ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05885.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:: Neural regulation of pituitary function can serve as a basis for understanding endocrine and reproduction dysfunction in epilepsy. Because the pituitary gland is the final common pathway for central neural modulation of the endocrine system, hypothalamic control of pituitary function is important. The syndrome of functional hypothalamic amenorrhea is an example of stress‐induced alteration in endocrine function and may serve as a model to suggest the impact of limbic system activation on reproduction and the endocrine milie

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05888.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol‐induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine‐evoked release of glutamate when a threshold depolarizing concentration (4 μg/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 μg/ml). However, LTG does not block potassium‐evoked transmitter release. LTG is a less potent inhibitor of the release of γ‐aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP‐like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05882.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:The pharmacokinetics and pharmacodynamics of lamotrigine (LTG), a new antiepileptic drug (AED), were studied in healthy volunteers. In an open dose‐escalating study, LTG 240 mg produced peak plasma concentrations of around 3 μg/mg with no significant adverse events. Subsequent pharmacokinetic studies revealed complete oral absorption, first‐order kinetics with a mean half‐life of approximately 1 day, and elimination mainly as a glucuronide in the urine. Early studies in patients with epilepsy revealed more rapid metabolism when given with enzyme‐inducing AEDs and delayed metabolism by valproate. A placebo‐controlled, double‐blind study compared LTG 120 and 240 mg with phenytoin (PHT) 500 and 1,000 mg, and diazepam (DZP) 10 mg. Visual analogue scales showed sedation after PHT 1,000 mg and DZP 10 mg, but not after LTG. Smooth pursuit eye movements and adaptive tracking were impaired by DZP and PHT 1,000 mg. LTG did not affect these variables. A comparison of LTG 150 and 300 mg and carbamazepine (CBZ) 200, 400, and 600 mg demonstrated impairment of smooth pursuit and saccadic eye movements by CBZ 600 and 400 mg, but not by LTG. Additionally, CBZ 600 mg impaired adaptive tracking and increased body sway and heart rate. These studies have shown LTG to have desirable and predictable pharmacokinetic properties for an AED. Pharmacodynamic effects were absent, suggesting a high thera

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05883.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

SUMMARY:The activity of carbonic anhydrase (CA), a glial enzyme, was measured in the epileptic cortex of audiogenic DBA/2 mice and of cats with a freeze lesion. In mice, the activity increased with age from birth to 24 days, but were always higher in audiogenic mice than in normal C57/BL mice, reflecting species differences. The difference between the two strains increased sharply from 25 to 40 days of age, after the period of maximal audiogenic susceptibility. Acetazolamide, a CA‐specific inhibitor, greatly decreased the seizure severity score of DBA/ 2 mice after a single intraperitoneal (i.p.) administration (150 mg/kg). After 24 days of age, when CA activities were high, the effect of acetazolamide was less important, suggesting that the increased cortical CA activity might reflect a protective mechanism. In cats with a freeze lesion, no significant changes in CA activities were observed in the actively discharging primary and secondary foci as compared with the nonepileptogenic perifocal cortex and the control cortex of sham‐operated animals. The results indicate that the cortex of genetically susceptible audiogenic mice has an increased CA activity. The hypothesis of an adaptive glial mechanism, relating to the age‐dependent decrease of seizure susceptibility in DBA/2 mice, is postulated.RÉSUMÉL'activité de I'anhydrase carbonique (AC), une enzyme gliale, a été mesurée dans des homogénats de cortex épileptique chez la souris audiogène DBA/2 et chez le chat porteur d'une lésion par le froid. Chez la souris, l'activité enzymatique augmente avec l'âge depuis la naissance jusqu'à 24 jours, mais est toujours supérieure chez la souris audiogéne par rapport à la souche contrôle C57/BL, reflétant des différences génétiques. Entre 25 et 40 jours de vie postnatale, c'est à dire après la période de susceptibilité audiogénique maximale, la différence entre les deux souches s'accroît fortement. L'acéHazolamide, un inhibiteur spécifique de l'AC, diminue de façon importante le score de sévéritéépileptique de la souris DBA/2 après une administration intrapéitonéale unique (150 mg/kg). Cet effet de l'acétazolamide est moins marqué lorsque l'activité AC est élevée, suggérant que l'augmentation de l'activité de l'AC après 24 jours chez la souris DBA/2 pourrait constituer un méanisme protecteur. Chez le chat porteur d'une léion par le froid, aucune modification significative de l'activité enzymatique n'est observée dans les foyers épileptiques actifs primaires et secondares par rapport au cortex périfocal non épileptique et au cortex contrôle de chats témoins. Ces résultats indiquent l'existence d'une augmentation de l'activité de l'AC dans le cortex de souris génétiquement audiogéniques. L'hypothèse d'un mécanisme glial adaptatif, en relation avec la disparition de la susceptibilité audiogénique avec l'âge chez la souris DBA/2, est évoquée.RESUMENSe ha medido la actividad de la carbónico‐anhidrasa (CA), una enzima glial, en la corteza epiléptica de los ratones audiogénicos DBA/2 y en gatos con lesiones por congelación. En las ratas la actividad se incrementa con la edad desde el nacimiento hasta los 24 días pero fue siempre más elevada en ratones audiogénicos que en ratones normales C57/BL, lo que refleja diferencias de especie. Las diferencias entre los dos tipos de ratón se incrementaron abruptamente desde los 25 a los 40 días de edad después de un período de susceptibilidad audiogénica máxima. La acetazolamida, un inhibidor específico de la CA, incrementó la severidad de la frecuencia de ataques de los ratones DBA/2 después de una inyección intraperitoneal única (150 mg/kg). Después del día 24 de edad, cuando la actividad de la CA era elevada, el efecto de la acetazolamida fue menos importante, lo que sugiere que el incremento de la actividad cortical de la CA puede reflejar un mecanismo de protección. En gatos con lesiones por congelación no se observaron cambios significativos en la actividad de la CA cuando se buscaron en la zona activamente primaria de descargas y en los focos secundarios, comparándolos con la corteza periofocal no‐epileptogénica y con los animales control con técnica operatoria similar (Sham). Los resultados indican que la corteza de ratones genéticamente susceptibles a crisis audiogénicas tiene un incremento de la actividad de la CA. Los autores postulan la existencia de un mecanismo adaptativo glial, en relatión con una reducción de la susceptibilidad para ataques edad‐dependientes, en los ratones DBA/2.ZUSAMMENFASSUNGDie Aktivität von Carboanhydrase (CA), einem glialen Enzym, wurde im epileptischen Kortex von audiogenen DBA/2‐Mäusen und Katzen mit Gefrierläsionen gemessen. Bei Mäusen stieg die Aktivität mit dem Alter von Geburt bis zum 24. Tag an, sie war bei audiogenen Mäusen immer höhen als bei normalen C57/BL‐Mäusen. Der Unterschied zwischen den beiden Stämmen stieg stark vom 25. zum 40. Lebenstag an, also nach der Periode der maximalen audiogenen Empfindlichkeit. Acetazolamid, ein spezifischer CA‐Hemmer, minderte nach einer einzigen intraperitonealen Gabe (150 mg/kg) stark den Schweregrad‐Rang von Anfällen von DBA/2‐Mäusen. Nach dem 24. Lebenstag, wenn die CA‐Aktivitäten hoch waren, war die Wirkung von Acetazolamid weniger deutlich, was nahelegt, daß die erhöhte kortikale CA‐Aktivität einen protektiven Mechanismus wiedergibt. Bei Katzen mit Gefrierläsionen waren keine signifikanten CA‐Aktivitätsänderungen bei aktiv entladenden primären und sekundären Foci zu sehen im Vergleich zum nichtepileptogenen perifokalen Kortex und zu scheinoperierten Kontrolltieren. Die Ergebnisse zeigen, daß der Kortex von genetisch‐audiogenen Mäusen eine erhöhte CA‐Aktivität hat. Es wird

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05603.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:: Several of the non‐sex hormones have been found to be useful in the treatment of seizures. These hormones have an effect on seizures, and seizures have an effect on these hormones. Adrenocorticotropic hormone (ACTH) and corticosteroid drugs have been found to be useful in the treatment of infantile spasms and other seizure disorders. Unfortunately, there is no clear consensus regarding superiority of ACTH versus prednisone in regard to efficacy and long‐term benefits, dosage, or duration of treatment. There is also considerable debate regarding reasons why ACTH and prednisone are useful in infantile spasms, their mechanism of action, and their long‐term effects on brain development. Thyrotropin‐releasing hormone also has been used in the treatment of infantile spasms and other seizure types in children, with modest success. As with ACTH and prednisone, the mechanisms of action remain

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05886.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:Testing the efficacy of lamotrigine (LTG) in epileptic patients has been approached in several ways. The first pilot study examined the effect of a single dose of LTG in patients with frequent interictal spikes, and a reduction in spike frequency was observed. Subsequently, single doses reduced photosensitivity in appropriate patients. Single‐blind administration of LTG for 1 week in addition to the patients' regular antiepileptic drugs (AEDs), in patients with refractory seizures, reduced seizures despite the short duration of therapy. This regimen was continued using a placebo‐controlled crossover study with 1‐week duration of treatment. Efficacy in partial and tonic‐clonic seizures was subsequently confirmed in four double‐blind crossover studies; a meta‐analysis of these four studies showed a 30% reduction in partial seizures despite the intractable nature of the seizures in the patients included. Current studies aim at evaluating the drug as monotherapy and in different se

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05880.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

SUMMARY:The effect of DN‐1417, a thyrotropin‐releasing hormone (TRH) analogue, on photosensitivity and cortically kindled seizures was examined in seven Senegalese baboons (Papio papio).Intravenous (i.v.) administration of 2 mg/kg had no effect on either photosensitivity or cortically kindled seizures. When this agent was administered intracisternally, both the photomyoclonic response and cortically kindled seizures were suppressed for 4–5 days. A study of the transcallosal response also showed a long‐lasting attenuation of the early positive wave (PI) amplitude (peak latency, 5–10 ms) elicited by a single stimulus after cisternal injection of DN‐1417. These findings are consistent with the assumption that endogenous TRH is involved in suppression of epileptic seizures.RÉSUMÉL'effet du DN‐1417, un analogue de la TRH, sur la photosensibilité et les crises après kindling cortical, a étéétudié chez sept babouins sénégalaisPapio papio.L'administration intraveineuse de 2 mg/kg n'a pas eu d'effet, ni sur la photosensibilité, ni sur les crises après kindling cortical. Cependant, lorsque cet agent a été administré par voie intraventriculaire, la réponse photomyoclonique et les crises induites par kindling cortical ont été supprimées pendant 4 à 5 jours. Une étude de la réponse transcalleuse a également montré une atténuation prolongée de la pointe positive précoce (Iatence du pic, 5–10 ms) provoquée par une stimulation isolée après injection intracisternale de DN‐1417. Ces constatations confirment l'hypothèse selon laquelle la TRH endogène est impliquée dans la suppression des crises épileptiques.RESUMENEn 7 babiones senegalesesPapio papio, se ha estudiado el efecto de la DN‐1417, un análogo de la hormona liberadora de tirotropina (TRH), sobre lafotosensibilidad de los ataques condi‐cionados corticalmente (kindled). La administración intravenosa de 2 mg/kg no produjo ningún efecto sobre la fotosensibilidad ni sobre los ataques condicionados corticalmente. Cuando este agente se administró intracistemalmente la respuesta fotomio‐clónica y los ataques condicionados corticalmente se suprimieron durante 4–5 días. Un estudio de la respuesta transcallosa también mostró una atenuación prolongada de la amplitud (latencia pico, 5–10 msec) producida por un estímulo único después de la inyección cisternal de DN‐1417. Estos hallazgos están de acuerdo con la presu

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05604.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:The clinical safety of lamotrigine (LTG), assessed in four completed randomized, double‐blind, placebo‐controlled crossover trials and an interim analysis of 27 12‐month open studies, is discussed. LTG was added to existing anti‐epileptic drugs (AEDs) of adult patients with refractory epilepsy, using a twice‐daily regimen. In the pooled data from the four double‐blind studies (n= 92), the incidence of adverse experiences with LTG and placebo did not differ significantly. Two patients were withdrawn on LTG due to adverse experiences (one rash, one nausea and vomiting). In the open studies (pooled data;n= 572) the most commonly reported adverse experiences were dizziness, diplopia, somnolence, headache, ataxia, and asthenia (10–14% incidence). Forty‐nine patients (8.6%) were withdrawn with adverse events, most commonly for rash (2.3%). No patients were withdrawn from any of the studies with physical, neurological, or ECG abnormalities thought attributable to LTG treatment. Laboratory measures, vital signs, and weight did not show any consistent changes of clinical significance, and no significant changes in plasma concentrations of concomitant AEDs after the addition of LT

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05881.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Summary:: The hypothalamic‐pituitary‐gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic‐pituitary‐gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1991.tb05887.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY