Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

(1) The first-line treatment for patients with partial epilepsy is carbamazepine monotherapy. Second-line options include monotherapy with valproic acid, gabapentin, lamotrigine or oxcarbazepine. Other antiepileptics are also available for combination therapy of refractory partial epilepsy. (2) Zonisamide is a sulphonamide derivative that inhibits carbonic anhydrase; it resembles topiramate, a drug already approved for use for this indication in the European Union. (3) The main clinical trial, a double-blind study lasting 36 weeks, compared the addition of zonisamide or placebo to ongoing treatment in 351 patients with refractory partial epilepsy. The "response rate" (the proportion of patients with at least a 50% reduction in the frequency of seizures) was significantly higher with zonisamide plus the previous treatment than with placebo plus the previous treatment (46.6% versus 17.6%). An indirect comparison suggests that this is no better than treatment with a second-line antiepileptic drug. (4) Results of three other placebo-controlled trials of third-line combinations in a total of 499 patients treated for 12 weeks were similar. (5) The main adverse effects of zonisamide are those typically seen with topiramate: neuropsychological disorders and disorders due to carbonic anhydrase inhibition (kidney stones, reduced perspiration, and hyperthermia). There are various other adverse effects, including a risk of severe skin rash. (6) The profile of interactions is complex. There is a risk of pharmacokinetic interactions, and of pharmacodynamic interactions with other carbonic anhydrase inhibitors. (7) In France, treatment with zonisamide costs nearly 20 times more than treatment with carbamazepine or valproic acid. (8) Zonisamide has no therapeutic advantages over other antiepileptics available for combination therapy of partial epilepsy.
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PMID:Zonisamide: new drug. No advantage in refractory partial epilepsy. 1758 22

Antiepileptic drugs (AEDs) suppress seizures by selectively modifying the excitability of neurons and blocking seizure firing with minimal disturbance of nonepileptic activity. All AEDs have been shown to work by at least one of 3 main mechanisms of action: through modulation of voltage-gated ion channels, enhancement of synaptic inhibition, and inhibition of synaptic excitation. Zonisamide is a novel AED that has a broad combination of complementary mechanisms of action, which may offer a clinical advantage over other antiepileptic agents. By altering the fast inactivation threshold of voltage-dependent sodium channels, zonisamide reduces sustained high-frequency repetitive firing of action potentials. Zonisamide also inhibits low-threshold T-type calcium channels in neurons, which may prevent the spread of seizure discharge across cells. In addition, zonisamide is a weak inhibitor of carbonic anhydrase. However, this mechanism is not believed to contribute to the antiepileptic activity of zonisamide. Although zonisamide also seems to alter dopamine, serotonin, and acetylcholine metabolism, it is not clear to what extent these effects on neurotransmitters are involved in the clinical actions of the drug. In addition to these actions, recent evidence suggests that zonisamide may exert neuroprotective actions, independent of its antiepileptic activity. These potential effects may be important in preventing neuronal damage caused by recurrent seizures. Therefore, it seems that the multiple pharmacological actions of zonisamide may contribute to the seizure reductions observed in a wide range of epilepsies and may help to preserve efficacy in individual patients despite possible changes in electrophysiological status.
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PMID:Clinical pharmacology and mechanism of action of zonisamide. 1776 20

A small library of indanesulfonamides was screened for the inhibition of the human carbonic anhydrase (CA, EC 4.2.1.1) isoforms involved in neuronal excitation, that is, isoforms VII, XII and XIV. These CA isoforms are becoming interesting target for the design of agents useful for the treatment of epilepsy. The inhibition pattern of these indanesulfonamide compounds towards these three isoforms was excellent, with many nanomolar inhibitors detected (K(I)s in the range of 0.78-10 nM against hCA VII; 0.32-56 nM against hCA XII, and 0.47-1030 nM against hCA XIV, respectively). The maximal electroshock seizure (MES) test performed on mice showed a good anticonvulsant activity for some compounds which protected the mice against convulsions in the 50-62.5% range at a dose of 50 mg/kg. In parallel, the blood-brain barrier passive permeation of these sulfonamides was also estimated by using a computational approach.
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PMID:Indanesulfonamides as carbonic anhydrase inhibitors and anticonvulsant agents: structure-activity relationship and pharmacological evaluation. 1840 97

A variety of newer antiepileptic drugs (AEDs) are now available for treating patients with epilepsy in addition to the 'conventional' drugs that have been available throughout a large part of the last century. Since these drugs act to suppress the pathological neuronal hyperexcitability that constitutes the final substrate in many seizure disorders, it is not surprising that they are prone to causing adverse reactions that affect the CNS.Information on adverse effects of the older AEDs has been mainly observational. Equally, whilst the newer drugs have been more systematically studied, their long-term adverse effects are not clearly known. This is illustrated by the relatively late emergence of the knowledge of visual field constriction in the case of vigabatrin, which only became known after several hundred thousand patient-years of use. However, older drugs continue to be studied and there has been more recent comment on the possible effect of valproate (valproic acid) on cognition following exposure to this drug in utero.With most AEDs, there are mainly dose-related adverse effects that could be considered generic, such as sedation, drowsiness, incoordination, nausea and fatigue. Careful dose titration with small initial doses can reduce the likelihood of these adverse effects occurring. Adverse effects such as paraesthesiae are more commonly reported with drugs such as topiramate and zonisamide that have carbonic anhydrase activity. Weight loss and anorexia can also be peculiar to these drugs. Neuropsychiatric adverse effects are reported with a variety of AEDs and may not be dose related. Some drugs, such as carbamazepine when used to treat primary generalized epilepsy, can exacerbate certain seizure types. Rare adverse effects such as hyperammonaemia with valproate are drug specific. There are relatively very few head-to-head comparisons of AEDs and limited information is available in this regard.In this review, we discuss the available literature and provide a comprehensive summary of adverse drug reactions of AEDs affecting the CNS.
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PMID:CNS adverse events associated with antiepileptic drugs. 1869 74

The mechanisms of paradoxical aggravation of epileptic seizures induced by selected antiepileptic drugs (AEDs) remain unclear. The present study addressed this issue by determining the seizure-threshold doses of carbamazepine (CBZ) and phenytoin (PHT), as well the dose-dependent effects of CBZ, PHT, and carbonic anhydrase-inhibiting AEDs, acetazolamide (AZM), topiramate (TPM), and zonisamide (ZNS), on neurotransmitter release in rat hippocampus. The dose-dependent effects of AEDs on hippocampal extracellular levels of glutamate (Glu), GABA, norepinephrine (NE), dopamine (DA), and serotonin (5-HT) were determined by microdialysis with high-speed and high-sensitive extreme liquid chromatography. Proconvulsive effects of AEDs were determined by telemetric-electrocorticography. Therapeutically relevant doses of AZM, CBZ, TPM, and ZNS increased hippocampal extracellular levels of GABA, NE, DA, and 5-HT, while PHT had no effect. Supratherapeutic doses of AZM, CBZ, PHT, TPM, and ZNS decreased extracellular levels of GABA, NE, DA, and 5-HT, without affecting Glu levels. Toxic doses of CBZ and PHT produced seizures (paradoxical intoxication), markedly increasing all transmitter levels, but TPM and ZNS even at toxic doses did not produce seizure. Co-administration experiments showed that therapeutically relevant doses of CBZ or PHT reduced the seizure-threshold doses of PHT or CBZ, respectively. In contrast, therapeutically relevant doses of AZM, TPM, and ZNS elevated the seizure-threshold doses of CBZ and PHT. These results suggested that blockade of high percentage of the population of voltage-dependent sodium channels by CBZ and PHT might be important in inducing paradoxical intoxication/reaction, and that inhibition of carbonic anhydrase inhibits this effect. TPM and ZNS are candidate first-choice agents in treatment of epilepsy when first-line AEDs are ineffective.
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PMID:Topiramate and zonisamide prevent paradoxical intoxication induced by carbamazepine and phenytoin. 1926 40

In seeking broad-spectrum anticonvulsants to treat epilepsy and other neurological disorders, we synthesized and tested a group of sulfamide derivatives (4a-k, 5), which led to the clinical development of 4a (JNJ-26990990). This compound exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures, with very weak inhibition of human carbonic anhydrase-II (IC(50) = 110 microM). The pharmacological profile for 4a supports its potential in the treatment of multiple forms of epilepsy, including pharmacoresistant variants. Mechanistically, 4a inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels but was not effective as a K(+) channel opener. The pharmacokinetics and metabolic properties of 4a are discussed.
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PMID:Novel, broad-spectrum anticonvulsants containing a sulfamide group: advancement of N-((benzo[b]thien-3-yl)methyl)sulfamide (JNJ-26990990) into human clinical studies. 1938 76

In previous studies we identified several 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives displaying potent anticonvulsant effects in different animal models of epilepsy. With the aim to deepen the structure-activity relationships (SAR) for this class of compounds and identify novel anticonvulsant agents we synthesized a series of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. The new compounds incorporate the main features of the above-mentioned anticonvulsants and a sulfonamide function capable to inhibit the enzyme carbonic anhydrase (CA, EC 4.2.1.1), which represents an attractive target in epilepsy. Pharmacological effects were evaluated in vivo against audiogenic seizures in DBA/2 mice and in vitro against several CA isoforms. Some of the new molecules showed anticonvulsant properties better than topiramate, but weak inhibitory activity and low selectivity in enzymatic assay.
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PMID:Synthesis and evaluation of pharmacological profile of 1-aryl-6,7-dimethoxy-3,4-dihydroisoquinoline-2(1H)-sulfonamides. 1939 4

Zonisamide is an antiepileptic drug that acts on voltage-sensitive sodium and calcium channels, with a modulatory effect on GABA-mediated neuronal inhibition and an inhibitory effect on carbonic anhydrase. It is used mainly for the treatment of partial seizures, and is generally well tolerated at therapeutic doses. The most common reported adverse effects are somnolence, anorexia, dizziness, and headache. There are limited data on zonisamide overdose in the literature, and no case of zonisamide mono-intoxication has been published to date. We describe the first case of zonisamide mono-intoxication in a 25-year-old woman who ingested 12.6 g of this substance with suicidal intent. Despite a plasma zonisamide concentration of 182 mg/L on admission, the patient exhibited a benign clinical course with vomiting and central nervous system depression, requiring brief intubation. Somnolence persisted for 50 hours, and normal-anion-gap metabolic acidosis and polyuria for several days. Complete recovery may be expected with supportive care, even after ingestion of large zonisamide overdoses.
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PMID:Moderate toxic effects following acute zonisamide overdose. 2146 69

Topiramate is an antiepileptic medicine that has been used adjunctively in the treatment of refractory seizures in Japan since 2007. Topiramate has been shown to inhibit specific carbonic anhydrase activity in the kidney and may induce a distal type of renal tubular acidosis. Case 1 : A 22-year-old male was referred to our hospital after complaining of left flank pain. He developed a seizure disorder and had been using topiramate for 4 months. Drip infusion pyelography showed a left ureteral stone. Case 2 : A 7-year-old boy presented with gross hematuria. He developed West syndrome and had been using topiramate for 6 months. A computed tomographic scan showed a right kidney stone.
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PMID:[Two cases of urolithiasis induced by topiramate]. 2158 83

Topiramate belongs to the new class of neuromodulators, which has carbonic anhydrase inhibitor activity and been associated with renal calculi. It has also been shown to cause renal potassium wasting; however, it is generally clinically insignificant. Here, we describe a case of refractory hypokalemia in a patient with severe comorbidities who was on topiramate for seizures.
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PMID:Topiramate-induced refractory hypokalemia. 2307 79


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