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PubMed1999

Progress report on new antiepileptic drugs: a summary of the fourth Eilat conference (EILAT IV).

The Fourth Eilat Conference on New Antiepileptic Drugs (AEDs) was held at the Royal Beach Hotel, Eilat, Israel, from 6th to 10th September 1998. Epileptologists and scientists from 20 countries attended the conference, which was held to discuss a number of issues in drug development, including outcome assessment in epilepsy (long-term efficacy, quality of life, safety), cost-effectiveness, an update on drugs in development, a progress report on recently marketed AEDs, and controversies in strategies for drug development. This review focuses on drugs in development and recently marketed AEDs. Drugs in development include ADCI, AWD 131-138, DP16, ganaxolone (CCD 1042), levetiracetam (ucb L059), losigamone, pregabalin (isobutyl GABA [CI-1008]), remacemide hydrochloride, retigabine (D-23129), rufinamide (CGP 33101), soretolide (D2916), TV1901, and 534U87. New information on the safety and efficacy of recently marketed drugs (felbamate, fosphenytoin, gabapentin, lamotrigine, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide) and of a new antiepileptic device, the neurocybernetic prosthesis (NCP), has become available. This paper summarizes the presentations made at the conference.

Animals↗
PubMed2003

The long-term effects of antiepileptic drugs on the visual system in rats: electrophysiological and histopathological studies.

OBJECTIVE: We quantified the long-term effects of antiepileptic drugs (AEDs) on the visual system of rats using electroretinograms (ERGs) and visual evoked potentials (VEPs). METHODS: Twenty adult Sprague-Dawley rats were divided into 4 groups (n=5). Each animal was treated by monotherapy of phenytoin (PHT), valproic acid (VPA), zonisamide (ZNS) or physiological saline as control. The AEDs were injected intraperitoneally daily for 180 days. ERGs and VEPs were recorded before the medication and on Days 30 and 180. RESULTS: There were no significant changes in the 4 groups on Day 30. On Day 180, the amplitudes of a- and b-waves of dark-adapted (DA) ERGs were reduced in the PHT group compared with those of the control group. In the VPA group, the amplitudes of the DA ERG a- and b-waves, light-adapted ERG b-wave and the DA VEP were reduced. No significant changes were observed in the ZNS group. There were no histopathological changes of the retina and visual cortex in all groups. CONCLUSIONS: Our results indicate that neurons along the visual pathways have different sensitivity to each AED. This may result from the differential pharmacological actions of each AED on visual neurons. SIGNIFICANCE: Our findings suggest that epileptic patients on long-term use of AEDs might have subclinical influences to the visual systems.

Adaptation, Ocular↗
PubMed2003

Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs.

There are two types of interactions between drugs, pharmacokinetic and pharmacodynamic. For antiepileptic drugs (AEDs), pharmacokinetic interactions are the most notable type, but pharmacodynamic interactions involving reciprocal potentiation of pharmacological effects at the site of action are also important. By far the most important pharmacokinetic interactions are those involving cytochrome P450 isoenzymes in hepatic metabolism. Among old generation AEDs, carbamazepine, phenytoin, phenobarbital, and primidone induce the activity of several enzymes involved in drug metabolism, leading to decreased plasma concentration and reduced pharmacological effect of drugs, which are substrates of the same enzymes (eg, tiagabine, valproic acid, lamotrigine, and topiramate). In contrast, the new AEDs gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, vigabatrin, and zonisamide do not induce the metabolism of other AEDs. Interactions involving enzyme inhibition include the increase in plasma concentrations of lamotrigine and phenobarbital caused by valproic acid. Among AEDs, the least potential interaction is associated with gabapentin and levetiracetam.

Anticonvulsants↗
PubMed2004

Efficacy and tolerability of the new antiepileptic drugs: comparison of two recent guidelines.

BACKGROUND: Until the early 1990s six major compounds (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproic acid) were available for the treatment of epilepsy. However, these drugs have pharmacokinetic limitations, teratogenic potential, and a negative effect on cognitive functions that impairs the quality of patients' lives and limits the use of these drugs in some patients. In addition, 20-30% of patients are refractory to these drugs. RECENT DEVELOPMENTS: The development of ten new antiepileptic drugs (vigabatrin, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin) has expanded treatment options. The newer drugs may be better tolerated, have fewer drug interactions, and seem to affect cognitive functions to a lesser extent than old drugs. Guidelines on the use of new antiepileptic drugs have been developed in the USA and in the UK. Both guidelines offer a clear picture of the efficacy, safety, and tolerability of the new antiepileptic drugs and agree on their use as add-on treatment in patients who do not respond to conventional drugs. The guidelines differ in the type and strength of recommendations. Whereas the US guidelines recommend treatment in newly diagnosed epilepsy with a standard drug or a new drug depending on the individual patient's characteristics, the UK guidelines recommend that a new antiepileptic drug should be considered only if there is no benefit from an old antiepileptic drug, an old drug is contraindicated, there is a previous negative experience with the same drug, or the patient is a woman of childbearing potential. WHERE NEXT: The limited amount of information on the new antiepileptic drugs may explain the discrepancies among the two guidelines and between these and other recommendations. Comparative, pragmatic, long-term and open trials should be done to show long-term efficacy and comparative features of the new antiepileptic drugs, and to better assess the effect on quality-of-life, cost-effectiveness, tolerability, and teratogenic potential. In addition, the conflicts should be resolved between the needs of the regulatory bodies and those of the treating physicians. Finally, there is a need for trial designs to be standardised.

Anticonvulsants↗
PubMed2002

Antiepileptic drug treatment in the developmentally disabled: treatment considerations with the newer antiepileptic drugs.

Epilepsy is a common comorbidity among developmentally disabled (DD) patients, and special considerations apply to its treatment. In particular, clinicians should try to avoid antiepileptic drugs (AEDs) with sedating properties or adverse cognitive effects that might further diminish quality of life for DD patients. Behavioral changes due to medication and significant pharmacokinetic interactions with other medications are also concerns. The newer AEDs, approved in the 1990s, offer new options for the treatment of individuals with developmental disability and epilepsy. Gabapentin does not interact with the hepatic metabolism of other AEDs or psychotropic agents, results in a statistically significant reduction in seizure frequency in mentally retarded children, and is generally well tolerated. Felbamate is an effective broad-spectrum AED, but has serious toxicity issues limiting its use. Lamotrigine has been extensively studied in the DD population, achieving seizure reduction rates of up to 50% in some trials. Although it is usually well tolerated in this population, its pharmacokinetic profile is influenced by concomitant medications. Levetiracetam has been found to be effective against kindled seizures and has been approved as adjunctive therapy for partial epilepsies. It does not cause any pharmacokinetic interactions, but may have behavioral side effects. Oxcarbazepine is a homologue of carbamazepine that has fewer drug interactions. It is approved for mono- or adjunctive therapy in patients with partial seizures, and its use in DD individuals appears to be worthwhile. Tiagabine is extensively bound to plasma proteins and is therefore subject to protein-binding displacement interactions by other highly protein-bound drugs, such as sodium valproate. While there are trial data showing its efficacy as adjunctive therapy in partial epilepsy in adults and children, there is a paucity of data specific to the DD population. Common side effects include sedation. Topiramate is a broad-spectrum AED approved as adjunctive therapy for partial and primary generalized tonic-clonic seizures. It appears to be particularly effective in patients with Lennox-Gastaut syndrome and those with cognitive disabilities. It appears to be better tolerated in the DD population than in the general population. Zonisamide has been effective in the DD population, yielding a seizure reduction of 50% in 41% of children in 1 trial. It has been associated with renal stone formation, sedation, and cognitive effects, however. The new AEDs have a role in treating seizures in the DD. Side effects that limit their use include anorexia, behavioral changes, and sedation. Seizure exacerbation can occur with the new AEDs and success is defined empirically and by improvements in quality of life.

Journal Article↗
PubMed1994

How about the new antiepileptic drugs?

No new antiepileptic drugs (AEDs) were licensed in the United States from 1978 to 1992. In late 1992, felbamate and gabapentin were recommended for approval, and in early 1993, lamotrigine. In July 1993, felbamate was licensed, and gabapentin and lamotrigine may soon follow. Lamotrigine, vigabatrin and clobazam are in use outside the US. Tiagabine, oxcarbazepine, fosphenytoin, topiramate, vigabatrin and zonisamide are in Phase II clinical testing in the US. All of the new AEDs are effective against partial and tonic-clonic seizures. Few controlled clinical trials have been done in patients with absence and myoclonic seizures. Mechanisms of action of the new drugs have not been clearly defined. The new AEDs will provide an opportunity to improve the care of epileptic patients. Even with optimal management with currently available drugs, some 30% of patients remain refractory to medical management.

Anticonvulsants↗
PubMed2003

New anticonvulsant medication uses in bipolar disorder.

Therapy of bipolar disorders is a rapidly evolving field. Lithium has efficacy in classic bipolar disorders whereas divalproex sodium and carbamazepine may have broader spectrum efficacy that includes non-classic bipolar disorder. In the last 10 years, a series of anticonvulsants have been approved for marketing in the United States. Gabapentin has indirect g-aminobuytric acid-ergic actions, is generally well tolerated, and appears to have anxiolytic, analgesic, and hypnotic effects. Lamotrigine has antiglutamatergic actions and is generally well tolerated (aside from rash in 1 in 10, and serious rash in 1 in 1,000 patients). Lamotrigine is indicated for maintenance treatment in bipolar disorder. Emerging evidence suggests lamotrigine may have utility in bipolar disorder patients with depression and treatment-refractory rapid cycling, as well as analgesic effects. Topiramate and zonisamide may allow both weight loss, while topiramate may have specific efficacy in bulimia, binge eating disorder, and alcohol dependence. Two small studies found oxcarbazepine had similar efficacy to lithium and haloperidol in acute mania. Phenytoin, an older anticonvulsant, may have adjunctive acute mania efficacy. Levetiracetam, a newer anticonvulsant, may be worth exploring and has minimal drug-drug interactions. None of these newer agents has been shown effective in a large placebo controlled trial for acute mania. Although the clinical profiles of these newer anticonvulsants do not appear to overlap markedly with divalproex and carbamazepine (except perhaps for oxcarbazepine), these novel agents may still offer important new options in relieving a variety of specific target symptoms in patients with bipolar disorder.

Anticonvulsants↗
PubMed2006

Carbonic anhydrase inhibitors: DNA cloning and inhibition studies of the alpha-carbonic anhydrase from Helicobacter pylori, a new target for developing sulfonamide and sulfamate gastric drugs.

We have cloned and sequenced Helicobacter pylori alpha-class carbonic anhydrase (hpCA) from patients with different gastric mucosal lesions, including gastritis (n=15), ulcer (n=6), and cancer (n=16). Although several polymorphisms were newly identified such as 12Ala, 13Thr, 16Ile, and 168Phe, there was no significant relevance of any polymorphism with gastric mucosal lesion types. A library of sulfonamides/sulfamates has been investigated for the inhibition of hpCA, whereas new derivatives have been obtained by attaching 4-tert-butyl-phenylcarboxamido/sulfonamido tails to benzenesulfonamide/1,3,4-thiadiazole-2-sulfonamide scaffolds. All types of activity for inhibition of hpCA have been detected. Dorzolamide and simple 4-substituted benzenesulfonamides were weak inhibitors (KI 873-4360 nM). Sulfanilamide, orthanilamide, some of their derivatives, and indisulam showed better activity (KI 413-640 nM), whereas most of the clinically used inhibitors, such as methazolamide, ethoxzolamide, dichlorophenamide, brinzolamide, topiramate, zonisamide, etc., acted as medium-potency inhibitors (KI 105-378 nM). Some potent hpCA inhibitors were detected too (KI 12-84 nM) among acetazolamide, 4-amino-6-chloro-1,3-benzenedisulfonamide and some newly designed compounds incorporating lipophilic tails. Some of the newly prepared derivatives had selectivity ratios for inhibiting hpCA over hCA II in the range of 1.25-3.48, showing thus some selectivity for inhibiting the bacterial enzyme. Since hpCA is essential for the survival of the pathogen in acid, it might be used as a new pharmacologic tool in the management of drug-resistant H. pylori.

Amino Acid Sequence↗
PubMed1999

Metabolism and excretion of mood stabilizers and new anticonvulsants.

1. The mood stabilizers lithium, carbamazepine (CBZ), and valproate (VPA), have differing pharmacokinetics, structures, mechanisms of action, efficacy spectra, and adverse effects. Lithium has a low therapeutic index and is renally excreted and hence has renally-mediated but not hepatically-mediated drug-drug interactions. 2. CBZ has multiple problematic drug-drug interactions due to its low therapeutic index, metabolism primarily by a single isoform (CYP3A3/4), active epoxide metabolite, susceptibility to CYP3A3/4 or epoxide hydrolase inhibitors, and ability to induce drug metabolism (via both cytochrome P450 oxidation and conjugation). In contrast, VPA has less prominent neurotoxicity and three principal metabolic pathways, rendering it less susceptible to toxicity due to inhibition of its metabolism. However, VPA can increase plasma concentrations of some drugs by inhibiting metabolism and increase free fractions of certain medications by displacing them from plasma proteins. 3. Older anticonvulsants such as phenobarbital and phenytoin induce hepatic metabolism, may produce toxicity due to inhibition of their metabolism, and have not gained general acceptance in the treatment of primary psychiatric disorders. 4. The newer anticonvulsants felbamate, lamotrigine, topiramate, and tiagabine have different hepatically-mediated drug-drug interactions, while the renally excreted gabapentin lacks hepatic drug-drug interactions but may have reduced bioavailability at higher doses. 5. Investigational anticonvulsants such as oxcarbazepine, vigabatrin, and zonisamide appear to have improved pharmacokinetic profiles compared to older agents. 6. Thus, several of the newer anticonvulsants lack the problematic drug-drug interactions seen with older agents, and some may even (based on their mechanisms of action and preliminary preclinical and clinical data) ultimately prove to have novel psychotropic effects.

Anticonvulsants↗
PubMed2002

Combining lithium and anticonvulsants in bipolar disorder: a review.

While the benefits of lithium in bipolar disorder are evident, its limitations as monotherapy are well recognized, particularly in bipolar depression. This has propelled trials of combined lithium-anticonvulsant therapy in many bipolar patients. The present review of the English-language literature examines both controlled and open studies of such combination therapy, including the risk of drug-drug interactions. Trials of lithium plus either carbamazepine or divalproex have generally produced favorable results, although increased rates of adverse effects may reduce treatment adherence. More recent reports suggest that lithium may be safely and effectively combined with lamotrigine, and perhaps with topiramate, although controlled studies are required. The combined use of lithium with newer, putative mood stabilizers, such as zonisamide or levetiracetam, cannot yet be recommended, but is an important area for future research. Provisional recommendations for combined treatment are provided.

Anticonvulsants↗
PubMed2003

The diverse roles of anticonvulsants in bipolar disorders.

Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and biochemical effects. Carbamazepine and valproate have mood-stabilizing actions, benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in rapid cycling and acute treatment and prophylaxis of bipolar depression, and topiramate and zonisamide can yield weight loss. Limited controlled data suggest the carbamazepine keto derivative oxcarbazepine has antimanic effects. A categorical approach to the diverse roles of ACs in bipolar disorders is proposed, using broad categories of ACs, on the basis of their predominant psychotropic profiles. Thus, some ACs have "sedating" profiles that may include sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic and/or anxiolytic effects. In contrast, some newer ACs have "activating" profiles that may include improved energy, weight loss, and possibly antidepressant and even anxiogenic effects. Still other newer ACs have novel "mixed" profiles, combining sedation and weight loss. A categorical-mechanistic extension of this approach is also presented, with hypotheses that "sedating" profiles might be related to prominent potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, "activating" profiles could be related to prominent attenuation of glutamate excitatory neurotransmission, and for "mixed" profiles, sedation and weight loss might be related to concurrent GABAergic and antiglutamatergic actions, respectively. The categorical approach may have utility as an aid to clinicians in reinforcing the heterogeneity ACs, and recalling psychotropic profiles of individual ACs, but is limited as it fails to address the etiology of the heterogeneity of AC psychotropic effects. The categorical-mechanistic extension strives to address this issue, but requires systematic clinical investigation of more precise relationships between psychotropic profiles and discrete mechanisms of action to assess its merits.

Affect↗
PubMed2004

Current and investigational antiobesity agents and obesity therapeutic treatment targets.

Public health efforts and current antiobesity agents have not controlled the increasing epidemic of obesity. Investigational antiobesity agents consist of 1) central nervous system agents that affect neurotransmitters or neural ion channels, including antidepressants (bupropion), selective serotonin 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, and cannabinoid-1 receptor antagonists (rimonabant); 2) leptin/insulin/central nervous system pathway agents, including leptin analogues, leptin transport and/or leptin receptor promoters, ciliary neurotrophic factor (Axokine), neuropeptide Y and agouti-related peptide antagonists, proopiomelanocortin and cocaine and amphetamine regulated transcript promoters, alpha-melanocyte-stimulating hormone analogues, melanocortin-4 receptor agonists, and agents that affect insulin metabolism/activity, which include protein-tyrosine phosphatase-1B inhibitors, peroxisome proliferator activated receptor-gamma receptor antagonists, short-acting bromocriptine (ergoset), somatostatin agonists (octreotide), and adiponectin; 3) gastrointestinal-neural pathway agents, including those that increase cholecystokinin activity, increase glucagon-like peptide-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitors), and increase protein YY3-36 activity and those that decrease ghrelin activity, as well as amylin analogues (pramlintide); 4) agents that may increase resting metabolic rate ("selective" beta-3 stimulators/agonist, uncoupling protein homologues, and thyroid receptor agonists); and 5) other more diverse agents, including melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of dehydroepiandrosterone sulfate, antagonists of adipocyte 11B-hydroxysteroid dehydrogenase type 1 activity, corticotropin-releasing hormone agonists, inhibitors of fatty acid synthesis, carboxypeptidase inhibitors, indanones/indanols, aminosterols, and other gastrointestinal lipase inhibitors (ATL962). Finally, an emerging concept is that the development of antiobesity agents must not only reduce fat mass (adiposity) but must also correct fat dysfunction (adiposopathy).

Anti-Obesity Agents↗
PubMed2001

Determination of effects of antiepileptic drugs on SNAREs-mediated hippocampal monoamine release using in vivo microdialysis.

1. To elucidate possible mechanisms underlying the effects of carbamazepine (CBZ), valproate (VPA) and zonisamide (ZNS) on neurotransmitter exocytosis, the interaction between these three antiepileptic drugs (AEDs) and botulinum toxins (BoNTs) on basal, Ca(2+)- and K(+)-evoked release of dopamine (DA) and serotonin (5-HT) were determined by microdialysis in the hippocampus of freely moving rats. 2. Basal release of monoamine was decreased by pre-microinjection of the syntaxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhibitor, BoNT/B. Ca(2+)-evoked release was inhibited by BoNT/C selectively. K(+)-evoked release was reduced by BoNT/B predominantly and BoNT/C weakly. 3. Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively. Perfusion with VPA increased basal 5-HT release concentration-dependently, whereas basal DA release was affected by VPA biphasic concentration-dependently, similar to CBZ and ZNS. This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly. 4. Ca(2+)-evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations. These effects of the AEDs on Ca(2+)-evoked release were inhibited by BoNT/C, but not by BoNT/B. 5. K(+)-evoked monoamine release was reduced by AEDs concentration-dependently. The inhibitory effect of these three AEDs on K(+)-evoked release was inhibited by BoNT/B, but not by BoNT/C. 6. These findings suggest that the therapeutic-relevant concentration of CBZ, VPA and ZNS affects exocytosis of DA and 5-HT, the enhancement of syntaxin-mediated monoamine release during resting stage, and the inhibition of synaptobrevin-mediated release during depolarizing stage.

Animals↗
PubMed2001

Clinical pharmacology and therapeutic use of the new antiepileptic drugs.

Although older generation antiepileptic drugs (AEDs) such as carbamazepine, phenytoin and valproic acid continue to be widely used in the treatment of epilepsy, these drugs have important shortcomings such as a highly variable and nonlinear pharmacokinetics, a narrow therapeutic index, suboptimal response rates, and a propensity to cause significant adverse effects and drug interactions. In an attempt to overcome these problems, a new generation of AEDs has been introduced in the last decade. Compared with older agents, some of these drugs offer appreciable advantages in terms of less variable kinetics and, particularly in the case of gabapentin, levetiracetam and vigabatrin, a lower interaction potential. Lamotrigine, topiramate, zonisamide and felbamate protect against partial seizures and a variety of generalized seizure types, vigabatrin is effective against partial seizures (with or without secondary generalization) and infantile spasms, while the use of oxcarbazepine, tiagabine and gabapentin is mainly restricted to patients with partial epilepsy (and, in the case of oxcarbazepine, also primarily generalized tonic-clonic seizures). Levetiracetam, the latest AED to be introduced, has been found to be effective in partial seizures, but its potentially broader efficacy spectrum remains to be determined in clinical studies. Currently, the main use of new generation AEDs is in the adjunctive therapy of patients refractory to older agents. However, due to advantages in terms of tolerability and ease of use, some of these drugs are increasingly used for first-line management in certain subgroups of patients. Due to serious toxicity risks, felbamate and vigabatrin should be prescribed only in patients refractory to other drugs. In the case of vigabatrin, however, first line use may be justified in infants with spasms.

Anticonvulsants↗
PubMed2001

Concerns with antiepileptic drug initiation: safety, tolerability, and efficacy.

A number of commonly used antiepileptic drugs (AEDs) produce severe adverse effects if they are introduced at their usual daily maintenance doses. Gradual slow titration of the dose often avoids these adverse effects almost entirely. Conversely, some AEDs can be started at their effective maintenance dose and perhaps even with a loading dose. Although the mechanisms of these distinctions among antiepileptic compounds are poorly understood, the phenomenon clearly has important implications for the optimal use of the drugs, especially when rapid seizure control is desired. Examples of drugs that require gradual introduction are lamotrigine, carbamazepine, topiramate, tiagabine, and zonisamide. Phenytoin, oxcarbazepine, gabapentin, valproate, and levetiracetam are examples of drugs that can be started at an effective dose.

Anticonvulsants↗
PubMed2002

Kidney stones, carbonic anhydrase inhibitors, and the ketogenic diet.

PURPOSE: Because carbonic anhydrase inhibitors and the ketogenic diet are each known risk factors for kidney stones, simultaneous use of these therapies has been discouraged. The objective of this study was to establish the prevalence of nephrolithiasis in children in this combination-therapy population. METHODS: Since 1996, 301 children have been started on the ketogenic diet at our institution. A retrospective cohort study of renal calculi in ketogenic diet patients was performed to evaluate the increased risk with combined use of a carbonic anhydrase inhibitor. RESULTS: In 15 (6.7%) of 221 children on the ketogenic diet without the use of carbonic anhydrase inhibitors, stones developed. In five (6.3%) of the 80 children on the diet in combination with topiramate or zonisamide, stones developed. There was no difference between these two groups (p = 0.82). No child was treated with either acetazolamide or more than one carbonic anhydrase inhibitor simultaneously. Prior ketogenic diet duration was shorter (10.4 vs. 22.4 months; p = 0.03), and more children had either a family history of renal stones or significant urologic abnormalities (80 vs. 27%; p = 0.04) in the combination-therapy group. CONCLUSIONS: The combined use of carbonic anhydrase inhibitors and the ketogenic diet does not increase the risk of kidney stones. We recommend that all patients treated with combination therapy should be treated with increased hydration. Urine alkalinization should be considered for children with previous renal abnormalities, family histories of kidney stones, hematuria, or elevated urine calcium-to-creatinine ratios. If renal stones are found, we advocate discontinuation of the carbonic anhydrase inhibitor.

Carbonic Anhydrase Inhibitors↗
PubMed2001

Phenytoin-induced choreoathetosis in patients with severe myoclonic epilepsy in infancy.

We describe three patients with severe myoclonic epilepsy in infancy (SME) who suffer from choreoathetosis due to the adverse effect of phenytoin. Choreoathetosis appeared when these patients were 8, 19, and 21 years old, 2 days to 6 months after increasing the phenytoin dosage. Choreoathetosis disappeared when the phenytoin dosage was decreased. The two elder patients experienced episodic and rather paroxysmal onset of long-lasting choreoathetosis, requiring the differential diagnosis from degenerative disease. In one of the patients, an ictal SPECT revealed decreased perfusion in the basal ganglia contralateral to the unilateral choreoathetosis. Polypharmacy, including carbamazepine and zonisamide, may have facilitated the onset of choreoathetosis. Phenytoin-induced choreoathetosis in the patients with SME is an important differential diagnosis among degenerative disorders involving involuntary movements. The episodic and paroxysmal nature of this movement disorder can delay its diagnosis and effective treatment. Patients with SME appear to be particularly vulnerable to this side effect of phenytoin, indicating the possible involvement of basal ganglia in the pathophysiology of this type of epilepsy.

Adolescent↗
PubMedDate not supplied

Carbonic anhydrase inhibitors that directly inhibit anion transport by the human Cl-/HCO3- exchanger, AE1.

Carbonic anhydrases (CA, EC 4.2.1.1.) catalyze reversible hydration of CO2 to HCO3- + H+. Bicarbonate transport proteins, which catalyze the transmembrane movement of membrane-impermeant bicarbonate, function in cooperation with CA. Since CA and bicarbonate transporters share the substrate, bicarbonate, we examined whether novel competitive inhibitors of CA also have direct inhibitory effects on bicarbonate transporters. We expressed the human erythrocyte membrane Cl-/HCO3- exchanger, AE1, in transfected HEK293 cells as a model bicarbonate transporter. AE1 activity was assessed in both Cl-/NO3- exchange assays, which were independent of CA activity, and in Cl-/HCO3- exchange assays. Transport was measured by following changes of intracellular [Cl-] and pH, using the intracellular fluorescent reporter dyes 6-methoxy-N-(3-sulfopropyl)quinolinium and 2',7'-bis-(2-carboxyethyl)-5-(and-6)carboxyfluorescein, respectively. We examined the effect of 16 different carbonic anhydrase inhibitors on AE1 transport activity. Among these 12 were newly-reported compounds; two were clinically used non-steroidal anti-inflammatory drugs (celecoxib and valdecoxib) and two were anti-convulsant drugs (topiramate and zonisamide). Celecoxib and four of the novel compounds significantly inhibited AE1 Cl-/NO3- exchange activity with EC50 values in the range 0.22-2.8 microM. It was evident that bulkier compounds had greater AE1 inhibitory potency. Maximum inhibition using 40 microM of each compound was only 22-53% of AE1 transport activity, possibly because assays were performed in the presence of competing substrate. In Cl-/HCO3- exchange assays, which depend on functional CA to produce transport substrate, 40 microM celecoxib inhibited AE1 by 62+/-4%. We conclude that some carbonic anhydrase inhibitors, including clinically-used celecoxib, will inhibit bicarbonate transport at clinically-significant concentrations.

Anion Exchange Protein 1, Erythrocyte↗