GABAA receptor pharmacology

Delivery of peptide and protein drugs over the blood-brain barrier.

Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation?

Nanotechnology, or systems/device manufacture at sizes generally ranging between 1 and 100 nm, is a multidisciplinary scientific field undergoing explosive development. The genesis of nanotechnology can be traced to advances in medicine, communications, genomics and robotics. One of the greatest values of nanotechnology will be in the development of new and effective medical treatments (i.e. nanomedicine). This review focuses on the potential of nanomedicine as it relates to the development of nanoparticles for enabling and improving the targeted delivery of therapeutic and diagnostic agents. We highlight the use of nanoparticles for specific intra-compartmental analysis using the examples of delivery to malignant cancers, to the central nervous system, and across the gastrointestinal barriers.

Targeted nanoparticle-based drug delivery and diagnosis

Sudden unexplained death syndrome (SUDS) accounts for about 10% of deaths in patients with epilepsy. It is associated with subtherapeutic postmortem serum antiepileptic drug (AED) levels but no anatomic cause of death on autopsy. The mechanisms of death are not known. We investigated 44 cases of SUDS for details of seizure history, treatment, medical and psychological history, events at the time of death, and postmortem findings. Cases of status epilepticus, drowning or other identifiable causes of death were excluded. Two groups emerged: five children with uncontrolled seizures receiving multiple AEDs and good compliance with medications, and 39 adults with less frequent seizures, often receiving monotherapy, but noncompliant with medications. Four children (80%) but only one adult (3%) had fully therapeutic postmortem AED levels. Sixty-three percent of adults recently had experienced an unusually stressful life event. Investigation of the circumstances at the time of death suggested two possible modes of death: (a) a seizure with an immediately fatal arrhythmia, or, (b) a seizure, recovery, then delayed secondary respiratory arrest or arrhythmia. Even though the mechanisms of death are unknown, the risk of SUDS may be reduced by encouraging patients to be compliant with medications, especially in times of unusual life stress.

The sudden unexplained death syndrome in epilepsy: demographic, clinical, and postmortem features.

Carbamazepine-induced cardiac conduction disturbance is reported in 2 patients suffering from epilepsy. The cardiac defects disappeared in both patients after carbamazepine was discontinued, and reappeared in 1 patient after treatment was resumed.

Carbamazepine and cardiac conduction disturbances.

We studied Sprague-Dawley rats with spike activity and myoclonus after intraperitoneal injections of penicillin. Twenty minutes after penicillin injection, one group received a random crossover treatment by intraperitoneal GABA (gamma-aminobutyric acid) or liposome-entrapped GABA (LEG) or phosphatidylserine alone. The other group received GABA, LEG, or phosphatidylserine followed 15 minutes later by the injection of penicillin. LEG decreased or prevented the epileptic activity, whereas no significant changes were seen with either GABA or phosphatidylserine given alone. LEG may enhance penetration of GABA across the blood-brain barrier because of the carrier action of the liposomes.

Liposome‐entrapped GABA modifies behavioral and electrographic changes of penicillin‐induced epileptic activity

Summary: Sprague—Dawley rats with interictal and ictal spike activity induced by intraperitoneally injected isoniazid (INH) were treated, 5 min before or 30 min later, with liposome-entrapped γ-aminobutyric acid (GABA) (LEG) or GABA or phosphatidylserine. Crossover injections were given in random sequence and INH alone was also injected in every animal as a control. LEG inhibited either seizures or interictal spikes in both groups. No decrease of epileptogenic activity was seen after GABA or phosphatidylserine treatment alone. It is suggested that LEG could contribute to the reconstitution of the GABA pool decreased by INH.



RESUME

Vingt Sprague-Dawley rats injectes avec Isoniazid (INH) et demontrant une activite ictal et interictal de pointes, ont ete traites avec GABA associea une preparation liposomal de Phosphatidylserine (LEG), ou GABA, ou PS. Le LEG demontre une activite inhibitrice soit sur l'activite de pointes interictales. soit sur l'activite de crise epileptique tandis que le GABA ou la PS n'ont aucune action. Cet observation suggere que le LEG peut contribuer a la reconstitution du pool de GABA. reduit par le INH.



RESUMEN

Se ha utilizado el GABA (LEG), el GABA o la Fosfatidilserina unidos a liposomas. en el tratamiento de ratas Sprague-Dowley con puntas interictales e ictales inducidas mediante la inyeccien intraperitoneal de Isoniazida (INH). Las inyecciones se administraron mediante teenica “crossover” en secuencia randomizada y la INH tambien se inyecto a cada animal como control. El LEG inhibio tanto los ataques como las puntas interictales en ambos grupos. No se observe un decremento de la aclividad epileptogenica despues del GABA o despues de la fosfatidilserina. administrados independientemente. Se sugiere que el LEG puede contribuir a la reconstitucion del reducido acumulo de GABA producido por la INH.



ZUSAMMENFASSUNG

Sprague-Dowley-Ratten mit interiktaler und iktaler spike-Aktivitat als Folge i.p.-injizierten Isoniazids (INH) wurden funf Minulen vorher oder dreissig Minulen spater mit in Liposomen verkapselter GABA (LEG) oder GABA oder Phosphatidylserin behandelt. Die unterschiedlichen Injektionen wurden in zufal-liger Folge verabreicht und INH alleine wurde ebenso als Kontrolle jedem Tier injiziert. LEG inhibierte in beiden Gruppen entweder Anfalle oder interiktale spikes. Eine Abnahme der epileptogenen Aktivitat fehlte nach GABA oder Phosphatidylserin alleine. Es wird vermutet, das LEG einen Beitrag zum Wiederherstellen des GABA-Pools leisten konnte, der durch INH vermindert ist.

E. Benassi

Papers

Carbamazepine and cardiac conduction disturbances.

Liposome‐entrapped GABA modifies behavioral and electrographic changes of penicillin‐induced epileptic activity

Liposome‐Entrapped γ‐Aminobutyric Acid Inhibits Isoniazid‐Induced Epileptogenic Activity in Rats

Preliminary evaluation of the effect of GABA and phosphatidylserine in epileptic patients.

GABA and phospholipids in penicillin-induced seizures.