Zonisamide: a new antiepileptic drug

Although the significant progress in pharmacotherapy of epilepsy during last decade was achieved, about one third of patients are resistant to the current treatment. When the monotherapy is not efficient, the polytherapy should be applied. Zonisamide (ZNS) is a new antiepileptic drug (AED) efficient in treating refractory epilepsy. Its efficacy in different types of seizures was confirmed in various animal studies as well as in clinical conditions. ZNS inhibits voltage-dependent Na(+) channels and Ca(2+) channels of T-type. The drug influences also monoamine neurotransmission and exhibits free radical scavenging properties. ZNS has a linear and favorable pharmacokinetics with excellent oral bioavailability. Furthermore, ZNS treatment, compared to other anticonvulsants, is relatively safe and well tolerated. Since ZNS is often used in polytherapy, its interactions with other AEDs seem to be of particular importance. However, the experimental data are rather inconsistent and further studies are necessary to elucidate exact effects of coadministration of ZNS with other AEDs. Recently, the clinical and experimental studies have suggested some new indications for ZNS administration, as mania, neuropathic pain, Parkinson's disease or migraine prophylaxis. Nowadays, it is also well established that ZNS exerts neuroprotective properties.     

Levetiracetam: new preparation. For some patients with refractory partial epilepsy

According to four placebo-controlled trials, levetiracetam (a piracetam derivative) reduces the frequency of seizures in 20 to 30% of patients with partial epilepsy when added to an existing but inadequate treatment. An indirect comparison suggests that levetiracetam is as effective as other second-line antiepileptics used for combination therapy.     

Citalopram: new indication. No advantage

(1) Citalopram, a serotonin reuptake inhibitor antidepressant, now has a new licensed indication, in the preventive treatment of panic attacks. In France, clomipramine, a tricyclic antidepressant, and paroxetine, another serotonin reuptake inhibitor, are already approved for this use. (2) In the only available comparative trial the efficacy of citalopram (20-60 mg/day) was similar to that of clomipramine (60-90 mg/day). (3) The safety profile of citalopram is different from that of clomipramine. (4) There are no data clearly comparing citalopram with paroxetine in terms of efficacy, safety, drug interactions, or convenience. (5) Clomipramine is much cheaper than citalopram.     

Topiramate: New preparation. Helpful in refractory partial epilepsy

(1) Topiramate is indicated in the treatment of refractory partial epilepsy, in combination with other antiepileptics. (2) Six placebo-controlled trials with sound methodology show that, in combination with an inadequately effective antiepileptic treatment, topiramate yields at least a 50% reduction in the frequency of attacks in 40-50% of patients. It seems effective in all forms of partial epilepsy. (3) There has been no direct comparison with other recent antiepileptics. (4) The adverse effects of topiramate are mainly neuropsychological. Some cases of weight loss at the outset of treatment, and kidney stones, have been described. No major adverse reactions to topiramate have been reported. (5) Topiramate seems to carry little risk of interactions with drugs with which it is likely to be combined. Enzyme inducers can reduce its efficacy. Combined oral contraception may fail in women on topiramate. (6) There is no evidence that the topiramate dose regimen can be based on plasma assays.     

Zonisamide: a review of its use in the management of partial seizures in epilepsy

Zonisamide (Zonegran, Excegran) is a new-generation, broad-spectrum antiepileptic drug (AED) currently approved as adjunctive therapy for the treatment of medically refractory partial seizures in adults in the US and as adjunctive therapy or monotherapy in the control of partial and generalised seizures in adults and children in Japan and Korea.Either as adjunctive therapy or monotherapy, zonisamide effectively reduces the frequency of partial seizures, with or without secondary generalisation to tonic-clonic seizures, in adults and children with epilepsy. The drug is generally well tolerated and, additionally, has a favourable pharmacokinetic profile permitting once- or twice-daily administration. Direct head-to-head comparisons with other AEDs would be beneficial in fully defining the place of zonisamide in therapy. In the meantime, adjunctive therapy or monotherapy with zonisamide is a convenient, useful option for the management of partial seizures, including those refractory to other AEDs.     

Zonisamide in the treatment of epilepsy

INTRODUCTION: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs. AREAS COVERED: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide. EXPERT OPINION: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

Zonisamide in the treatment of epilepsy

Introduction: Epilepsy affects approximately 3 million people in the USA and up to 2% of the worldwide population. The yearly direct medical cost of epilepsy in the USA alone is estimated to be $9.5 billion. Epilepsy affects both children and adults and can significantly impair quality of life. Zonisamide is a second-generation antiepileptic drug (AED) that has broad-spectrum efficacy, a favorable side-effect profile and simpler dosing than earlier drugs.

Areas covered: The history of the development of zonisamide is reviewed in this paper. The data available demonstrating zonisamide's mechanism of action as a voltage-gated sodium channel inhibitor, a T-type calcium channel inhibitor, an enhancer of GABA release and an inhibitor of glutamate release are also reviewed. Four key Phase III clinical trials are reviewed in detail, as are subsequent postmarketing trials that have expanded the therapeutic indication for zonisamide.

Expert opinion: From the available clinical data, zonisamide is a viable first-line and adjunctive therapeutic for partial-onset epilepsy and should be considered as an adjunctive therapeutic for a wide-range of generalized epilepsies.     

Olanzapine for injection: new formulation. No advantage in agitated patients

(1) The intramuscular neuroleptic of choice for the treatment of agitated schizophrenic patients and patients with acute mania is haloperidol, at a dose of 5 mg. Olanzapine is now marketed in France for hospital use in both these indications. (2) In two comparative trials in patients with schizophrenia, olanzapine 10 mg was shown to be no better than haloperidol 7.5 mg (a high dose). Control of agitation was satisfactory in three-quarters of patients after a single injection of either neuroleptic. (3) Olanzapine has not been compared with other neuroleptics in the treatment of acute mania. In one trial, olanzapine acted faster than lorazepam for injection (used at a rather low dose). (4) In one trial, patients given olanzapine had a lower incidence of acute dystonia and extrapyramidal symptoms (about 1%) than patients given haloperidol (about 6-7%), but the haloperidol dose (7.5 mg) was higher than recommended in the SPC (5 mg). The incidence of postural hypotension was significantly higher among patients given olanzapine (about 12%) compared with haloperidol (about 3%). (5) In practice, haloperidol remains the intramuscular neuroleptic of choice for the treatment of agitated patients with schizophrenia or acute mania.     

Zonisamide in the treatment of epilepsy

Importance of the field: More than 1 million epilepsy patients suffer from insufficiently controlled epilepsy, both in the USA and in Europe. Zonisamide is an antiepileptic drug with multiple mechanisms of action, corresponding to efficacy in diverse epilepsy syndromes.

Areas covered in this review: Here, an update on pharmacodynamics, pharmacokinetics, clinical efficacy and safety in childhood and adult epilepsies is given based on an analysis of controlled and uncontrolled studies, European, US and East Asian, and on clinical experience with zonisamide (ZNS) published up to 2009.

What the reader will gain: Evidence is presented that ZNS is effective not only in adult focal epilepsies, for which it has been approved in the USA and in Europe, but also may offer treatment options for compassionate use in a spectrum of difficult-to-treat epilepsy syndromes. Its favorable pharmacokinetic profile allows for easy combination with most available antiepileptic drugs.

Take home message: Provided that additional studies on ZNS are performed to extend approval and to generate comparative data, ZNS has a potential to gain importance in the treatmnt of a wide spectrum of epilepsy patients.     

Zonisamide: review of its use in epilepsy therapy

Zonisamide is an antiepileptic drug used as adjunctive therapy for refractory partial seizures in adults. Because of the multiple mechanisms of action, it shows a broad spectrum of anticonvulsant activity and has been effective in several types of seizures, including partial and generalized seizures, tonic-clonic seizures and absence seizures in patients unresponsive to other anticonvulsants. Myoclonic epilepsy, Lennox-Gastaut syndrome and infantile spasms have also been treated effectively with zonisamide. Recent clinical studies have demonstrated additional potential for therapeutic use in neuropathic pain, bipolar disorder, migraine, obesity, eating disorders and Parkinson's disease. Despite adverse events, zonisamide is relatively safe and well tolerated in patients, and shows low discontinuation rate. It has a good pharmacokinetic profile and a low drug interaction potential. Zonisamide is considered as a drug that effectively reduces the frequency of partial seizures.     

Safety of lacosamide in children with refractory partial epilepsy

Objectives: The study was carried out to investigate the safety of lacosamide on children with refractory partial epilepsy. Materials & methods: The study was carried out at a tertiary care hospital after obtaining approval from the institutional ethics committee. Patients aged between 5 and 15 years taking oral lacosamide (LCM) tablets that were given orally as an adjunctive anti-epileptic drug were enrolled for assessing safety, tolerability and its effect on the behavioural life at every visit of titration, during the treatment period (3 months) and at 2 follow up visits that were done at monthly intervals. Adverse events reported by caregiver or by investigator were recorded. Patients/caregivers also completed a 25 items on Connor’s behavioural rating clinical scale at every visit. Results: Out of 531 screened patients, 79 patients with refractory partial epilepsy were enrolled after they fulfilled the inclusion and exclusion criteria. Mean age of the children was 8.84 ± 3.09 years (5–15 years), of which 53 were males and 26 females. The mean age at onset of seizures in males was 6.46 ± 3.57 and in females, 6.38 ± 3.39 years. Seventy-six children of 79, completed 3 months of treatment period showed significant (p < 0.001) decrease in the frequency of seizures, significant improvement in behaviour and showed good tolerability. Three (3.79%) patients dropped out of the study due to hyperactive behaviour, vomiting and lack of seizure control respectively. Conclusions: Lacosamide is a well-tolerated newer antiepileptic drug that is effective in refractory partial epilepsy paediatric patients and concurrently improved patient’s behaviour.     

Darbepoetin alfa: new indication/new dosage. No proven advantage in chemotherapy-induced anaemia

(1) Current treatments for anaemia in patients receiving cancer chemotherapy include blood transfusion and epoetin alfa and beta. These epoetins correct anaemia in 40% to 65% of patients and reduce the number of patients who require transfusions during the second and third months of treatment by 12-35% in absolute terms. (2) Darbepoetin alfa is slightly more glycosylated than epoetin alfa and beta. It is no more effective than these two drugs in chronic renal failure. Darbepoetin alfa is now approved for the treatment of anaemia in patients who are receiving chemotherapy for non myeloid malignancies. (3) Two placebo-controlled dose-finding studies and two placebo-controlled trials involving nearly 1000 patients in total have shown that darbepoetin alfa decreases the number of transfused patients by 17-25% in absolute terms, and that it probably reduces fatigue. However, one-quarter of patients receiving darbepoetin were nonetheless transfused. (4) In the absence of reliable comparisons, there is no firm evidence that darbepoetin alfa is more effective than other epoetins. (5) According to relatively imprecise company reports, darbepoetin alfa increased the risk of thromboembolic events during clinical trials (6% versus 3%), including pulmonary embolism (1.3% versus 0%); the company also states that darbepoetin alfa does not increase the risk of arterial hypertension, a classical effect of epoetin that is mentioned in the summary of product characteristics (SPC). Placebo-controlled trials and dose-finding studies show no impact on the outcome of cancer, but follow-up is limited and a negative effect cannot be ruled out. The company states that no cases of erythroblastopenia have occurred among more than 70 000 treated patients. (6) According to the SPC, darbepoetin alfa can be given once a week. However, the optimal epoetin dosing schedule is unknown. Epoetin therapy takes several weeks to correct anaemia, whereas transfusion is immediately effective. (7) In practice, darbepoetin alfa seems a little easier to administer than epoetin alfa or beta, but the advantages and disadvantages of these drugs as compared with blood transfusion are not entirely clear.     

Oxcarbazepine: new preparation. An alternative to carbamazepine in partial epilepsy

(1) The reference treatment for partial epilepsy in adults and children is carbamazepine. (2) Oxcarbazepine is available in the European Union for the treatment of partial epilepsy in adults and children aged over 6 years, alone or in combination with other antiepileptic drugs. (3) The clinical file on oxcarbazepine monotherapy of recent-onset generalised or partial epilepsy mainly contains data from one trial versus carbamazepine, two trials versus phenytoin, and one trial versus valproate sodium. In these trials, 52-60% of patients had no seizures on oxcarbazepine, a proportion not significantly different from that obtained with the comparators. Oxcarbazepine may, in fact, be slightly less effective than carbamazepine. (4) For refractory partial epilepsy (especially forms refractory to carbamazepine), oxcarbazepine is more effective than a placebo, when combined with the inadequately effective treatment, as shown in two trials. Two dose-finding studies show that 2 400 mg/day oxcarbazepine is more effective than 300 mg/day. (5) In trials comparing single-drug treatments there were fewer withdrawals for adverse events among patients on oxcarbazepine than among those on carbamazepine or phenytoin. Compared with carbamazepine, the risk of cutaneous hypersensitivity reactions seems to be lower with oxcarbazepine, while the risk of hyponatraemia is higher. This risk of hyponatraemia necessitates laboratory monitoring. (6) The risk of clinically significant interactions appears to be lower on oxcarbazepine than on carbamazepine, and is limited mainly to combined contraceptives (contraceptive inefficacy) and phenytoin. (7) In practice, carbamazepine remains the reference treatment for partial epilepsy, but oxcarbazepine is one of several second-line options, either alone or in combination with other antiepileptics.     

Ezetimibe: new preparation. A cholesterol-lowering drug with no clinical advantage

(1) Simvastatin and pravastatin are the drugs of choice for secondary or primary prevention of cardiovascular events in patients with hypercholesterolaemia. Both these statins have proven clinical efficacy. If statin therapy is inadequate, the dose can be increased or a drug combination can be tried, while keeping a lookout for adverse effects. (2) Ezetimibe is a cholesterol-lowering drug that is said to inhibit intestinal absorption of cholesterol and related phytosterols, while not affecting the uptake of other nutrients (unlike resins). (3) The clinical evaluation dossier contains no data from trials with relevant morbidity or mortality endpoints. Primary and secondary prevention were not studied separately. (4) In patients with hypercholesterolaemia, two placebo-controlled trials show that ezetimibe reduces total cholesterol concentration (by about 13%), and LDL-cholesterol (by about 18%). Its effects on HDL-cholesterol and triglyceride levels are at best moderate. It is not known whether these effects reduce mortality or prevent cardiovascular events. (5) Four trials tested initial combination therapy with a statin plus ezetimibe, in comparison with statin alone and ezetimibe alone. They showed an additive effect of the two drugs on LDL-cholesterol levels. Ezetimibe alone was no better than statin monotherapy. (6) A trial in patients who did not respond adequately to statin monotherapy showed that adding ezetimibe increased the number of patients whose LDL cholesterol level fell to a predetermined cutoff point. But the clinical relevance of this result is unknown. Two other trials have shown that, in this setting, adding ezetimibe to simvastatin or to atorvastatin increased the number of patients who reached the LDL-cholesterol cutoff relative to continued statin monotherapy at a higher dose. (7) In homozygous familial hypercholesterolaemia, high-dose statin and ezetimibe combination therapy reduced the LDL-cholesterol more effectively than high-dose statin alone. It is not known whether adding ezetimibe is more effective than LDL apheresis alone. (8) In homozygous familial sitosterolaemia, a very rare disorder due to increased absorption of dietary cholesterol and phytosterols, a placebo-controlled trial showed that ezetimibe had no significant impact on the absolute sitosterol value. (9) Comparative trials reported no major adverse effects associated with ezetimibe, but their duration (maximum three months) is too short to rule out long-term adverse effects. Initial pharmacovigilance reports cases of muscular and hepatic adverse effects. (10) In practice, ezetimibe has discernible effects in the laboratory. But the absence of data based on clinical endpoints and trials versus other cholesterol-lowering drugs with proven clinical benefits, together with the lack of information on possible long-term adverse effects, means ezetimibe must be evaluated more thoroughly before it can be recommended for routine use.     

Levetiracetam--a new drug for epilepsy

Levetiracetam (Keppra--UCB Pharma) is a new anti-epileptic drug, marketed in the UK since 2000. It is licensed for use as adjunctive treatment for partial seizures, with or without secondary generalisation, in people aged over 16 years. The company claims that levetiracetam is "highly effective", with a "therapeutic starting dose", "excellent tolerability", and "no known drug/drug interactions". Here, we discuss the place of levetiracetam in the treatment of patienTs with epilepsy.     

Topiramate: new indication. Single-agent therapy in refractory epilepsy: for a few patients only

(1) Topiramate is helpful for some adults and children (aged over 4 years) with partial or generalised epilepsy, when combined with an inadequate ongoing treatment. (2) The indications for topiramate have now been extended in France to cover single-agent therapy of refractory epilepsy, from the age of 2 years. (3) A dose-finding study of 48 patients with refractory partial epilepsy suggests that the efficacy of topiramate monotherapy is dose-dependent. In a non comparative trial in 170 patients with refractory partial or generalised epilepsy, 12 patients were able to switch to topiramate alone after a phase of combining topiramate with their ongoing treatment. (4) The licence extension to children over 2 years of age is based solely on the results of previous trials. (5) Two dose-finding studies, and a trial versus a standard antiepileptic in which topiramate was used alone, confirmed that the safety profile of topiramate is similar to that of other antiepileptics, neuropsychological disturbance predominating. (6) Other adverse effects more specific to topiramate include cognitive and language problems, weight loss and reduced appetite, acute myopias sometimes associated with intraocular hypertension, an increased risk of renal lithiasis, reduced sweating with a risk of hyperthermia, and metabolic acidosis. (7) In practice, some patients whose epilepsy is refractory to an optimally administered treatment may improve when topiramate is added; and a small minority of them can gradually discontinue their previous treatment.     

治疗局灶性癫痫发作新药:cenobamate

癫痫是神经系统常见疾病,症状易反复发作,给社会、家庭及个人生活均带来沉重负担.2019年11月美国食品和药物管理局批准钠通道阻滞剂cenobamate上市,用于治疗成人局灶性癫痫发作.临床研究显示,cenobamate能显著降低局灶性癫痫发作的频率,且耐受性和安全性较好,常见不良反应为眩晕、嗜睡、疲劳、头痛等.     

The role of common variation in drug transporter genes in refractory epilepsy

Resistance to antiepileptic drugs (AEDs) is one of the most serious clinical problems in epilepsy, and along with AED teratogenicity, perhaps the major concern of epilepsy pharmacogenetics. Studying the genetics of drug resistance in epilepsy is important, as it may identify or confirm key mechanisms underlying this phenomenon that have real clinical importance; it might also offer insights into its prediction and management. Drug resistance in epilepsy is likely to be multifactorial: overactivity of multi-drug transporters provides one likely underlying mechanism through lowering of AED concentration in the epileptogenic focus. Genetic association studies may provide a tool to assess this 'transporter' hypothesis by determining whether differences between individuals contribute to resistance phenotypes. Most of these studies have investigated one variant in the ABCB1 gene, and have provided, thus far, inconclusive evidence. This review also considers current knowledge of the role of genetic polymorphisms in multi-drug transporters in pharmacoresistant epilepsy, to highlight possible confounding factors affecting the implementation and interpretation of association studies in this field.     

Erlotinib: new drug. Non small-cell lung cancer: like gefitinib, no established advantage

(1) There is no standard third-line treatment for locally advanced or metastatic non small-cell lung cancer. (2) Erlotinib, like gefitinib, inhibits the tyrosine kinase activity of the epidermal growth factor (EGF) receptor, and has been licensed for sale in the European Union. (3) A double-blind placebo-controlled trial involving 713 patients who had failed to respond to one or two previous chemotherapy regimens showed that erlotinib increased the median survival time by about 2 months (6.7 versus 4.7 months), without improving the quality of this survival. It is not possible to predict precisely which patients are most likely to respond to erlotinib. (4) In first-line treatment, erlotinib was no more effective than placebo as an adjunct to chemotherapy in 2 trials involving 1079 and 1172 patients. (5) The adverse effect profile of erlotinib seems similar to that of gefitinib, mainly consisting of gastrointestinal disturbances (especially diarrhoea: 54% of patients versus 18% on placebo), skin rash (75% versus 17%), and ocular disorders (conjunctivitis: 12% versus 2%). In the comparative trial of second- or third-line treatment, 0.8% of patients developed interstitial pneumonia. (6) Erlotinib, like gefitinib, is metabolized by the cytochrome P450 isoenzyme CYP3A4, potentially creating a high risk of interactions. (7) In practice, the limited benefit of erlotinib seems to be outweighed by its frequent adverse effects. Erlotinib should therefore only be used in clinical trials designed to identify subgroups of patients in whom the risk-benefit balance may be favourable.