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OBJECTIVE: To assess the effect of ranitidine on the pharmacokinetics of eprosartan in healthy male volunteers. DESIGN: Single-center, randomized, open-label, two-period, period-balanced, crossover study. PATIENTS: Seventeen healthy men aged 19 to 43 years. INTERVENTION: In each period (separated by a ≥7 d washout), subjects received a single 400-mg oral dose of eprosartan alone, or a single oral dose of eprosartan 400 mg and ranitidine 150 mg on day 4 after 3 days of ranitidine 150 mg twice daily. Serial pharmacokinetic samples were obtained for up to 24 hours following eprosartan dosing. MAIN OUTCOME MEASURES: Plasma and urine eprosartan concentrations during each treatment session. RESULTS: Eprosartan maximum concentration (Cmax), the AUC from time zero to the last quantifiable concentration (AUC0-t), and renal clearance (Clr) values were approximately 7%, 11%, and 4% lower, respectively, when administered with ranitidine compared with eprosartan alone. The 95% CIs for the ratio of eprosartan plus ranitidine compared with eprosartan alone were 0.81 to 1.07, 0.77 to 1.03, and 0.64 to 1.43, for Cmax, AUC0-t, and Clr, respectively, indicating no statistically significant difference between regimens. CONCLUSIONS: Repeated doses of ranitidine did not have a marked effect on the single-dose pharmacokinetics of eprosartan. OBJETIVO: Evaluar el efecto de ranitidina en la farmacocinética de eprosartan en pacientes voluntarios saludables. DISEÑO: Centro sencillo, estudio randomizado, rotulación abierta, dos períodos, período cruzado balanceado. PACIENTES: Díecisiete hombres saludables entre 19 a 43 años. INTERVENCIÓN: En cada período (separado por 7 d o más sín medicamento), los pacientes recibieron una dosis oral de eprosartan 400 mg solamente, o una dosis oral eprosartan 400 mg y ranitidina 150 mg 2 veces al día. Muestras en serie sobre la farmacocinética fueron obtenidas hasta 24 horas después de la dosis de eprosartan. MEDICIÓN DE RESULTADOS: Concentraciones en plasma y orina de eprosartan durante cada período de tratamiento. RESULTADOS: Los valores promedio de concentración máxima (Cmax), ABC0-t, y depuración renal (Clr) de eprosartan fueron aproximadamente 7%, 11%, y 4% más bajo, respectivamente, comparado con eprosartan sólo. En intervalos de un 95% de confianza, la razón de eprosartan y ranitidina comparado con eprosartan sólo fueron 0.81 a 1.07, 0.77 a 1.03, y 0.64 a 1.43 para Cmax, ABC0-t, y Clr, respectivamente, indicando que no hay diferencia estadística entre ambos régimenes. CONCLUSIONES: Dosis repetidas de ranitidina no producen un efecto marcado en la farmacocinética de eprosartan en dosis sencillas. OBJECTIF: Évaluer l'effet de la ranitidine sur la pharmacocinétique de l'éprosartan chez des volontaires sains. DEVIS EXPÉRIMENTAL: Étude à échantillonagealéatoire, ouverte, en chassécroisé comprenant deux périodes, et réalisée dans un seul établissement. PATIENTS: Dix-sept hommes sains, âgés entre 19 et 43 ans. INTERVENTION: Dans chaque période (séparée par 7 j de sevrage thérapeutique), les volontaires reçurent soit une dose unique de 400 mg d'éprosartan, ou une dose unique de 400 mg d'éprosartan et 150 mg de ranitidine au jour 4, suivant l'administration de 150 mg de ranitidine aux 12 heures les 3 premiers jours. Plusieurs échantillons pharmacocinétiques furent obtenus durant les 24 heures suivant l'administration d'éprosartan. MESURES DE L'ÉFFET: Concentrations urinaires et plasmatiques d'éprosartan durant chacune des deux périodes de traitement. RÉSULTATS: Quand l'éprosartan fut administré avec la ranitidine, la concentration maximale, la surface sous la courbe, et la clairance rénale d'éprosartan étaient en moyenne approximativement 7%, 11%, et 4% inférieures, respectivement, aux valeurs obtenues avec l'éprosartan administré seul. Aucune différence statistiquement significative n'a été observée entre l'éprosartan administré avec la ranitidine et l'éprosartan seul. Les intervalles de confiance à 95% pour les rapports des valeurs entre les deux groupes sont pour la concentration maximale 0.81 à 1.07, la surface sous la courbe 0.77 à 1.03, et la clairance rénale 0.64 à 1.43. CONCLUSIONS: L'administration de doses répétées de ranitidine n'a pas démontré d'effet marqué sur la pharmacocinétique d'une dose unique d'éprosartan.

The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development. Copyright © 2002 John Wiley & Sons, Ltd.

Most analysts who look at the future development of travel predict a steady increase in the frequency of travel over at least the coming decade. Since vehicles are steadily improving in terms of speed and comfort, we can see how plans for new infrastructure investments are developed further year by year. New high-speed train connections are planned, the most advanced of which require completely new tracks for the trains to run smoothly and safely at high speed. In the same manner, new airline routes turn up all the time as regional airlines with smaller planes find that the frequency of travel between two regional centres is high enough for a route to become economically viable. In the car industry, we see how companies develop new types of car with lower emission rates that need less fuel.

The paradigm shifts that are discussed in this book are based on the idea that new technologies in the field of IT, media and telecommunications will become the key drivers that have the power to change the entire structure of many industries and markets. Many people would argue that this is not new. Over the past 20 years new advanced technologies have emerged continuously that have had the power to revolutionise industries but have failed to do so. For example, large investments have been made in new computer systems for the past two decades without any significant benefits in terms of efficiency. This argument was already one of the foundations of the process re-engineering trend that started in the early 1990s. However, this trend has not had the extreme impact on companies that its proponents expected.

‘Transparency’ is a word that points to one of the most important characteristics of the emerging electronic marketplace. Transparency’ refers to the fact that an object can be seen through (light can pass through it). In a more general sense, it also means ‘open’, ‘frank’ and ‘clear’. In this book, the word is intended to indicate the fact that every aspect of a system or an object is visible to the viewer. The analogy is meant to stress a major difference between the marketplace of today, in which only a limited amount of information can be accessed, and the market of tomorrow, in which all relevant information on any subject could be accessed by anyone, anywhere.

The fact that suppliers can serve all the customers with whom they can communicate makes the potential market for each supplier enormous. This means that a producer who has substantial competitive advantages in production can initially grab a larger share of the market than he or she has at present. This, together with the fact that customers on the Internet will be able to compare offerings from different suppliers much more accurately than they can today, could lead to a situation in which many companies that have seemingly secure local markets today could lose a large share of these to Internet-based players. Therefore, companies are advised to enter the Internet as soon as possible, for several reasons.

The changes we have discussed so far may seem only to affect companies, but the consequences will not stop there. We will see a number of rapid changes that have to be considered by states and governments if they want to avoid ending up with two types of society, one physical in which the government has a substantial influence, and one virtual, in which other rules apply, that is, the Internet and its players.

So far, we have discussed the development towards transparency driven by the development of the new electronic marketplace on the Internet. To be able to get a good position in this new market, it is necessary to know more about this development and to try to structure this knowledge into a firm picture of the market that is emerging. This chapter will start the journey into the future market by taking a close look at some of today’s trends.