Zonisamide anticonvulsant

The anticonvulsant activity of some 1,3-benzisoxazoles was discovered in routine testing. One of the more interesting of the subsequent analogues prepared was zonisamide (39). One of its syntheses starts with l,2-benzisoxazole-3-acetic acid (36) which is brominated and subsequently decarboxylated to give 37. Displacement of halogen in 37 with sodium bisulfite interestingly... 

MISSELLANEOUS ANTICONVULSANTS. Valproic acid (Depakene) is unrelated chemically to the other anticonvulsants. This drug is absorbed rapidly when taken orally Tablets should not be chewed but swallowed whole to avoid irritation to the mouth and throat. The capsules may be opened and the drug sprinkled on a small amount of food, such as pudding or applesauce This mixture must be swallowed whole immediately and not chewed. Zonisamide is administered orally once a day or in divided doses. The dose may be increased by 100 mg day every 1 to 2 weeks until control of the seizures is obtained or the patient reaches the maximum dosage of 600 mg/d. 

Zonisamide is a sulfonamide anticonvulsant approved for use as an adjunctive therapy in adults with partial-onset seizures. 

Changes in body weight associated with anticonvulsants have been reviewed (116), including the effects of the antiepileptic drugs that have been most commonly associated with this adverse effect (valproic acid, carbamazepine, vigabatrin, and gabapentin) (117). Unlike most anticonvulsants, topiramate, felbamate, and zonisamide can cause weight loss. 

Therapeutic Function Anticonvulsant Antiepileptic Chemical Name l,2-Benzisoxazole-3-methanesulfonamide Common Name Fenisoxine Zonisamide Structural Formula ... 

In addition to phenytoin, carbamazepine, and lamotrigine, metabolically optimized analogs of these drugs, such as fosphenytoin and oxcarbazepine, show clinical promise. Other anticonvulsants that block sodium channels, among several mechanisms of action, include zonisamide, felbamate, topiramate, and valproate (Fig. 5). 

Chronic intake of caffeine may lower brain zonisamide concentrations and attenuate its anticonvulsant effects... 

Schachter SC. The next wave of anticonvulsants focus on levetiracetam, oxcarbazepine and zonisamide. CNS Drugs 2000 14 229 9. 

Serum zonisamide concentrations are reduced by enzyme-inducing anticonvulsants (17). 

Certain anticonvulsants developed initially for the treatment of epilepsy, such as topiramate and zonisamide, have been found to have a beneficial effect in mood disorders, particularly bipolar disorder. In addition, patients treated with these compounds lose weight. They were therefore seen as potential therapeutic agents for use in obese patients with BED. 

Zonisamide. Zonisamide is a new sulfonamide anticonvulsant. In one study it was noted that 4% of the patients developed clinically possible or confirmed kidney stones (18). Patients should report the appearance of sudden back pain, abdominal pain, or blood in the urine that could indicate a kidney stone. In several clinical studies, zonisamide was associated with a statistically significant 8%mean increasefrom the baseline of serum creatinine and blood urea nitrogen (BUN). This was indicative of a decrease in the glomerular filtration rate (GFR). Therefore, do not use this... 

A review of the second-generation anticonvulsants reveals that screening or serendipity led to the development of felbamate (10), 1am-otrigine (11), zonisamide (13), topiramate (15), and levetiracetam (16) on the other hand, clobazam (4d) and oxcarbazepine (12) were developed by structural variation of known agents (78). Only three, vigabatrin (8), gabapentin (9), and tiagabine (14), were developed by mechanism-based rational development (78). 

Figure 6.11. Suggested pharmacophore model for anticonvulsants acting at the voltage-dependent sodium channel on the basis of molecular dynamics simulations on phenytoin (1), carbamazepine (2), lamotrigine (11), zonisamide (13), and rufinamide (60). Rema-oemide (58)is discussed in the text. (AfterRef 281.)...

Several authors have provided insight into the putative MBS receptor based on their structure-activity data. As noted by Unverferth et al. (281), there have been several attempts to postulate a general pharmacophore for the different anticonvulsant classes, all of which are anti-MES in animal studies and are, or have the potential to be, effective in generalized tonic-clonic seizures. These include benzodiazepines (282) barbiturates (283) triazolines (284) semicarbazones (248-261) and enami-nones (286-288), respectively and for different compounds with similar anticonvulsant profiles (289-292). The Unverferth model (Fig. 6.11) provides an excellent representation of the current anticonvulsants phenytoin (1), carbamazepine (2), lamotrigine (11), zonisamide (13), and rufinamide (60). Remace-mide (58) is also included as a possible candidate (Fig. 6.12). 

Figure 6.12. Selected anticonvulsants for the development of a pharmacophore model. The essential structural elements are indicated by dotted rectangles. 1 = phenytoin 2 = carbamazepine 11 = lamotrigine 13 = zonisamide 60 = rufinamide inset, 58 = remacemide. R, hydrophobic unit D, electron-donor group HAD, hydrogen donor/acceptor unit. (AfterRef 281.)...

FIGURE 15.9 The thiophene isostere of zonisamide is practically inactive as an anticonvulsant. 

Newer anticonvulsants such as levetiracetam and zonisamide have several published case reports or open trials showing efficacy in mania and treatment-refractory rapid cycling, but it is too early to predict whether they have a place in either acute or maintenance... 

Zonisamide is an anticonvulsant/sulfonamide that may exert its anticonvulsant effects through action at sodium and calcium channels. It is indicated as an adjunctive therapy in the treatment of partial seizures in adult epileptic patients. 

In all these cases no essential activity difference is found between the original drug and its isostere. However, it can happen that the procedure fails. Binder et al for example, reported that thieno[2,3-d]isoxazole-3-methanesulfona-mide, the thiophene analogue of the anticonvulsant drag zonisamide (Fig. 13.7), ° was practically inactive against... 

Commercial immunoassays have long been available for the classic anticonvulsants such as phenytoin, carbamazepine, valproic acid, primidone, and ethosuximide and generally provide useful results under normal TDM conditions. Kits for the newer anticonvulsants such as lamotrigine, gabapentin, zonisamide, and levetiracetam have become available only recently so their effectiveness in monitoring in a broad population cannot yet be evaluated. While targeted immunoassay can be a very efficient and cost-effective way... 

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