Disease relevance of Zonegran

• Zonisamide for weight loss in obese adults: a randomized controlled trial [1].
• In an intent-to-treat analysis using the available data for all randomized participants with the last observation carried forward, the zonisamide group lost more body weight than the placebo group (mean [SE], 5.9 [0.8] kg [6.0% loss] vs 0.9 [0.4] kg [1.0% loss]; t = 5.5; P<.001) during the 16-week period [1].
• Long-term response to zonisamide in patients with West syndrome [2].
• Zonisamide in the treatment of binge-eating disorder: an open-label, prospective trial [3].
• Additional pharmacokinetic studies will help to establish the change in pharmacokinetic profile that occurs with dosage titration in patients outside Japan. Among 700 patients treated with zonisamide in Europe/US, a high incidence of renal calculi (1.9%) has been noted, however, the causal relationship to zonisamide is disputed [4].

Psychiatry related information on Zonegran

• A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients [5].
• CONCLUSIONS: This study suggests improvement of depressive symptoms in this sample with 8 weeks of open-label zonisamide treatment [6].
• Zonisamide, a new anticonvulsant effective against maximal electroshock (MES) seizures in mice reduced T-type Ca2+ current in a dose-dependent manner [7].
• It is thought that this elevation of the thermal and mechanical withdrawal thresholds after local injection of zonisamide is not generated secondarily via impaired motor activity, since zonisamide (30 microg, i.c.v. or i.t.) did not affect locomotor activity, as assessed in sciatic-nerve-ligated mice [8].
• Visual hallucinations associated with zonisamide [9].

High impact information on Zonegran

• Weight loss was an adverse effect associated with zonisamide treatment in epilepsy clinical trials [1].
• CONCLUSION: In this short-term, preliminary trial, zonisamide and hypocaloric diet resulted in more weight loss than placebo and hypocaloric diet in the treatment of obesity [1].
• A longitudinal mixed-model regression for weight change controlling for age, race, sex, body mass index, and percent body fat estimated that zonisamide treatment over the 16-week study duration was associated with significantly greater weight loss than was placebo (t = 6.4; P<.001) [1].
• The metabolism of zonisamide to SMAP was almost completely inhibited by anti-P450 3A4 antibody but not by anti-P450 2C9 or anti-P450 2D6 antibodies, suggesting that the amount of P450 3A enzyme may be a major factor influencing the level of metabolism of zonisamide to SMAP in human liver microsomes [10].
• Characterization of human liver microsomal cytochrome P450 involved in the reductive metabolism of zonisamide [10].

Chemical compound and disease context of Zonegran

• Other newer anticonvulsants, levetiracetam, oxcarbazepine, phenytoin, and zonisamide offer promise, but further studies are required before they can be recommended for routine use to treat bipolar disorder [11].
• A MEDLINE search (1966-2001) was performed for clinical trials that were published in English using the keywords lamotrigine, gabapentin, topiramate, oxcarbazepine, tiagabine, and zonisamide, plus the terms bipolar disorder and mania [12].
• Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment [13].
• However, lamotrigine, topiramate, zonisamide and felbamate appear to have broader efficacy against both partial and many generalized seizure types, while vigabatrin is also valuable in the management of infantile spasms [14].
• Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (ethosuximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available [15].

Biological context of Zonegran

• Moreover, although plasma concentrations of zonisamide are empirically regarded to be proportional to therapeutic doses in patients in Japan, nonlinear pharmacokinetics have been reported for this drug in patients in the US and may further complicate its use in this patient population [4].
• Competitive binding enzyme immunoassay for zonisamide, a new antiepileptic drug, with selected paired-enzyme labeled antigen and antibody [16].
• Several 3-(sulfamoylmethyl)-1,2-benzisoxazole derivatives were synthesized from 3-(bromomethyl)-1,2-benzisoxazole by the reaction with sodium bisulfite followed by chlorination and amination [17].
• It is rapidly absorbed, 50% bound to plasma proteins and is eliminated predominantly by biotransformation; zonisamide has a half-life of 50 to 70 hours in monotherapy patients, or 25 to 35 hours in patients comedicated with enzyme-inducing anticonvulsants [18].
• Safety measures included adverse events, routine blood chemical and hematology laboratory values, urinalyses, plasma zonisamide levels, physical examination findings, and electrocardiograms [3].

Anatomical context of Zonegran

• However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin [15].
• From these results, it is suggested that zonisamide suppresses both seizures originating from the thalamus and the cortex through the mechanism differing from that of phenytoin [19].
• Zonisamide did not affect the posttetanic potentiation of the monosynaptic reflexes (ventral root potentials) in urethane-chloralose-anesthetized spinal rats [19].
• ZNS is absorbed slowly from the gastrointestinal tract, and its biological half-life is long as compared with that of other common antiepileptic drugs [20].
• Protective effect of zonisamide, an antiepileptic drug, against transient focal cerebral ischemia with middle cerebral artery occlusion-reperfusion in rats [21].

Associations of Zonegran with other chemical compounds

• The formation of SMAP was remarkably inhibited by cimetidine, n-octylamine, ketoconazole, and carbon monoxide, indicating that a cytochrome P450 is involved in the metabolism of zonisamide to SMAP in human liver microsomes [10].
• A second aim was to characterise zonisamide pharmacokinetics in the presence of valproic acid [22].
• Micellar electrokinetic capillary chromatography (MEKC) with a diode array detector simultaneously determined concentrations of zonisamide, a new type of antiepileptic drug, and phenobarbital, phenytoin and carbamazepine, typical antiepileptic drugs, in human serum [23].
• A series of interaction studies has revealed zonisamide to be without effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine [24].
• Tiagabine is highly protein bound and zonisamide shows nonlinear pharmacokinetics; both these drugs are extensively metabolised [25].

Gene context of Zonegran

• In addition, topiramate and zonisamide were observed to behave as weak hCA XII inhibitors, while zonisamide was an effective hCA IX inhibitor (K(I) of 5.1 nM) [26].
• On the other hand, the formation of reductive metabolite of zonisamide was the highest in COS-7 cells expressing CYP3A4, followed by CYP3A7 and CYP3A5 [27].
• RESULTS: From the experiments using ten expressed human CYPs, CYP2C19, CYP3A4 and CYP3A5 were shown to be capable of catalyzing zonisamide reduction [28].
• In vitro, zonisamide did not inhibit CYP1A2 and 2D6, and only weakly inhibited CYP2A6, 2C9, 2C19, and 2E1 [29].
• Carbonic anhydrase inhibitors. Zonisamide is an effective inhibitor of the cytosolic isozyme II and mitochondrial isozyme V: solution and X-ray crystallographic studies [30].

Analytical, diagnostic and therapeutic context of Zonegran

• Zonisamide levels in human serum obtained by MEKC correlated well with levels obtained by high-performance liquid chromatography [23].
• This MEKC method could provide a simple and efficient therapeutic drug monitoring method for antiepileptic drugs, especially in patients treated with a combination of zonisamide and other antiepileptic drugs [23].
• 3. Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively [31].
• Interaction between Ca2+, K+, carbamazepine and zonisamide on hippocampal extracellular glutamate monitored with a microdialysis electrode [32].
• Zonisamide (ZNS) is a broad-spectrum antiepileptic drug in both animal models of epilepsy and patients with epilepsy [33].

References