Fármacos que pueden producir somnolencia excesiva / Drugs promoting excessive sleepiness

La somnolencia es un acontecimiento frecuente y fisiológico en ciertas circunstancias. La somnolencia excesiva durante el día se caracteriza por una sensación anormal de sueño con fuerte tendencia a dormirse en situaciones o momentos inapropiados, que debe diferenciarse de la fatiga. Entre las posibles causas de una somnolencia excesiva diurna está el consumo de fármacos. Hay dos posibilidades por las que los fármacos pueden considerarse como agentes etiológicos: a) a través de un mecanismo indirecto (compuestos que alteran la cantidad y la calidad del sueño y condicionan su fragmentación o deprivación) o b) por un efecto directo que propicia de forma mediada un aumento de la somnolencia diurna. Este favorecimiento de la somnolencia diurna debería identificarse como reacción adversa. Se describen los nuevos términos que la investigación de los mecanismos implicados en el control de la sucesión de sueño-vigilia está introduciendo en la farmacología de los fármacos productores de sueño: hipnóticos, promotores del sueño, intensificadores del sueño, modificadores de la biestabilidad y cronobióticos. Se identifican los factores farmacocinéticos que principalmente determinan la duración del efecto hipnótico tras administración única (volumen de distribución) y tras administración múltiple (eliminación) y se expone la importante variación interindividual en la frecuencia e intensidad con que los fármacos inducen una somnolencia excesiva. Por último, se completa la visión del posible impacto de los fármacos sobre el ciclo sueño-vigilia refiriendo los posibles efectos durante la noche de los fármacos tomados por la mañana, enfatizando la importancia de considerar el proceso como un todo continuo y no como compartimentos estancos (AU)

In certain circumstances sleepiness is a frequent and physiological event. Excessive daytime sleepiness is characterized by an abnormal sleep sensation with a strong tendency to fall asleep in inappropriate situations and time moments, which should be differentiated from fatigue. Among the possible causes of excessive daytime sleepiness there is drug consumption. There are two different possibilities to consider drugs as etiological agents: a)thought an indirect mechanism (compounds disrupting sleep quantity and quality resulting in sleep fragmentation or deprivation) or b) by a straight effect directly promoting an increase of daytime sleepiness. This promotion of daytime sleepiness should be identified as an adverse reaction. The new terms that research on the mechanisms which control the wake-sleep cycle is introducing in the pharmacology of drugs favouring sleep are described: hypnotics, sleep promoters, sleep enhancers, bi-stability modifiers and chronobiotics. The pharm acokinetic factors which mainly determine the duration of the hypnotic effects are identified, either after a single administration (volume of distribution) or after a repetitive administration (elimination) and the important interindividual variation in frequency and intensity of drug induced excessive sleepiness is explained. Lastly, the description of the potential drug impact on the wake-sleep cycle is completed by referring thee ventual effects that drug ingestion at morning time could induce during the night, highlighting the importance to consider the process as a continuum non-compartmental one (AU)

Eberconazole cream: topical and general tolerability, sensitisation potential, and systemic availability.

Eberconazole is a topical imidazole derivative, which has shown high potency against dermatophytes and yeasts (several species of Candida, Malassezia) in vitro and in experimental models. Clinical trials have found that the compound has a high degree of efficacy against dermatophytes and good tolerability. Evaluation of its a) topical and general tolerability, b) eventual development of sensitisation, c) local availability, and d) degree of systemic absorption. Two clinical trials with 28 healthy young volunteers of both sexes were performed. In Study I, placebo or eberconazole cream (2%) were applied at increasing doses: day 1 (0.5 g), days 2-3 (1 g), days 4-5 (2 g), days 6-7 (4 g), days 8-9 (8 g), and days 10-11 (12 g). On day 1, each application area was washed with ethanol-soaked gauzes at different times to assess availability of the active compound. In Study II, eberconazole cream (1%) was applied on day 1 and again at least one week later. After the first application, blood and urine samples were obtained at different times to assess systemic absorption. The only change observed was slight redness in a few volunteers after both active and placebo applications. This remitted spontaneously without intervention and we were able to continue with the administration of repeated increasing-doses. A few participants described side effects; these were all of mild intensity, and occurred in areas where placebo or eberconazole were applied, mainly within the first hour postapplication. The most frequent effect after the first application was coldness, and after repeated increasing-doses there was itching. No signs or symptoms of skin reactivity were observed following reexposure to the product. No clinically relevant changes were observed in vital signs (systolic and diastolic blood pressure, heart rate, body temperature), ECG, or analytical parameters (clinical haematology and biochemistry). The quantity of compound collected through washing gauzes decreased progressively over time. Plasma and urine concentrations of eberconazole were below the quantification limit of the analytical method (5 ng/ml) at all times. Eberconazole cream is a topical antimycotic drug that has good local and general tolerability. It has acceptable topical availability, no detectable systemic drug levels, and does not appear to cause skin sensitivity.

A study comparing the inhibitory effects of single and repeated oral doses of ebastine and fexofenadine against histamine-induced skin reactivity.

OBJECTIVE: The aim of this double-blind, randomized, crossover, placebo-controlled clinical trial was to compare the inhibition of the histamine-induced skin reaction induced by ebastine 20 mg with respect to that induced by fexofenadine 120 mg or placebo. METHODS: Eighteen volunteers (10 males, 8 females) received the three treatments once daily for 5 days, with a mean 7-day washout period between treatments. Intradermal tests, using 0.05 ml from a solution containing 100 microg/ml of histamine, were performed at baseline and at 1, 1.5, 2, 3, 10 and 24 h after a single dose and repeated 5-day dose, and in addition after 34, 48, 58 and 72 h after repeated 5-day dose. RESULTS: After 24 h of acute administration, ebastine 20 mg was significantly more effective than fexofenadine 120 mg in reducing the wheal and flare induced by histamine challenge (p<0.001). Although fexofenadine 120 mg had the shortest onset of action (1.5 vs. 3 h in ebastine 20 mg), the duration of its antihistamine effect was the shortest (24 vs. 58 h in ebastine 20 mg) and wheal reduction after 24 h was not significantly different from placebo. The overall effect after single and repeated 5-day dose, expressed as the AUC of reduction of wheal and flare area (%/h), showed the following order of magnitude: ebastine 20 mg>fexofenadine 120 mg>placebo. No significant differences in the incidence of adverse events were found between the three treatments. CONCLUSIONS: The present results clearly show a superior and long-acting effect of ebastine 20 mg compared with fexofenadine 120 mg on the skin response to histamine 24 h after dosing.

Proof of safety of drugs: focus on vigilance.

It is well accepted that all new compounds, before administration to patients, should undergo safety evaluations in healthy subjects, including central nervous system (CNS) toxicity and as such the assessment of vigilance effects a relevant hallmark. The original concept of vigilance as a phenomenon observed only under conditions of monotony and signal regularity is increasingly falling into disfavor, embracing at present a much broader spectrum of behavior. Currently, vigilance may be regarded as a "readiness to adopt the appropriate behavior in a given situation, which thus finds outward expression through the quality and quantity of the behavior occurring in response to a given (internal or external) stimulus situation". The assumption that vigilance is a multifactorial phenomenon and not merely EEG data should be taken into account in order to study it accurately. Specifically, in drug research, apart from subjective reports and psychomotor performance tests, neurophysiological evaluations are regularly used such as Multiple Sleep Latency Test, Vigilance Epoch Classification or Parameters within a continuous scale. Although with limitations, temporal patterns of changes in activity of different frequency bands, indexes as the alpha slow-wave or the alpha anteriorization, computed from the EEG quantification, yielded different definitions of the intermediate states of the transition from wakefulness to sleep through the so-called subvigil stages. Spatial patterns are less documented. The recently proposed mathematical models to explain and predict variations in alertness are presented. Examples of the effects of different classes of drugs with the methods reported and its theoretical and practical relevance to vigilance research are introduced.