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Patrick Kwan

Publications and source records attributed to Patrick Kwan.

16 recordsLinked to original sources
PubMed2006

Refractory epilepsy: mechanisms and solutions.

Pharmacoresistance remains a major challenge in epilepsy management. The availability of ten new antiepileptic drugs since the late 1980s has not dramatically improved the outcome of refractory epilepsy. This article provides an overview of the contemporary understanding of epilepsy and the limitation of current treatment modalities, discusses putative biological mechanisms of medical intractability and reviews some of the novel strategies under investigation to overcome the challenge of pharmacoresistance.

Anticonvulsants↗
PubMed2006

Combination therapy in epilepsy: when and what to use.

After being regarded as a last resort for over two decades, the role of combination therapy as a treatment strategy for epilepsy is undergoing re-evaluation. This is a result of the growing appreciation that all seizures cannot be controlled by monotherapy in a substantial proportion of patients, and of the development of a range of modern antiepileptic drugs (AEDs), some of which are better tolerated and less prone to complex pharmacokinetic drug interactions than their older counterparts.Robust evidence to guide clinicians on when and how to combine AEDs is lacking, and current practice recommendations are largely empirical. Monotherapy should remain the treatment of choice for newly diagnosed epilepsy. A combination of two AEDs can be considered after failure, resulting from lack of efficacy, of one or two different monotherapy regimens. A few patients will become seizure-free with a combination of three AEDs, but treatment with a combination of four or more is unlikely to be successful. There is some evidence to support a pharmacomechanistic approach to AED combination. Care should be taken to avoid excessive drug load, which is associated with increased toxicity. Bigger and better randomised, controlled studies are needed to determine the optimal time and way to combine AEDs.

Anticonvulsants↗
PubMed2005

Simple partial status epilepticus in Chinese adults.

Simple partial status epilepticus (SPSE) is uncommon compared with generalized tonic-clonic status epilepticus. We evaluated the clinical profile and predictors of poor outcome in a group of Chinese patients with this condition. We identified 32 patients above the age of 14 years with SPSE from a large urban hospital over an eleven-year period. Factors for poor outcome, defined as death or morbidity, were analyzed. The most common underlying causes were due to cerebrovascular disease (46.9%), CNS infection (15.6%), metabolic derangement (12.5%) and tumor (12.5%). At 30 days from the onset of seizures, 13(40.5%) patients had recovered fully and seven (21.9%) had died. Poor outcome was associated with the presence of an acute symptomatic injury.

Adolescent↗
PubMed2005

Potential role of drug transporters in the pathogenesis of medically intractable epilepsy.

The pathogenesis underlying pharmacoresistance in epilepsy is unclear. One of the candidate mechanisms that has attracted growing interest is the limitation of antiepileptic drug (AED) access to the seizure focus by a range of efflux transporters, the prototype of which is P-glycoprotein (P-gp). P-gp is encoded by the multidrug resistance (MDR1 or ABCB1) gene. Predominantly expressed in organs with excretory functions and at blood-tissue barriers, P-gp is thought to act as a physiologic defense by extruding xenobiotics from mammalian cells and affording protection of sensitive organs. The high level of P-gp in the cerebrovascular endothelium is believed to contribute to the functionality of the blood-brain barrier. Overexpression of P-gp causes multidrug resistance in certain cancers. It has been hypothesized that overexpression of P-gp and other efflux transporters in the cerebrovascular endothelium, in the region of the epileptic focus, also may lead to drug resistance in epilepsy. This hypothesis is supported by the findings of elevated expression of efflux transporters in epileptic foci in patients with drug-resistant epilepsy, induction of expression by seizures in animal models, and experimental evidence that some commonly used AEDs are substrates. Conflicting reports suggest a possible association between variants of the MDR1 gene and medical intractability in epilepsy. Further studies to delineate the exact role, if any, of P-gp and other efflux transporters in drug-resistant epilepsy are warranted.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Overtreatment in epilepsy: how it occurs and how it can be avoided.

In pharmacotherapy, overtreatment may be defined as an excessive drug load (that is, excessive drug dosages or unnecessary polypharmacy) leading to a suboptimal risk-to-benefit ratio. The risk of overtreatment in the pharmacological management of epilepsy is substantial and may have serious consequences in terms of a greater incidence and severity of adverse effects. These effects can range from subtle CNS impairment to overt toxic effects, including teratogenicity. Overtreatment also causes increased treatment costs and may even lead to a paradoxical deterioration in seizure control. The prevention and correction of overtreatment requires a thorough understanding of the situations and mechanisms that lead to inappropriate prescribing of antiepileptic drugs. These include initiating treatment in conditions where it is not indicated (for example, long-term prophylaxis after head trauma or supratentorial surgery in seizure-free patients), use of excessively fast titration rates, prescription of excessively high initial target dosages, failure to consider conditions associated with reduced dosage requirements (for example, old age or comorbidities associated with impaired drug clearance), and failure to consider the dose-response characteristics of the selected drug. Many patients whose seizures do not respond to the initially prescribed medication can be optimally managed by switching to monotherapy with an alternative agent; premature use of combination therapy represents another common form of overtreatment. Overtreatment may also result from a failure to adjust the dosage to prevent or compensate for adverse pharmacokinetic or pharmacodynamic drug interactions, and from a failure to reduce drug load in patients who have not benefited from high dosages or polypharmacy. While the measurement of drug concentrations can aid in minimising adverse effects, there is also a danger of overtreatment resulting from inappropriate interpretation of drug concentration data. Continuation of drug therapy in seizure-free patients in whom the risk-benefit ratio is in favour of gradual withdrawal may also be regarded as overtreatment. Tailoring therapy to the needs of the individual patient is the key to the successful management of epilepsy. Even though the importance of complete seizure control cannot be overemphasised, no patient should be made to suffer more from the adverse effects of treatment than from the manifestations of the seizure disorder.

Anticonvulsants↗
PubMed2004

Epidemiology and management of epilepsy in Hong Kong: an overview.

Over half of the estimated 50 million people with epilepsy live in Asia, but there has been limited information on the epidemiology, aetiology and management of epilepsy from this region. In this article, we summarise some of the main problems faced by patients and the current treatment options available in an urban area of China.

Anticonvulsants↗
PubMed2004

Drug treatment of epilepsy: when does it fail and how to optimize its use?

Although modern community-based studies have shown that a majority of people with newly diagnosed epilepsy will enter long-term remission, seizures remain refractory to treatment in a substantial proportion of this population--perhaps as much as 40%. A consensus is being reached that, for operational purposes, pharmacoresistance can be suspected when two appropriately chosen, well-tolerated, first-line antiepileptic drugs (AEDs) or one monotherapy and one combination regimen have failed due to lack of efficacy. Poor prognostic factors include lack of response to the first AED, specific syndromes, symptomatic etiology, family history of epilepsy, psychiatric comorbidity, and high frequency of seizures. These observations suggest that prognosis can often be determined early in the course of the disorder. We propose a management paradigm that aims to maximize the chance of successful AED therapy, including the early use of "rational polytherapy" for patients not responding to monotherapy, and to identify efficiently patients suitable for "curative" resective surgery, in particular those with mesial temporal lobe epilepsy. An orderly approach to each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.

Adolescent↗
PubMed2004

Phenobarbital for the treatment of epilepsy in the 21st century: a critical review.

SUMMARY: Phenobarbital (PB) is the most widely used antiepileptic drug (AED) in the developing world and remains a popular choice in many industrialized countries. Meta-analyses of randomized controlled trials suggest that few differences in efficacy exist between PB and other established AEDs, but its possible deleterious cognitive and behavioral side effects remain a concern in the developed world. In contrast, high degrees of efficacy and tolerability in everyday clinical use have been demonstrated consistently in observational studies in developing countries. We propose that a pragmatic, comprehensive outcomes program be carried out, perhaps under the aegis of the Global Campaign Against Epilepsy, to optimize the conditions of the use of PB, so that more people around the world can benefit from this cost-effective medication and live more fulfilling lives.

Adolescent↗
PubMed2003

Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy.

Results from add-on antiepileptic drug (AED) trials performed in patients with chronic refractory epilepsy cannot be directly extrapolated to newly diagnosed patients because of fundamental differences in disease characteristics between the two patient populations. This article reviews the results of randomized, controlled trials of AEDs as monotherapy in newly diagnosed patients, focusing on the newer drugs. None of the newer AEDs has shown superior efficacy when tested against established agents for the treatment of partial seizures and generalized tonic-clonic seizures, the most common seizure types. Some of the newer drugs have shown good tolerability, resulting in better overall effectiveness in the case of lamotrigine over carbamazepine and oxcarbazepine over phenytoin, whereas vigabatrin and remacemide were demonstrated to have inferior efficacy compared with carbamazepine. The difficulty in detecting differences in efficacy among the AEDs might be attributed to the strategies underlying their development and the characteristics of the patient population under investigation. A better understanding of the pathophysiology of seizures and its relationship to epileptogenesis, and the use of more innovative strategies to identify new molecular targets, are needed for the development of a new generation of more effective AEDs that are not merely antiseizure but will hinder or reverse the deleterious processes that underlie the genesis of refractory epilepsy.

Anticonvulsants↗
PubMed2003

Differential expression of multidrug resistance genes in naïve rat brain.

The multidrug resistance (mdr1) gene family encodes the efflux transporter P-glycoprotein (P-gp) which contributes to the functionality of the blood-brain barrier. We have characterised the regional expression of mdr1 genes in nai;ve rat brain. Adult male Sprague-Dawley rats (n=6) were sacrificed and their brains rapidly removed. Seven distinct anatomical regions were isolated by microdissection and the expression of mdr1a and mdr1b determined by quantitative reverse-transcriptase polymerase chain reaction. The mdr1a isoform was expressed in all brain regions investigated, while mdr1b was expressed to a quantifiable degree in hippocampus alone. These findings reveal a differential expression of mdr1 genes in normal rodent brain tissue and suggest that P-gp may afford a broader protection of the hippocampus than other brain structures.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Staged approach to epilepsy management.

The natural history of treated epilepsy has substantial relevance to its pharmacologic and surgical management. In our center, 525 unselected, untreated patients were given a diagnosis of epilepsy, started on antiepileptic drug (AED) therapy, and followed for a median of 5 years. Sixty-three percent of patients had been seizure-free for at least the previous year. Forty-seven percent of 470 previously drug-naïve patients responded to their first AED. Thirteen percent were seizure-free on the second AED, and 1% on the third monotherapy choice. Only 3% were controlled with two AEDs and none with three. The prognosis for patients whose epilepsy did not respond to the first AED was strongly associated with the reason for failure. Only 11% of patients with inadequate control on the first AED later became seizure-free. These results suggest that patients with newly diagnosed epilepsy comprise two distinct populations. Around 60% will be controlled on monotherapy, usually with the first or second AED chosen. The remaining 30 to 40% will be difficult to control from the outset. A management plan should be formulated for each patient when treatment is started. Strategies for combining drugs should involve individual assessment of patient-related factors, including seizure type and epilepsy syndrome classification, combined with an understanding of the mechanisms of action, side effects, and interactions of the AEDs. Epilepsy surgery should be considered after failure of two well-tolerated treatment regimens, whether as monotherapy or with one monotherapy and the first combination. Prevention of refractory epilepsy should be the goal of treatment when the first AED is prescribed. A staged approach to the pharmacologic management and, when appropriate, surgical work-up for each epilepsy syndrome will optimize the chance of perfect seizure control and help more patients achieve a fulfilling life.

Adolescent↗
PubMed2002

P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice.

Evidence suggests that the efflux transporter P-glycoprotein (P-gp) may play a facilitatory role in refractory epilepsy by limiting the brain access of antiepileptic drugs (AEDs). We have conducted a preliminary pharmacokinetic study of seven commonly used AEDs in mdr1a knockout mice, devoid of P-gp at the blood-brain barrier. A parallel group of matched wild-type mice served as controls. AEDs were administered by subcutaneous injection and serum and brain drug concentrations determined at 30, 60, and 240min post-dosing. The brain-serum concentration ratio for topiramate was higher in mdr1a(-/-) mice than in wild-type controls at all time points investigated. No consistent effects were observed with any other AED investigated. These findings suggest that topiramate may be a substrate for P-gp-mediated transport. Further studies employing a range of model systems are required to substantiate this observation and to address the potential role of drug transporters in refractory epilepsy.

Journal Article↗
PubMed2002

Regional expression of multidrug resistance genes in genetically epilepsy-prone rat brain after a single audiogenic seizure.

PURPOSE: The multidrug resistance (mdr) gene family encodes the drug transport macromolecule P-glycoprotein (P-gp), which contributes to the functionality of the blood-brain barrier. Recent evidence suggests that P-gp-mediated drug extrusion may play a facilitatory role in refractory epilepsy. We investigated the regional expression of mdr genes in genetically epilepsy-prone rat (GEPR) brain after a single audiogenic seizure. METHODS: Three groups of adult male GEPRs (n = 5/group) were exposed to a seizure-inducing audiogenic stimulus and killed at 4 h, 24 h, and 7 days thereafter. A further group (n = 5) served as a stimulus-naïve control. Expression of mdr1a and mdr1b in distinct anatomic brain regions (cortex, midbrain, pons/medulla, hippocampus) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in the presence of competitive internal standards. RESULTS: When compared with control, mdr1a expression in cortex and midbrain was significantly (p < 0.05) increased at 24 h after a single audiogenic seizure. Cortical mdr1a expression remained elevated at 7 days after stimulus. In contrast, mdr1a expression in pons/medulla and hippocampus was unchanged. The mdr1b isoform was quantifiable in hippocampus alone and not influenced by seizure activity. CONCLUSIONS: These findings suggest that acute seizures in the GEPR can induce the expression of mdr genes. The pattern of increased expression appears to follow the anatomic pathway of audiogenic seizures in these animals, with initiation in the midbrain and propagation to the cortex. Further studies are required to investigate the effects of recurrent seizure activity and to characterise mdr expression in other experimental seizure models.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2002

Refractory epilepsy: a progressive, intractable but preventable condition?

Intractable seizures are just one manifestation of 'refractory epilepsy', which can be recognized as a distinct condition with multifaceted dimensions, including neurobiochemical plastic changes, cognitive decline and psychosocial dysfunction, leading to dependent behaviour and a restricted lifestyle. The biological basis of 'refractoriness' is likely to be multifactorial, and may include the severity of the syndrome and/or underlying neuropathology, abnormal reorganization of neuronal circuitry, alteration in neurotransmitter receptors, ion channelopathies, reactive autoimmunity, and impaired antiepileptic drug (AED) penetration to the seizure focus. Some of these deleterious changes may be a consequence of recurrent seizures. We hypothesize that 'refractory epilepsy' may be prevented by interrupting this self-perpetuating progression. There is increasing evidence that these patients can be identified early in the clinical course and, thus, be targeted early for effective therapeutic intervention. Failure of two first-line AEDs due to lack of efficacy or poor tolerability should prompt consideration of epilepsy surgery in a patient with a resectable brain abnormality. For the majority not suitable for 'curative' surgery, AEDs should be combined with the aim of achieving 'synergism'. This strategy has the potential to improve outcome by preventing the insidious progression to intractable 'refractoriness' and a downward spiraling quality of life.

Animals↗