摘要:

Summary:The therapeutic action of vigabatrin (gamma vinyl GABA, GVG) has been reported to be mediated by GABAergic neurotransmission. In the present study, we evaluated different neurotransmitter systems in the cerebrospinal fluid (CSF) of patients with complex partial epilepsy, before and during GVG treatment. The markers of the GABAergic system (free GABA, total GABA, homocarnosine) showed a two‐ to threefold elevation. There was also an increase in glycine during the 6 months of GVG treatment. In contrast, we did not find any constant CSF changes in either excitatory amino acids or in markers of the cholinergic (acetylcholinesterase), dopaminergic (homovanillic acid), serotonergic (5‐hydroxyin‐doleacetic acid), or peptidergic (somatostatin, prolactin, β‐endorphin) systems. This finding (except an elevation in glycine) was in agreement with previous studies which suggest a specific action of GVG on the GABAergic system. The role of glycine in antiepileptic efficacy of GVG needs further ev

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05828.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Data from 50 patients with juvenile myoclonic epilepsy (JME) were analyzed retrospectively to assess the response to drug therapy–long‐term seizure control, relapse rates, and confounding factors in seizure recurrence. Valproate is the only available antiepileptic drug that has been shown to be effective in controlling the generalized seizure components of JME–myoclonic, tonoclonic, and absence seizures–without significant side effects. Data were collected using the EpiMonitor software and represented case follow‐up from 2 months to 9 years. Forty‐three patients (86%) were seizure free for at least 1 year; 25 patients (50%) relapsed at some point during follow‐up. Relapses were precipitated most frequently by fatigue, noncompliance, stress, sleep deprivation, and alcohol consumption. With accurate diagnosis and appropriate therapy, seizures in JME can be adequately controlled, although JME is a chronic disorder that may require lifelong therapy. To minimize relapse, patient management must also focus on patient lifestyle to eliminate or control lifestyle‐associated precipitants of

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05833.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC‐9653). This water‐soluble compound is metabolized rapidly into P04 and PHT. A four center open‐label, baseline‐controlled study of 43 patients with epilepsy maintained on oral twice‐daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC‐9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC‐9653 via whichever route they had not yet received. TheTmsxof the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half‐life of ACC‐9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC‐9653 was not dependent on dose or route of administration and averaged 19.8 ± 1.16 and 17.8 ± 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC‐9653 was 1.17 ± 0.13 which was not significantly different from 1. These findings indicate that both i.v. and i.m. administrations of ACC‐9653 maintained stable levels of PHT. Unlike i.v. PHT infusion, serious cardiovascular and respiratory adverse reactions were not observed during the administration of i.v. ACC‐9653. Postural hypotension was reported in two patients. Paresthesia was the most frequent adverse experience reported during the i.v. infusion of ACC‐9653. The tingling sensation was transient and localized to the groin, lower back, abdomen, head and neck regions. Phlebitis, tissue necrosis, induration, cording and sclerosis were not observed in this patient population following either i.m. or i.v. ACC‐9653 administration. In summary, PHT plasma levels in patients with epilepsy who were receiving chronic oral PHT monotherapy were maintained by the i.m. or i.v. administration of ACC‐9653. Both i.v. and i.m. ACC‐9653 were well tolerated by the patients as evidenced by the absence of serious cardiovascular events, laboratory variable a

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05821.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Vigabatrin (gamma vinyl GABA, GVG) has been shown to be an effective antiepiieptic agent. GVG specifically and irreversibly inhibits GABA‐transaminase (GABA‐T). Long‐term animal toxicology studies have demonstrated that GVG can induce nonprogressive, reversible intramyelinic edema in central white matter tracts. The response to GVG varies among species, with rodents being the most dramatic and monkeys showing an equivocal effect even at high doses. The response in dogs is marked and measurable. The detection of these subtle findings requires the use of sophisticated technology. Evoked potentials are becoming reliable and sensitive tools in clinical neurology. This study, involving 54 patients for 11 months, was undertaken to assess the effect and safety of GVG in humans with refractory epilepsy. No data from this investigation indicate prolongation of neuronal conduction time in CNS pathways, suggesting that this agent is safe in h

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05829.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05834.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The effects of feeding a diet enriched in caffeine or carbamazepine (CBZ) were investigated in rats in a quantitative autoradiographic study of adenosine Al receptors (labeled by [3H]cyclohexyladenosine, [3H]CHA) and adenylate cyclase (labeled by pHJforskolin). Although regional distribution of [3H]CHA and [3H]‐forskolin binding sites differed in some areas, chronic CBZ as well as chronic caffeine upregulated both of them. The changes in receptor densities occurred in the same brain microregions, suggesting that caffeine and CBZ act as antagonists at similar subpopulations of adenosine Al receptors and [3H]forskolin binding sites. Therefore, a selective interaction of these two drugs with distinct adenosine Al receptors (and adenylate cyclase) probably does not explain the differential effects of caffeine and CBZ on neuronal activity.RÉSUMÉLes conséquences d'une alimentation enrichie en caféine ou en carbamazépine ont été examinees chez le rat au cours d'une etude autoradiographique quantitative des récepteurs Al de l'adénosine (marques par la cyclohexyladénosine[3H], [3H]CHA) et de l'adénylate cyclase (marquée par la forskoline[3H]). Quelque soit la distribution des sites de liaison de la CHA[3H] et de la forskoline[3H] différent dans quelques structures, un traitement chronique à la carbamazepine, comme à la cafeine, augmente le nombre de ces deux types de recepteurs. Les changements de densité des sites de liaison ont été observés dans les mêmes microrégions cérébrales, suggèrant que la caféine et la carbamazépine agissent comme antagonistes au niveau des mêmes subpopulations de récepteurs Al de l'adénosine et de sites de liaison de la forskoline[3H]. Ainsi, une interaction sélective de ces deux drogues avec des récepteurs distincts (Al de l'adénosine et aussi de l'adénylate cyclase) ne rend probablement pas compte des effets différents de la caféine et de la carbamazépine sur l'activité nerveuse.RESUMENSe nan investigado los efectos, en ratas, de la administración de una dieta rica en cafeina o en carbamazepina, mediante un estudio autorradiágrafico cuantitativo de los receptores de ade‐nosina Al (marcados mediante [3H] ciclohexiladenosina, [3H] CHA) y de la ciclasa‐adenilato (marcada con [3H] forskolina). Mientras que la distribución regional de los lugares de acoplamiento de [3H] CHA y [3H] forskolina eran diferentes en algunas areas, la presencia crónica de carboamazepina y de cafeina elevaron la regulación de ambos tipos de receptores. Los cambios de las densidades de los receptores ocurrieron en las mismás microregiones del cerebro lo que sugiere que la cafeina y la carbamazepina actuan como antagonistas en subpoblaciones semejantes de receptores de adenosina Al y de los lugares de acoplamiento de la [3H] forskolina. Por lo tanto la existencia de una interaction selectiva de estas dos drogas con distintos receptores de adenosina Al (y ciclasa‐adenilato) probablemente no explica los efectos diferenciales de la cafeina y la carbamazepina sobre la actividad neuronal.ZUSAMMENFASSUNGDie Auswirkungen einer mit Coffein oder Carbamazepin an‐gereicherten Diät wurden in der Ratte in einer quantitativen au‐toradiographischen Studie von Adenosin‐Al Rezeptoren (mark‐iert mit [3H]Cyclohexyladenosin, [3H]CHA) und Adenylat Cyclase (markiert mit [3H]Forskolin) untersucht. Es konnte gezeigt werden, dass sowohl chronische Carbamazepin als auch Coffein‐Diat zentrale Adenosin‐Al Rezeptoren und [3H] forskolin‐bindungsstellen hochregulieren. Die Veranderungen der Rezep‐tordichte ereignétén sich in denselben Hirnregionen. Dieses Ergebnis legt nahe, dass Coffein und Carbamazepin als Antago‐nisten an ahnlichen Untergruppen von an Adenosin Al Rezeptoren und [3H]Forskolin‐Bindungsstellen wirken. Eine selektive Interaktion dieser beiden Substanzen mit unterschiedlichen Adenosin Al Rezeptoren (und Adenylat Cyclasen) erklart daher wahrscheinlich nicht die unterschi

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05276.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The bioavailability of phenytoin from ACC‐9653 versus intravenously administered sodium phenytoin was determined using a crossover design for intravenous and intramuscular administration of ACC‐9653 to healthy volunteers. Absolute bioavailability of phenytoin derived from ACC‐9653 in each subject was calculated as the ratio of the phenytoin area under the plasma concentration time curve for time 0 to infinity [AUC(0‐inf)] after ACC‐9653 divided by the phenytoin AUC(O‐inf) after intravenous sodium phenytoin. The mean absolute bioavailability of ACC‐9653 was 0.992 after intravenous administration and 1.012 after intramuscular administration. These data establish that the bioavailability of ACC‐9653 is complete following intravenous or intramuscular administration in single‐dose volunteer studies. The absolute bioavailability of phenytoin derived from ACC‐9653 in subjects with therapeutic plasma phenytoin concentrations is being studied in patients given simultaneous infusions of stable isotope‐labeled tracer doses of ACC‐06

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05822.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:Our understanding of how new antiepileptic drugs work mirrors what we know about how currently marketed antiepileptic compounds exert their action–that information is scarce and elusive. The mechanism of action of antiepileptic drugs is nevertheless inextricably linked to epileptogenesis itself, and investigations of several promising new compounds are underway to establish the levels at which these drugs act. Compounds act on synapses and membranes as well as affecting receptors, neurotransmitters, and peptides. The most extensive data are available on drugs that inhibit the action of GABA or its receptors, including new benzodiazepine‐like agents and barbituric‐acid derivatives. The few drugs that act by inhibiting the effects of excitatory amino acids are reviewed. Finally, the maximal electroshock test is an empirical method to determine the antiepileptic properties of a drug; several agents under development have been effective in this screening tech

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05811.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The goal of management in epilepsy is to make patients completely seizure‐free without side effects. Currently, this goal can be achieved fully in only about one‐half of the 50,000,000 people in the world with epilepsy. Epilepsy is not a benign condition. Uncontrolled epilepsy produces significant morbidity and mortality. Even infrequent seizures put a patient at risk of sudden death and compromise employability and other social functions. The potential risk of a new antiepileptic drug has to be weighed against the potential risk of continuing seizures and the potential for the new drug to control those seizures. Vigabatrin (gamma vinyl GABA, GVG) is one of the promising new antiepileptic drugs now under development. In four large clinical trials half of the patients in each trial had a ≥ 50% reduction in seizure frequency when GVG was added to existing antiepileptic drug. This represents a significant response rate in add‐on trials, which are a severe test of a new antiepileptic drug. Although microvacuoles have been seen in the white matter of the brains of rats and dogs treated with GVG, such pathological changes have not yet been observed in humans. Evoked potential studies have failed to reveal any evidence of microvacuolization in humans. Because of the potential efficacy of GVG in controlling previously therapeutic‐resistant seizures and of the absence of evidence of significant toxicity in humans, carefully monitored clinical trials of GVG in therapy‐resistant patients with epilepsy shou

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05831.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary:The drugs currently used in the emergency management of seizures are chiefly phenytoin, phenobarbital, diazepam, lorazepam, and paraldehyde. The combination of intravenous phenytoin and lorazepam has the advantages of rapid onset of action, sustained efficacy, and freedom from drug interactions. The intermittent oral or rectal administration of diazepam is especially useful for acute home treatment of recurrent seizures. Phenytoin prodrug (ACC‐9653), an investigational new drug, is promptly absorbed after intramuscular injection. Unlike phenytoin, it does not require propylene glycol and high alkalinity for solubility and therefore does not produce soft‐tissue injury after parenteral administration. It appears to be close to an ideal drug for the emergency management of seizu

ISSN:0013-9580    

DOI:10.1111/j.1528-1157.1989.tb05823.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY