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Advanced Drug Delivery Reviews (v.64, #10)
Chemical properties of antiepileptic drugs (AEDs) by Meir Bialer (pp. 887-895).
Between 1990 and 2011 the following fifteen new antiepileptic drugs (AEDs) were approved: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. These AEDs (except felbamate) offer appreciable advantages in terms of their favorable pharmacokinetics, improved tolerability and lower potential for drug interactions. All AEDs introduced after 1990 that are not second generation drugs (with the exception of vigabatrin and tiagabine) were developed empirically (sometimes serendipitously) utilizing mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of new AEDs in the last three decades coupled with their multiple mechanisms of action explains their diverse chemical structures. The availability of old and new AEDs with various activity spectra and different tolerability profiles enables clinicians to better tailor drug choice to the characteristics of individual patients.With fifteen new AEDs having entered the market in the past 20years the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2011 to the pharmaceutical industry even though the clinical need of refractory epilepsy remains unmet. Due to this situation, future design of new AEDs must also have a potential in non-epileptic CNS disorders such as neuropathic pain, migraine prophylaxis and bipolar disorder or fibromyalgia as demonstrated by the sales revenues of pregabalin, topiramate and valproic acid. This review analyzes the effect that the emerging knowledge on the chemical properties of the old AEDs starting from phenobarbital (1912) has had on the design of subsequent AEDs and new therapeutics as well as the current approach to AED discovery.Display Omitted
Keywords: Abbreviations; (CBZ); carbamazepine; (ESL); eslicarbazepine acetate; (FBM); felbamate; (FOS); fosphenytoin; (GBP); gabapentin; (LCS); lacosamide; (LTG); lamotrigine; (LEV); levetiracetam; (OXC); oxcarbazepine; (PB); phenobarbital; (PHT); phenytpoin; (PGB); pregabalin; (PRM); primidone; (RTG); retigabine; (RUF); rufinamide; (STR); stiripentol; (TGB); tiagabine; (TPM); topiramate; (VPA); valproic acid; (VGB); vigabatrin; (ZNS); zonisamideAntiepileptic drugs (AEDs); Chemical properties; Second-generations antiepileptic drugs; Structure–pharmacokinetic–pharmacodynamic relationship; Antiepileptic drug discovery
Host factors affecting antiepileptic drug delivery—Pharmacokinetic variability by Cecilie Johannessen Landmark; Svein I. Johannessen; Torbjörn Tomson (pp. 896-910).
Antiepileptic drugs (AEDs) are the mainstay in the treatment of epilepsy, one of the most common serious chronic neurological disorders. AEDs display extensive pharmacological variability between and within patients, and a major determinant of differences in response to treatment is pharmacokinetic variability. Host factors affecting AED delivery may be defined as the pharmacokinetic characteristics that determine the AED delivery to the site of action, the epileptic focus. Individual differences may occur in absorption, distribution, metabolism and excretion. These differences can be determined by genetic factors including gender and ethnicity, but the pharmacokinetics of AEDs can also be affected by age, specific physiological states in life, such as pregnancy, or pathological conditions including hepatic and renal insufficiency. Pharmacokinetic interactions with other drugs are another important source of variability in response to AEDs. Pharmacokinetic characteristics of the presently available AEDs are discussed in this review as well as their clinical implications.Display Omitted
Keywords: Antiepileptic drugs; Drug delivery; Epilepsy; Host factors; Pharmacokinetics
Current oral and non-oral routes of antiepileptic drug delivery by Gail D. Anderson; Russell P. Saneto (pp. 911-918).
Antiepileptic drugs are commonly given orally for chronic treatment of epilepsy. The treatment of epilepsy requires administration of medications for both acute and chronic treatment using multiple types of formulations. Parenteral routes are used when the oral route is unavailable or a rapid clinical response is required. Lorazepam and midazolam can be administered by the buccal, sublingual or intranasal routes. Consensus documents recommend rectal diazepam, buccal midazolam or intranasal midazolam for the out-of-hospital treatment of early status epilepticus. In the United States, diazepam is the only FDA approved rectal formulation. With the lack of parenteral, buccal or intranasal formulations for many of the antiepileptic drugs, the use of the rectal route of delivery to treat acute seizures or to maintain therapeutic concentrations is suitable for many, but not all antiepileptic medications. There is a significant need for new non-oral formulations of the antiepileptic drugs when oral administration is not possible.Display Omitted
Keywords: Antiepileptic drugs; Formulations; Parenteral; Rectal; Buccal; Intranasal
Cerebral expression of drug transporters in epilepsy by Eleonora Aronica; Sanjay M. Sisodiya; Jan A. Gorter (pp. 919-929).
Over-expression of drug efflux transporters at the level of the blood–brain barrier (BBB) has been proposed as a mechanism responsible for multidrug resistance. Drug transporters in epileptogenic tissue are not only expressed in endothelial cells at the BBB, but also in other brain parenchymal cells, such as astrocytes, microglia and neurons, suggesting a complex cell type-specific regulation under pathological conditions associated with epilepsy. This review focuses on the cerebral expression patterns of several classes of well-known membrane drug transporters such as P-glycoprotein (Pgp), and multidrug resistance-associated proteins (MRPs) in the epileptogenic brain. Both experimental and clinical evidence of epilepsy-associated cerebral drug transporter regulation and the possible mechanisms underlying drug transporter regulation are discussed. Knowledge of the cerebral expression patterns of drug transporters in normal and epileptogenic brain will provide relevant information to guide strategies attempting to overcome drug resistance by targeting specific transporters.Display Omitted
Keywords: Multidrug resistance; Associated protein; Rodent brain; Human brain; Brain tumors; Hippocampal sclerosis; Malformations of cortical development; Blood–brain barrier; Astrocytes
The transport of antiepileptic drugs by P-glycoprotein by Chunbo Zhang; Patrick Kwan; Zhong Zuo; Larry Baum (pp. 930-942).
Epilepsy is the most common serious chronic neurological disorder. Current data show that one-third of patients do not respond to anti-epileptic drugs (AEDs). Most non-responsive epilepsy patients are resistant to several, often all, AEDs, even though the drugs differ from each other in pharmacokinetics, mechanisms of action, and interaction potential. The mechanisms underlying drug resistance of epilepsy patients are still not clear. In recent years, one of the potential mechanisms interesting researchers is over-expression of P-glycoprotein (P-gp, also known as ABCB1 or MDR1) in endothelial cells of the blood–brain barrier (BBB) in epilepsy patients. P-gp plays a central role in drug absorption and distribution in many organisms. The expression of P-gp is greater in drug-resistant than in drug-responsive patients. Some studies also indicate that several AEDs are substrates or inhibitors of P-gp, implying that P-gp may play an important role in drug resistance in refractory epilepsy. In this article, we review the clinical and laboratory evidence that P-gp expression is increased in epileptic brain tissues and that AEDs are substrates of P-gp in vitro and in vivo. We discuss criteria for identifying the substrate status of AEDs and use structure–activity relationship (SAR) models to predict which AEDs act as P-gp substrates.Display Omitted
Keywords: Antiepileptic drugs; Blood brain barrier; Drug resistance; Epilepsy; P-glycoprotein; Structure–activity relationship
Role of CNS efflux drug transporters in antiepileptic drug delivery: Overcoming CNS efflux drug transport by Heidrun Potschka (pp. 943-952).
Experimental support for the transporter hypothesis of drug resistance in epilepsies has triggered efforts developing and validating approaches to overcome enhanced blood–brain barrier efflux transport. Testing in rodent models has rendered proof-of-concept for an add-on therapy with antiepileptic drugs. However, further development of the approach would require tolerability considerations as efflux transporters serve an important protective function throughout the body limiting distribution of harmful xenobiotics. Relevant progress has been made in the elucidation of mechanisms driving up-regulation of the multidrug transporter P-glycoprotein in response to seizure activity. Based on this knowledge, novel strategies have been evaluated targeting the signaling cascade that regulates P-glycoprotein in the epileptic brain. Further concepts might include by-passing blood–brain barrier transporters by intracerebral administration or by encapsulation of antiepileptic drugs in nano-sized carrier systems.It is important to note that the future perspectives of respective approaches are still questionable based on the limited evidence for a clinical relevance of transporter expression. Thus, techniques are urgently needed for non-invasive assessment of blood–brain barrier transporter function. Respective techniques would allow testing for a clinical correlation between pharmacosensitivity and transporter function, validating therapeutic strategies targeting efflux transporters and selecting patients with transporter over-expression for respective clinical trials. Provided that further clinical data render support for the transporter hypothesis, the main question remains whether patients exist in which transporter over-expression is the predominant mechanism of drug resistance and in which overcoming drug efflux is equivalent with overcoming drug resistance. Imaging techniques might provide a tool to address these questions in clinical epileptology. However, the complex pharmacological interactions between antiepileptic drugs, radiotracers, and transporter modulators used in these approaches as well as interindividual differences in the brain pathology might hamper clear-cut conclusions and limit the diagnostic significance.Display Omitted
Keywords: Pharmacoresistance; Blood–brain barrier; Multidrug transporter; Cyclooxygenase-2; Epilepsy; NMDA receptor
Novel methods of antiepileptic drug delivery — Polymer-based implants by Amy J. Halliday; Simon E. Moulton; Gordon G. Wallace; Mark J. Cook (pp. 953-964).
Epilepsy is a neurological disorder characterised by spontaneous seizures. Over one third of patients receive insufficient benefit from oral anti-epileptic drug (AED) therapy, and continue to experience seizures whilst on medication. Epilepsy researchers are consequently seeking new ways to deliver AEDs directly to the seizure focus in the brain in order to deliver higher, more effective doses to the seizure focus whilst bypassing the remainder of the brain and body to prevent side effects. The focus of this review will be polymer-based implants, which are polymeric devices loaded with AED that are designed for implantation at the seizure focus in order to achieve gradual, continuous release of AED direct into the region of the brain responsible for seizures. Polymer-based implants produced for epilepsy to date are based on a range of polymers, both biodegradable and non-biodegradable, and range from simple materials development studies through to investigations of implants in animal models of seizures and epilepsy, with varying degrees of success. This review describes the range of methods employed to manufacture polymer-based implants and compares their advantages and potential appeal to industry, and describes and compares the results and successes of polymer-based materials and devices produced to date for the treatment of epilepsy. We also discuss disadvantages and hurdles to be overcome in the field, and describe our predictions for advances to be made in the field in the coming decade.Display Omitted
Keywords: Controlled release; Biodegradable; Polymers; Liposomes; Epilepsy; Drug delivery; Implants