (serotonin, norepinephrine) re-uptake. Its major (M1) metabolite mono-O-desmethyltramadol, which is rapidly formed in vivo, has a markedly higher affinity for mu receptors and may thus contribute to the effects of the parent compound. Furthermore, the pharmacological effects of tramadol appear to be related to the different, but complementary and interactive pharmacologies of its enantiomers. In the present study, we evaluated (±)-tramadol, its enantiomers, and its M1 metabolite ((+)-enantiomer) in the amygdala kindling model of epilepsy in rats. Adverse effects determined in kindled rats were compared to those in nonkindled rats. At doses within the analgesic range, (±)-tramadol and its enantiomers induced anticonvulsant effects in kindled rats. However, at only slightly higher doses Seizures occurred. With (±)-tramadol, generalized Seizures were observed at 30 mg kg−1 in most kindled but not in nonkindled rats. The (−)-enantiomer induced Myoclonic Seizures at 30 mg kg−1 in most kindled but not in nonkindled rats, although Myoclonic Seizure activity was observed in some nonkindled rats at 10 or 20 mg kg−1. Seizures were also observed after the (+)-enantiomer and the (+)-enantiomer of the M1 metabolite, but experiments with higher doses of these compounds were limited by marked respiratory depression. The data demonstrate that kindling enhances the susceptibility of rats to convulsant adverse effects of tramadol and its enantiomers, indicating that a preexisting lowered Seizure threshold increases the risk of tramadol-induced Seizures. Keywords: Opioids, analgesics, Seizures, noradrenaline, serotonin Introduction The centrally acting analgesic tramadol possesses weak opioid agonist properties and inhibits norepinephrine (NE) and serotonin (5-hydroxytryptamine, 5-HT) uptake (Dayer et al., 1994; Raffa et al., 1995; Lewis & Han, 1997). Tramadol is an effective and relative safe analgesic that has been prescribed for almost two decades in Europe, and was approved for marketing in the United States in 1995 for the treatment of moderate to moderately severe pain (Lee et al., 1993; Gibson, 1996; Lewis & Han, 1997; Bamigbade & Langford, 1998). However, in the years after its release in the United States, an increased risk of Seizures associated with tramadol was reported (Kahn et al., 1997). This adverse drug effect occurred at recommended dosages, although an overdose may increase the risk of tramadol-related Seizures (Kahn et al., 1997). It is long known that opioid analgesics such as morphine and related drugs can produce convulsions, but with most opioids convulsions occur only in doses far in excess of those required to produce profound analgesia (c.f., Frenk, 1983). With respect to tramadol, animal experiments also indicated that convulsions only occur in high, toxic doses (Friderichs et al., 1978; Osterloh et al., 1978; Matthiesen et al., 1998). This apparent paradox between preclinical data and the risk of Seizures associated with tramadol in patients may be related to the fact that most clinical reports were from patients receiving concomitant treatment with other drugs which may increase the risk of tramadol-related Seizures (Khan et al., 1997; Jick et al., 1998). In the present study, we used the kindling model of temporal lobe epilepsy to evaluate the proconvulsant activity of tramadol in more detail. Because a recent study indicated that tramadol exerts anticonvulsant effects in the maximal electroshock Seizure (MES) test in mice (Manocha et al., 1998), we also assessed whether tramadol possesses anticonvulsant activity in the kindling model. In view of our previous finding that kindling-induced epileptogenesis may enhance the adverse effect potential of drugs (Loscher & Honack, 1991; Honack & Loscher, 1995; Loscher, 1998; Wlaz & Loscher, 1998), adverse effects of tramadol in kindled rats were compared to those in nonkindled rats. Tramadol is a racemic 1:1 mixture of two enantiomers, (+)-tramadol and (−)-tramadol which differ in their potencies at opioid receptors and monoamine uptake sites (Raffa et al., 1993). Furthermore, (±)-tramadol is rapidly metabolized to mono-O-desmethyltramadol (M1 metabolite; see Figure 1) which also binds to opioid receptors (Raffa et al., 1995; Gibson, 1996). In addition to testing tramadol, we therefore evaluated the extent to which the enantiomers and the M1 metabolite contribute to tramadol's anticonvulsant and proconvulsant effects in rats. Figure 1 Stereochemistry of tramadol and metabolic activation to the M1-metabolite O-desmethyltramadol. Methods Animals Female Wistar rats (Harlan-Winkelmann, Borchen, Germany), weighing 200–300 g, were used. The animals were purchased from the breeder at a body weight of 180–220 g. Following arrival in the animal colony, the rats were kept under controlled environmental conditions (ambient temperature 24–25°C, humidity 50–60%, 12/12 h light/dark cycle, light on at 0700) for at least 1 week before being used in the experiments. Standard laboratory chow (Altromin 1324 standard diet) and tap water were allowed ad libitum. All animal care and handling was conducted in compliance with the German Animal Welfare Act and was approved by the responsible governmental agency in Hannover. With respect to the use of females, it is important to note that we previously showed that neither Seizure susceptibility nor anticonvulsant drug effects are affected by the estrous cycle in fully kindled female rats as used in the present study (Rundfeldt et al., 1990; Wahnschaffe & Loscher, 1992).
Weiwei Li - One of the best experts on this subject based on the ideXlab platform.
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abhd6 blockade exerts antiepileptic activity in ptz induced Seizures and in spontaneous Seizures in r6 2 mice
Neuron, 2014Co-Authors: Alipi V Naydenov, Eric A Horne, Christine S Cheah, Katie Swinney, William R Marrs, Jacqueline L Blankman, Sarah Tu, Allison E Cherry, Susan Fung, Weiwei LiAbstract:Summary The serine hydrolase α/β-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and Myoclonic Seizure incidence and severity. This effect is retained in Cnr1 −/− or Cnr2 −/− mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABA A receptors. ABHD6 inhibition also blocked spontaneous Seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of Seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.
Lynn S Olberding - One of the best experts on this subject based on the ideXlab platform.
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lamotrigine adjunctive therapy in childhood epileptic encephalopathy the lennox gastaut syndrome
Epilepsia, 1997Co-Authors: Jennifer A Donaldson, Tracy A Glauser, Lynn S OlberdingAbstract:Summary: Purpose: We assessed efficacy and safety of adjunctive lamotrigine (LTG) therapy in patients with the Lennox-Gastaut syndrome (LGS). Methods: The study was a single-center, retrospective chart review of open-label adjunctive LTG therapy in patients with LGS. Initial LTG dose and titration was dependent on concomitant antiepileptic drugs (AEDs). Efficacy was based on the change in Seizure frequency between the initiation of LTG therapy and December 1, 1995 (or LTG discontinuation). Seizure diaries were used to count patient Seizures. A secondary evaluation of efficacy was a parental or guardian assessment of the patient's global status. The evaluation of safety involved chart review for treatment-emergent adverse events (AE). Results: Data from 16 LGS patients were analyzed. Fifty-three percent (8 of 15) had a >50% reduction in Seizure frequency with LTG adjunctive therapy. Tonic, atonic, generalized tonic-clonic (GTCS), and atypical absence Seizure frequency but not Myoclonic Seizure frequency decreased significantly during LTG therapy. Fifty-three percent of the patient's parents (8 of 15) reported that their child's quality of life (QOL) was much or very much improved during the study. The major treatment-emergent AE were infection (50%, 8 of 16) and sleep disturbance (19%, 3 of 16). A rash was noted in 13% (2 of 16) of the patients and resulted in LTG discontinuation in 1. No clinically significant changes were noted in neurologic examination or laboratory tests during the study. Conclusions: Our results indicate that LTG adjunctive therapy is effective and well tolerated in patients with LGS.
Siavash Parvardeh - One of the best experts on this subject based on the ideXlab platform.
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anticonvulsant effects of thymoquinone the major constituent of nigella sativa seeds in mice
Phytomedicine, 2004Co-Authors: Hossein Hosseinzadeh, Siavash ParvardehAbstract:Summary The anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, were investigated using pentylenetetrazole (PTZ)- and maximal electroshock (MES)-induced Seizure models. We also studied the effect of thymoquinone on pentobarbital-induced hypnosis, locomotor activity, and motor coordination. In PTZ-induced Seizure, the intraperitoneally injection of thymoquinone with doses of 40 and 80 mg/kg, prolonged the onset of Seizures and reduced the duration of Myoclonic Seizures. The protective effect of thymoquinone against mortality was 71.4% and 100% in the mentioned doses, respectively. In MES model, thymoquinone failed to reduce the duration of Seizure, whereas exhibited a complete protection against mortality. In PTZ model, flumazenil (10 mg/kg, ip), an antagonist of benzodiazepine (BZD) site in the GABAA-BZD receptor complex, inhibited the prolongation of Seizure latency, but did not show any effect on the duration of Myoclonic Seizures. Also, pretreatment with naloxone (0.1 and 0.3 mg/kg, ip) inhibited the prolongation of Myoclonic Seizure latency and antagonized the reduction of Myoclonic Seizure duration induced by thymoquinone (40 and 80 mg/kg) in the PTZ model. Moreover, thymoquinone (40 and 80 mg/kg) did not have any hypnosis effect in the pentobarbital-induced hypnosis, but impaired the motor coordination and reduced the locomotor activity. These results indicate that thymoquinone may have anticonvulsant activity in the petit mal epilepsy probably through an opioid receptor-mediated increase in GABAergic tone.
András Fogarasi - One of the best experts on this subject based on the ideXlab platform.
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a detailed analysis of frontal lobe Seizure semiology in children younger than 7 years
Epilepsia, 2008Co-Authors: Eduardo Faveret, Thorsten Pieper, András Fogarasi, József Janszky, Ingrid TuxhornAbstract:Summary: Purpose: We sought to analyze semiology of Seizure onset and evolution in young children with frontal lobe epilepsy (FLE), compare this with adult reports, and assess age-related differences. Methods: We analyzed 111 videotaped Seizures from 14 patients with FLE based on focal cortical dysplasia aged 3‐81 months (mean, 30 months). Ictal events were categorized into behavioral, consciousness, autonomic, and sensory features, as well as motor patterns, which included tonic, clonic, epileptic spasm, and Myoclonic Seizure components. We developed a time-scaled datasheet to record each epileptic event as onset, very early, early, or late manifestation. Results: Patients had a high Seizure frequency with up to 40 attacks/day; half of them showed a cluster tendency. Fortyseven percent of the Seizures started in sleep. Mean duration of Seizures was short (29 s). Most common Seizure components were motor manifestations, mostly tonic‐clonic Seizures, and epileptic spasms. Behavioral change was frequent, and hypermotor Seizures were not seen. In five patients, the motor features were contralateral to the epileptic focus, including two children with asymmetric epileptic spasms. Secondarily generalized tonic‐clonic Seizures (SGTCSs) were not recorded, but had been reported in the history of two patients. Complex motor automatisms were not seen, whereas oral automatism appeared in three children. Conclusions: Motor features are common in young children with FLE, as reported in adults. The characteristics, however, differ. Epileptic spasms and subtle behavioral change were frequent. Hypermotor Seizures and complex motor automatisms were not seen, and SGTCSs were unusual. Our results suggest that FLE in young children shows age-related features differing from those of adults. Key Words: Frontal lobe epilepsy— Seizure semiology—Children—Age.
