[Analysis of the cost-effectiveness of treatment for refractory partial epilepsy: a simulation model for pregabalin and levetiracetam]. / Analisis coste-efectividad del tratamiento de la epilepsia parcial refractaria: un modelo de simulación de pregabalina y levetiracetam.

AIM: To estimate the cost-effectiveness (C-E) of pregabalin (PGB) or levetiracetam (LEV) relative to standard therapy (ST) as add-on anti-epileptic therapy in patients with partial refractory epilepsy in Spain. PATIENTS AND METHODS: Using stochastic simulation techniques, we estimated the C-E of PGB (300 mg/day) and LEV (2,000 mg/day) in a hypothetical cohort of 1,000 patients (vs ST). The model used data of efficacy and safety from two randomized controlled clinical trials. Direct medical costs (caused by handling of the disease and the adverse events were estimated using year-2007 prices. Model outcomes included number of additional seizure-free days (over one year), adverse events and quality adjusted life-years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) per additional seizure-free day and QALY gained. RESULTS: Compared with ST, treatment with PGB yielded an estimated 43.3 +/- 4.8 (mean +/- standard error) additional seizure-free days, and a gain of 0.04 +/- 0.0006 QALYs over one year. Comparable results for LEV vs ST were 24.3 +/- 6.2 and 0.025 +/- 0.007 QALYs, respectively. The annual total cost (in euros) per patient was 1,843 with PGB, 3,018 with LEV and 897 with ST. Mean ICER for PGB vs ST were 22 euros (95% CI = 19-27) per additional seizure-free day, and 23,881 euros (95% CI = 19,206-30,247) per QALY gained; estimates for LEV were 95 euros (CI 95% = 60-177) and 95,904 euros (CI 95% = 57,137-203,169) respectively. CONCLUSIONS: In patients with partial refractory epilepsy, when compared with ST, PGB demonstrated better ICER per additional seizure-free day and QALY gained than LEV.

[Natalizumab in the treatment of multiple sclerosis]. / Natalizumab en el tratamiento de la esclerosis multiple.

AIM: To review and update the mechanism of action of natalizumab and its efficacy in the treatment of multiple sclerosis (MS). DEVELOPMENT: Natalizumab, an anti-alfa-4 integrin monoclonal humanized antibody, binds to lymphocyte surface receptors to prevent transmigration of lymphocytes to areas of inflammation into the brain tissue. Furthermore, natalizumab appears to reduce T-cell activation following their infiltration of the brain parenchyma and may contribute to T-cell apoptosis in these tissues. Two large two-year, multicenter phase III trials (AFFIRM and SENTINEL) have been completed and demonstrate previously unseen efficacy in preventing MS relapses and disease progression. Natalizumab reduced the rate of clinical relapse at one year by 68 and 54% respectively in these trials (p < 0.001). Moreover, natalizumab reduced significantly the risk of sustained progression of disability by 42 and 24% respectively. Based on results from the AFFIRM study, the adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 vs. 21%) and allergic reaction (9 vs. 4%). There was a low incidence (< 1%) of serious systemic hypersensitivity reactions described as anaphylactoid or anaphylactic, and they appear to be effectively managed by post-treatment observation and by timely and appropriate medical treatment. In the SENTINEL study, two cases of progressive multifocal leukoencephalopathy (PML), one of which was fatal, were diagnosed in natalizumab plus interferon beta-1a treated patients. CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing MS. In spite of their low risk of adverse reactions, patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML, and natalizumab use must be restricted to the indicated patients.

[Pregabalin: new therapeutic contributions of calcium channel alpha2delta protein ligands on epilepsy and neuropathic pain]. / Pregabalina. Aportaciones de los ligandos alpha2delta de canales de calcio en el tratamiento de la epilepsia y el dolor neuropático.

AIM: To review and update the contributions of a new class of drugs, named calcium channel alpha2delta protein ligands, on the treatment of epilepsy and neuropathic pain. DEVELOPMENT: A novel class of anticonvulsants are ligands for the auxiliary-associated protein alpha2delta subunit of voltage-gated calcium channels in the central nervous system. Gabapentin and pregabalin are members of this group. Pregabalin is a higher-potency and higher-effective analogue of gabapentin that act as a potent ligand for this site. The anticonvulsant action of pregabalin is probably due to its ability to reduce neurotransmitter release from activated epileptogenic neurons, without demonstrated effects on GABAergic receptors or mechanisms. In well-done clinical trials, pregabalin 150-600 mg/day has been shown to be highly effective and well tolerated as adjunctive therapy in patients with partial seizures. In several randomized, double-blind, clinical trials, oral pregabalin 150-600 mg/day was superior to placebo in relieving neuropathic pain associated with diabetic neuropathy and postherpetic neuralgia. Pregabalin demonstrates in humans an extensive and rapid absorption and a highly predictable and linear pharmacokinetics, a profile that makes it easy to use in clinical practice. The pharmacological activity of pregabalin is similar but not identical to that of gabapentin, and pregabalin shows possible advantages. CONCLUSIONS: Pregabalin and calcium channel alpha2delta protein ligands showed relevant advances on epilepsy and neuropathic pain treatment. In peripheral neuropathic pain conditions, if the criteria for efficacy are based on both pain relief and quality of life measures, pregabalin/gabapentin are suggested as choice treatment.

[Oxcarbazepine in the treatment of epilepsy. A review and update]. / Oxcarbazepina en el tratamiento de la epilepsia. Revisión y actualización.

AIM: To review and update the most important information concerning the mechanism of action, efficacy, safety and clinical use of oxcarbazepine (OXC), one of the new antiepileptic drugs (AED). DEVELOPMENT: In humans, OXC is rapid and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). OXC is a molecule derived from carbamazepine (CBZ), but these two drugs showed differences in their mechanism of action. OXC pharmacokinetics presents advantage over CBZ: in contrast with CBZ, OXC does not show autoinduction, the OXC dose-MHD serum concentration relationship displays a linear kinetics over the therapeutic dose range, and the frequency of drug-drug interactions is lower. So, we can establish standardized dose regimen and titration schedules in monotherapy and polytherapy. OXC shows better tolerability and safety than CBZ, in part at consequence of absence of 10-11-epoxi metabolites from CBZ. The better safety profile of OXC is reflected in less adverse drug reactions incidence, lower patient risk in overdosing, absence of reported cases of agranulocytosis or aplastic anemia, scarce cases founded of cardiotoxicity and lower risk of neurotoxicity. Common side effects of OXC are nausea, dizziness, vomiting, fatigue, diplopia and somnolence. During treatment with OXC must pay attention to development of hyponatremia, neurotoxicity or cutaneous hypersensitivity reactions. OXC is approved for use in infants. OXC is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures with or without secondarily generalized seizures in adults and in children age 6 and over. CONCLUSIONS: OXC showed important advances on safety and pharmacological properties for administration to adults and infants. OXC has similar clinical antiepileptic efficacy than older AED in the treatment of partial seizures, and it is recommended as a treatment of choice for partial seizures by several international guidelines.

[Risk of drug-induced agranulocytosis: an approximation to risk analysis arising from spontaneous notification of agranulocytosis cases among patients treated with calcium dobesilate]. / Riesgo de agranulocitosis por fármacos: una aproximación al análisis de riesgos a partir de notificaciones espontáneas de casos de agranulocitosis en pacientes tratados con dobesilato de calcio.

BACKGROUND: Frequently, decisions about the safety of drugs are based on isolated cases of patients that develop a disease, while they have been taken a drug. A new method to detect, using spontaneous reporting, increases in agranulocytosis risk among patients treated with calcium dobesilate is shown. METHOD: Using data of dobesilate sales, the maximum number of patients treated in a year was calculated. Spontaneous reports of agranulocytosis associated to dobesilate notified along the period 1985-2000 were identified. The number and the maximum number of cases explained by the agranulocytosis risk in a general population were calculated using the distribution of Poisson, assuming several reporting rates. Similarly, the influence of number of patients older than 60 and the duration of exposure to the drug were analysed. RESULTS: The number of spontaneously reporting cases of agranulocytosis associated to dobesilate, in the period 1985-2000 was not greater than the maximum number of cases predicted by the agranulocytosis risk in a general population. Probably, a high number of dobesilate-treated patients had an advanced age and/or took the drug during several months. In these conditions, it is more difficult to identify an increase of risk associated to drug. CONCLUSIONS: To calculate the risk of agranulocytosis associated to a drug is required to consider the basal risk of agranulocytosis in a general population as well as its possible modifications in the population of patients treated with the drug.

[Entacapone: is it useful as complimentary treatment with levodopa?]. / Entacapona: es útil como tratamiento complementario a la levodopa?

Entacapone (Comtan) is a potent, selective inhibitor of peripheral catechol-O-methyltransferase (COMT) with therapeutic potential as an adjuvant to levodopa therapy in patients with Parkinson's disease. Entacapone decreases peripheral conversion of levodopa to 3-O-methyldopa increasing central extracellular levodopa and consequently striatal dopamine concentrations. At doses of 200 mg 2 to 10 times daily coadministered with levodopa/carbidopa or levodopa/benserazide entacapone may increase the duration of clinical response both after the first single dose and after repeated dosing in patients with end-of-dose fluctuations. At this dosage, it has a time to peak-plasma concentration of 1.2 hours and an elimination half life of 3.4 hours. In two multicentric, long-term (approximately 6 month), randomized and placebo-controlled studies, the duration of 'on' time was increased and the duration of 'off time' was decreased in patients who received adjunctive entacapone therapy. Moreover, patients randomized to entacapone reduced their levodopa requirements. In these and other phase III studies, entacapone was generally well tolerated, with few reported adverse events, mainly dyskinesias and gastrointestinal disorders. The dyskinesias were generally well controlled by decreasing the mean daily levodopa dose. Entacapone appears as a clinically significant and beneficial adjunct to levodopa therapy in Parkinson's disease patients with end-of-dose fluctuations.

[Entacapone++ : a new catechol-O-methyltransferase inhibitor which improves the response to levodopa in patients with Parkinson disease and fluctuating motor function]. / Entacapona: un nuevo inhibidor de catecol-O-metiltransferasa que mejora la respuesta a levodopa en pacientes parkinsonianos con fluctuaciones motoras.

INTRODUCTION AND DEVELOPMENT: Selective inhibitors of peripheral catechol-O-methyltransferase (COMT) seem to be useful drugs for the treatment of patients with Parkinson's disease. When associated with levadopa and a dopa-decarboxylase inhibitor they are clearly effective in patients with progressive illness, who are particularly dependent on the plasma concentration of levadopa, or may have fluctuating motor function when the effect of the dose is wearing off. Entacapone, a prototype of this group of drugs, has been shown to modify the pharmacokinetics of levadopa in such a way that the plasma concentration of levadopa is raised (between 21% and 50% in different studies): to reduce variations in plasma level between doses, which allows some patients to reduce the total daily dose of levadopa at the same time as the response time (time 'on') increases by between 20% and 78%. CONCLUSION: Entacapone is a well tolerated drug and could form part of a regular 'triple therapy' in the patients described.