[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.

Análisis coste-efectividad del tratamiento de la epilepsia parcial refractaria: un modelo de simulación de pregabalina y levetiracetam / Analysis of the cots-effectiveness of treatment for refractory partial epilepsy: a simulation model for pregabalin levetiracetam

Estimar el coste-efectividad del tratamiento adyuvante con pregabalina (PGB) o levetiracetam (LEV)frente a la terapia estándar (TE) en pacientes con epilepsia parcial refractaria en España. Pacientes y métodos. Mediante técnicas de simulación dinámica, se estimó el coste-efectividad de PGB (300 mg/día) y LEV (2.000 mg/día) frente a la TE en una cohorte hipotética de 1.000 pacientes. Los datos de eficacia y seguridad proceden de dos ensayos clínicos multicéntricos aleatorizados con placebo. Los costes sanitarios directos (derivados del manejo de la enfermedad y de los eventos adversos) se estimaron utilizando costes de 2007. Los resultados incluyeron el número anual de días libres de crisis adicionales, los efectosadversos y los años de vida ajustados por calidad de vida (AVAC) ganados. Se calculó el coste-efectividad incremental (ICER) por día adicional libre de crisis y por AVAC ganado. Resultados. Comparado con la TE, la PGB proporciona 43,3 ± 4,8 (media ± error estándar) días adicionales libres de crisis y 0,04 ± 0,006 AVAC ganados. Los correspondientes resultadoscon LEV fueron 24,3 ± 6,2 y 0,025 ± 0,007, respectivamente. El coste total anual por paciente (en euros) fue de 1.843 con PGB, 3.018 con LEV y 897 con TE. El ICER medio de PGB frente a la TE fue de 22 euros (IC 95% = 19-27) por día libre de crisis adicional y 23.881 euros (IC 95% = 19.206-30.247) por AVAC ganado. Las estimaciones correspondientes para el LEVfueron 95 euros (IC 95% = 60-177) y 95.904 euros (IC 95% = 57.137-203.169), respectivamente. Conclusiones. En pacientes con epilepsia parcial refractaria, en comparación con la TE, la PGB proporciona un mejor coste-efectividad que el LEV por día adicional libre de crisis y por AVAC ganado

To estimate the cost-effectiveness (C-E) of pregabalin (PGB) or levetiracetam (LEV) relative to standardtherapy (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 seizurefree 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

Réplica. A propósito de los antiepilépticos genéricos / Reply. Regarding generic antiepileptic drugs

No disponible

No disponible

Estatus compulsivo / Seizure status

No disponible

[The clinical and economic impact of generic drugs in the treatment of epilepsy]. / Impacto clínico y económico de los fármacos genéricos en el tratamiento de la epilepsia.

AIMS: The aim of this study was to determine whether the introduction of generic formulations of antiepileptic drugs (AED) would lead to an economic saving for the public health service. DEVELOPMENT: The narrow therapeutic index, low solubility and non-linear pharmacokinetics of some AED mean that the ranges of bioequivalence that are authorised for generic formulations do not offer the same results regarding effectiveness and safety as those obtained by brand name drugs. This is why the potential saving stemming from the use of generic AED may be exceeded by the costs deriving from the consequences conditioned by their utilisation. These are the conclusions that can be drawn from the results of cost and effectiveness analyses conducted on two hypothetical cases of substituting (9 and 20%) treatments involving brand name carbamazepine (CBZ) with generic formulations. If a generic CBZ were introduced into the treatment of 9% of the patients taking this drug, the annual cost for one person with epilepsy would rise by 38.17 as compared to treating all these patients with brand name CBZ (marginal cost-effectiveness), and overall spending on health care in the country would grow by 2,748,000 (cost-benefit analysis). These figures rise sharply when 20% of treatments with brand name CBZ are replaced by generic formulations. CONCLUSIONS: The bioequivalence ranges authorised for generic formulations may be inappropriate for generic AED. With certain AED, replacing a brand name product with a generic version of the same medication can have negative effects on the amount of health care resources that are consumed and, therefore, on the overall economic expenditure associated with epilepsy.

Impacto clínico y económico de los fármacos genéricos en el tratamiento de la epilepsia / The clinical and economic impact of generic drugs in the treatment of epilepsy

Objetivo. Determinar si la introducción de las formulacionesgenéricas de los fármacos antiepilépticos (FAE) conlleva unahorro económico para la sanidad pública. Desarrollo. El estrechoíndice terapéutico, la baja solubilidad y la farmacocinética no linealde algunos FAE hace que los intervalos de bioequivalencia permitidospara las formulaciones genéricas no consigan los mismosresultados de eficacia y de tolerabilidad que los obtenidos por fármacosde marca. Por esta razón, el ahorro potencial derivado deutilizar FAE genéricos puede superarse por el coste de las consecuenciascondicionadas por su utilización. Así lo demuestran losanálisis de coste y de eficacia calculados en dos supuestos de sustitución(9 y 20%) de tratamientos con carbamacepina (CBZ) demarca por formulaciones genéricas: si se introdujese una CBZgenérica en el 9% de los pacientes que toman este fármaco, el costeanual de una persona con epilepsia aumentaría 38,17 € conrespecto a tratar a todos estos pacientes con CBZ de marca (coste-efectividad marginal), y el gasto sanitario del país crecería2.748.000 € (análisis beneficio-coste). Estas cifras aumentan significativamentecuando se sustituye el 20% de los tratamientos conCBZ de marca por formulaciones genéricas. Conclusiones. Losmárgenes de bioequivalencia permitidos para las formulacionesgenéricas pueden ser inapropiados para los FAE genéricos. Condeterminados FAE, la sustitución de un producto de marca por sucorrespondiente genérico puede repercutir negativamente en los recursossanitarios consumidos y, por lo tanto, en el gasto económicoasociado a la epilepsia

Aims. The aim of this study was to determine whether the introduction of generic formulations of antiepileptic drugs(AED) would lead to an economic saving for the public health service. Development. The narrow therapeutic index, lowsolubility and non-linear pharmacokinetics of some AED mean that the ranges of bioequivalence that are authorised for genericformulations do not offer the same results regarding effectiveness and safety as those obtained by brand name drugs. This iswhy the potential saving stemming from the use of generic AED may be exceeded by the costs deriving from the consequencesconditioned by their utilisation. These are the conclusions that can be drawn from the results of cost and effectiveness analysesconducted on two hypothetical cases of substituting (9 and 20%) treatments involving brand name carbamazepine (CBZ) withgeneric formulations. If a generic CBZ were introduced into the treatment of 9% of the patients taking this drug, the annualcost for one person with epilepsy would rise by 38.17 € as compared to treating all these patients with brand name CBZ(marginal cost-effectiveness), and overall spending on health care in the country would grow by 2,748,000 € (cost-benefitanalysis). These figures rise sharply when 20% of treatments with brand name CBZ are replaced by generic formulations.Conclusions. The bioequivalence ranges authorised for generic formulations may be inappropriate for generic AED. Withcertain AED, replacing a brand name product with a generic version of the same medication can have negative effects on theamount of health care resources that are consumed and, therefore, on the overall economic expenditure associated withepilepsy

[Oxcarbazepine in monotherapy in 324 patients with partial seizures (TRINOVA study)]. / Oxcarbacepina en monoterapia en 324 pacientes con crisis parciales (estudio TRINOVA).

AIMS: The purpose of this study was to evaluate the effectiveness and tolerability of oxcarbazepine (OXC) administered as monotherapy in patients with partial seizures as a first therapeutic alternative or after the failure of other monotherapies. PATIENTS AND METHODS: A prospective, open, multicentre trial based on observation involving 324 patients between 6 and 87 years of age with partial seizures who had not received prior treatment with antiepileptic drugs (AED) (n = 114) or in whom other monotherapies had failed (n = 210). These patients were administered OXC in the conditions usually found in clinical practice over a period of 52 weeks; effectiveness was evaluated by the reduction in the frequency of the seizures, tolerability was measured through the side effects related to the drug and quality of life was assessed by means of the changes reflected in the CAVE questionnaires, in the case of children, and the QOLIE-31 for adults. RESULTS: At the end of the study, total control over the seizures was 73.7% in patients who had not been treated previously and 43.8% in those in whom other monotherapies had failed; at the same time there was an improvement in the quality of life parameters. 42.9% reported side effects, which were usually tolerable or transient since they led to the withdrawal of OXC in only 9.6% of the patients. CONCLUSIONS: OXC is a very effective AED and is well tolerated as monotherapy in patients of all ages with partial seizures, either as the first choice therapy or as a substitution for other ineffective or poorly tolerated drugs.

Actuación ante un niño con una convulsión aguda / Action when faced with a child suffering acute seizure

No disponible

[Characteristics and indications of oxcarbazepine]. / Características e indicaciones de la oxcarbacepina.

OBJECTIVE: To review the major studies published concerning the pharmacokinetic characteristics, mechanism of action, clinical efficacy and adverse effects of oxcarbazepine (OXC). DEVELOPMENT: OXC is a ketoderivative of carbamazepine (CBZ), with a similar mechanism of action, possibly widening the voltage dependent potassium channels. Its pharmacokinetic characteristics are much better than those CBZ but the frequency and intensity of interactions is much less. In several double blind trials, using the drug in monotherapy in previously untreated patients, similar efficacy was found after OXC, phenytoin, valproate and CBZ but the fewest adverse effects were seen after OXC. CONCLUSIONS: OXC is an antiepileptic drug with better pharmacokinetic properties than CBZ and similar clinical efficacy, but better tolerated, so it may therefore be expected to replace this classical antiepileptic drug for use in monotherapy and polytherapy of both children and adults in all types of partial seizures.

[Characteristics and indications of levetiracetam]. / Características e indicaciones del Levetiracetam.

OBJECTIVE: To describe the data contained in the most important studies published on the pharmacokinetic and pharmacodynamic properties of levetiracetam, and also the main clinical trials carried out using this new antiepileptic drug. DEVELOPMENT: Derived from piracetam, but with very different properties, levetiracetam is ineffective in the usual models of seizures induced in experimental animals, although it acts in models of prolonged activation, audiogenous seizures and absences and has a novel mode of action. It has pharmacokinetic properties which are nearer to that of the ideal anti epileptic drug. In clinical trials done in adults with partial epilepsies use of 1,000 to 4,000 mg of levetiracetam was significantly more effective than a placebo, and the drug was very well tolerated. CONCLUSIONS: Levetiracetam is the newest antiepileptic drug to appear on the market. Its pharmacodynamic and pharmacokinetic characteristics are excellent. It has currently been approved for use in the polytherapy of patients with partial seizures aged over 16 years. Several studies indicate that its therapeutic spectrum is probably wider, particularly in generalized seizures such as the myoclonias, absences and seizures induced by light stimulation. Thus the indications for levetiracetam may become clear over the next few years.

[Reflex epilepsy from hot water: a new case and review of the literature]. / Epilepsia refleja por agua caliente: un nuevo caso y revisión de la bibliografia.

INTRODUCTION: In approximately 5% of epilepsy patients, seizures are triggered off by a specific sensory stimulus, in other words, they have reflex epilepsies. Among these, seizures triggered off by hot water are exceptional, and especially so in our community as nearly all the cases have been reported as occurring in India. CASE REPORT: Our case involves a 2 year old girl who, from the first weeks onwards, presented bouts of paleness, hypotonia and loss of consciousness when her head came into contact with hot water. The findings from clinical, neurophysiological and neuroimaging studies are described and there was a good response to treatment with valproate. DISCUSSION: The induction of epileptic seizures by immersion in hot water has only rarely been reported in western countries. Its physiopathology remains unknown but genetic factors that determine an alteration in cranial thermoregulation seem to be involved. With similar clinical and electroencephalographic characteristics in patients, the prognosis is usually favourable because of a good response to pharmacological treatment and the tendency toward spontaneous remission of the seizures.

Características e indicaciones del levetiracetam / Characteristics and indications of levetiracetam

Objetivo. Referir los datos de los principales trabajos publicados sobre las propiedades farmacocinéticas y farmacodinámicas del levetiracetam, así como de los principales ensayos clínicos realizados con este nuevo antiepiléptico. Desarrollo. Derivado del piracetam, pero con unas propiedades muy diferentes, el levetiracetam es ineficaz en los modelos habituales de crisis inducidas en animales de experimentación, mientras que actúa en modelos de activación prolongada, de crisis audiógenas y de ausencias, a lo que se une un novedoso mecanismo de acción. Con las caracteristicas farmacocinéticas más próximas a las del antiepiléptico ideal, en los ensayos clínicos efectuados en adultos con epilepsias parciales, la asociación de 1.000 a 4.000 mg de levetiracetam resulta significativamente más eficaz que el placebo, con una excelente tolerabilidad del fármaco. Conclusiones. El levetiracetam es el último antiepiléptico comercializado y tiene unas características farmacodinámicas y farmacocinéticas muy favorables, habiéndose aprobado su utilización, de momento, en politerapia en pacientes mayores de 16 años con crisis parciales. Diversos estudios sugieren un espectro terapéutico más amplio del fármaco, concretamente en crisis generalizadas como las mioclonías, las ausencias y las crisis inducidas por estímulos luminosos, de modo que en los próximos años podrán concretarse las indicaciones del levetiracetam (AU)

Características e indicaciones de la oxcarbacepina / Characteristics and indications of oxcarbazepine

Objetivo. Revisar los principales estudios publicados sobre las características farmacocinéticas, mecanismos de acción, eficacia clínica y efectos adversos de la oxcarbacepina (OXC). Desarrollo. La OXC es un cetoderivado de la carbamacepina (CBZ) con similar mecanismo de acción, posiblemente ampliado a los canales de potasio dependientes de voltaje. Con características farmacocinéticas muy mejoradas respecto de la CBZ, la frecuencia e intensidad de interacciones es muy inferior a la misma. En diversos ensayos doble ciego en monoterapia en pacientes no tratados previamente, se ha referido análoga eficacia de la OXC que fenitoína, valproato y CBZ, con menor incidencia de efectos adversos que en dichos fármacos. Conclusiones. La OXC es un antiepiléptico con mejores propiedades farmacocinéticas que la CBZ, con una eficacia clínica similar pero con mejor tolerabilidad, por lo que debe suponerse que va a sustituir a dicho antiepiléptico clásico en la monoterapia y politerapia de niños y de adultos con cualquier tipo de crisis parciales (AU)

Epilepsia refleja por agua caliente:un nuevo caso y revisión de la bibliografía / Reflex epilepsy from hot water: a new case and review of the literature

Introducción. En aproximadamente el 5 por ciento de los pacientes con epilepsia, las crisis están desencadenadas por un estímulo sensorial específico, es decir, tienen epilepsias reflejas. Entre ellas, las crisis desencadenadas por agua caliente son excepcionales, en especial en nuestro medio, puesto que casi todos los casos han sido identificados en la India. Caso clínico. Se refiere el caso de una niña de 2 años que, desde las primeras semanas de vida, presenta crisis de palidez, hipotonía y pérdida de conciencia cuando recibe agua caliente sobre su cabeza. Se describen los hallazgos clínicos, neurofisiológicos y neuroimagen, así como una buena respuesta al tratamiento con valproato. Discusión. La inducción de crisis epilépticas por inmersión en agua caliente se ha descrito raramente en países occidentales. Su fisiopatología se desconoce, pero parecen estar implicados factores genéticos que determinan una alteración en la termorregulación craneal. Con características clínicas y electroencefalográficas similares en la mayoría de los pacientes, el pronóstico suele ser favorable, por haber una buena respuesta al tratamiento farmacológico y la tendencia a la remisión espontánea de las crisis (AU)

No disponible

Aspectos epidemiológicos de la diabetes mellitus tipo 1 / Epidemiological features of type1 diabetes mellitus

No disponible

La repercusión económica de las enfermedades crónicas: El coste de la epilepsia infantil en el año 2000 / The economic repercussion of chronic diseases : The cost of childhood epilepsy in the year 2000

Introducción: El coste económico de la enfermedad incrementa la repercusión de ésta sobre el paciente y su familia. Las enfermedades más prevalentes son las principales consumidoras de los presupuestos sanitarios de un país. Objetivos: Cuantificar el impacto económico de la epilepsia infantil en España, como prototipo de enfermedad crónica, y analizar sus componentes más importantes. Material y métodos: Se solicita a varios neuropediatras que cumplimenten un cuestionario en el se incluyen los datos que permitan calcular, desde la perspectiva de la sociedad, los costes directos (médicos y no médicos) e indirectos, durante los últimos doce meses de evolución de niños menores de 14 años con epilepsia controlada y con epilepsia no controlada. Resultados: Durante el 2000, el coste medio anual de los niños con epilepsia controlada fue de 334.143 pesetas y el de los niños con epilepsia no controlada de 848.105, es decir, 2,7 veces superior al primero. El coste de la prevalencia de la epilepsia en España para el 2000 se aproximó a los 11.500 millones de pesetas, representando los costes directos el mayor porcentaje del coste total. Conclusiones: El coste medio anual asociado a la epilepsia infantil es mayor que el generado por el asma, la dermatitis atópica y la diabetes tipo I e inferior al de la fibrosis quística, la insuficiencia renal o el SIDA. Conocer la distribución de los costes generados por una enfermedad es una herramienta útil para mejorar la eficiencia de las intervenciones sanitarias y disminuir el impacto familiar de la enfermedad (AU)

[Characteristics of drugs used in the treatment of acute convulsions and convulsive status]. / Características de los fármacos utilizados en el tratamiento de las convulsiones agudas y de los estados convulsivos.

OBJECTIVE: To evaluate the pharmacokinetic and pharmacodynamic characteristics of the drugs used in the treatment of acute seizures and status epilepticus. DEVELOPMENT: After emphasizing the clinical importance of seizure episodes and the pathophysiology of status epilepticus, we describe the ideal characteristics of the drugs used for their treatment. Subsequently we analyze the pharmacokinetic characteristics, efficacy and toxicity of phenobarbitone, phenytoin, diazepam and valproate given parenterally. Although the efficacy of the four drugs is similar when given parenterally, fewer side-effects are seen with valproate. CONCLUSIONS: Parenteral valproate should be included in the normal guidelines for the treatment of convulsions. In this paper we include the recommended measures for the treatment of acute seizures and status epilepticus in childhood and suggest the development of similar measures for adult patients.

[Proposals for the treatment of children with West's syndrome]. / Propuestas para el tratamiento de los niños con síndrome de West.

OBJECTIVE: The justification of guidelines for the treatment of children with infantile spasms and West's syndrome. DEVELOPMENT: We review, by means of prospective studies of suitable methodology, the efficacy and side-effects of adrenocorticotropin, sodium valproate, vigabatrin and other drugs used in the treatment of children with West's syndrome. CONCLUSIONS: In view of the information obtained from these studies, we suggest that in children with idiopathic or cryptogenic West's syndrome, treatment should be started with oral prednisone up to a dose of 8 mg/kg/day which should be changed to vigabatrin in the case of inefficacy or side effects. In children with secondary or symptomatic West's syndrome, treatment should be started with vigabatrin, up to a maximum dose of 200 mg/kg/day and if this is ineffective or there are side-effects it should be replaced by prednisone. If neither of these forms of treatment are successful, topiramate (up to 24 mg/kg/day) or valproate (up to 200 mg/kg/day) should be given.

Características de los fármacos utilizados en el tratamientode las convulsiones agudas y de los estados convulsivos / Characteristics of the drugs used in the treatment of acute seizures and in status epilepticus

Objetivo. Valorar las características farmacocinéticas y farmacodinámicas de los fármacos utilizados en el tratamiento de las convulsiones agudas y de los estados convulsivos. Desarrollo. Tras subrayar la trascendencia clínica de las crisis convulsivas y la fisiopatología de los estados convulsivos, se indican las características ideales de los fármacos que deben administrarse para su tratamiento. A continuación, se analizan las características farmacocinéticas, eficacia y toxicidad del fenobarbital, fenitoína, diacepam y valproato por vía parenteral. Aunque la eficacia es similar en los cuatro fármacos por vía parenteral, el valproato tiene menos efectos adversos. Conclusiones. El valproato parenteral debe ser incorporado a las pautas habituales del tratamiento de las convulsiones. En el presente artículo, adjuntamos la pauta recomendable en el tratamiento de convulsiones agudas y de estados convulsivos en la infancia, y sugerimos el desarrollo de unas pautas similares para pacientes adultos (AU)

[Economic aspects of epilepsy]. / Aspectos económicos de la epilepsia.

INTRODUCTION: The economic magnitude of epilepsy is determined by its effect on the employment status of the patients, the cost of drug treatment for them and the healthcare system and the repercussion worldwide. DEVELOPMENT: Studies of the cost of the disease show that it has economic importance due to the sum of the direct and indirect costs caused by it. In the case of epilepsy, the results of studies in various countries led to the creation of a Commission on Economic Aspects of Epilepsy. The lack of epidemiological studies regarding epilepsy in Spain may explain the lack of publications on this subject in our country. The percentage of the total cost due to antiepileptic drugs is considerable and will probably increase in the future. The pharmaco-economic evaluation made by cost-benefit, cost-effectiveness, cost-usefulness analysis and studies to minimize costs should serve to use healthcare resources in the most effective manner and justify the rational use of the new antiepileptic drugs. CONCLUSIONS: The economic impact of epilepsy is added to the repercussion of the disease itself on the patient and his family. The different distribution of costs in children and adults with epilepsy suggest the need for intervention at an early age to try to reduce the long term economic and personal repercussions. The pharmaco-economic evaluation of the new antiepileptic drugs will make it clear whether their considerable cost is worth paying for their greater effectivity.