Development of an in silico model for human skin permeation based on a Franz cell skin permeability assay.

A multiple linear regression QSAR model was developed based on a set of 61 compounds with internally consistent permeability data measured across Franz cell. The data was normalized using a mean permeability value of a reference compound, 3-isobutyl-1-methylxanthine (IBMX). The QSAR model contained only five simple descriptors and had a correlation coefficient, r(2) of 0.77 between experimental and calculated values for skin permeability. The mean absolute error (MAE) was 0.3 for the entire set and the cross validation coefficient, q(2) was 0.71. The in silico skin permeability model was used as a filter for virtual libraries and to optimize skin permeation of specific compounds for several dermatology discovery projects.

Bioavailability of oral isbufylline in rabbits.

The bioavailability of isbufylline was assessed in male rabbits given 12 mg/kg i.v. (intravenous) or per os (oral) according to a randomized design. The concentrations of unbound (fu = 54.0) isbufylline were considered in plasma as a function of time, after i.v. and oral administration. After oral administration in saline solution, a mean absolute oral bioavailability of 59.6% was calculated. The drug is rapidly absorbed and the comparison of the kinetic profiles after i.v. and per os administration, revealed a rapid elimination: t1/2 27.3 and 28.8 min respectively, and a total body clearance of 67.06 ml/min/kg. Urinary recovery 0-48 h accounted for less than 1% of the dose.

Chocolate, café, té y otros estimulantes: bebidas energéticas avant la lettre (II) / No disponible

Las bebidas estimulantes naturales con metilxantinas (chocolate, café y té entre otras) vienen usándose desde la más remota antigüedad por sus propiedades para eliminar la fatiga, aumentar la alerta y combatir el sueño. En el presente artículo se revisan las principales características botánicas, historia, composición, procesamiento, formas de uso y efectos sobre la salud de estas bebidas, así como los principales aspectos farmacodinámicos, farmacocinéticos y toxicológicos del principio activo responsable de sus efectos estimulantes, la cafeína. Dado que los polifenoles juegan también un papel importante en los efectos sobre la salud de estas bebidas, se hace también hincapié en su relevancia en la prevención de enfermedades crónicas

Natural stimulating beverages with methylxanthines (chocolate, coffee and tea, among others) have been used since ancient times because of their properties for avoiding fatigue, enhancing alertness and fighting sleepiness. In this paper we review the main botanical characteristics, the history, composition, processing, use and health effects of these natural beverages, as well as the main pharmacodynamic, pharmacokinetic and toxicological aspects of caffeine, the active ingredient responsible for their stimulant effects. Polyphenols play an important role in the effects of these beverages on health, so we also place stress on their relevance in the prevention of chronic diseases

Segmental heterogeneity of electrogenic secretions in human ascending colon and rectum.

AIMS: We have attempted to ascertain putative segmental differences in the secretory responses of the human ascending colon and rectum. METHODS: From the mucosal biopsy samples of two segments, the short-circuit current (I(sc)) and tissue resistance (R(te)) were compared under control conditions, as well as after the induction of secretion, using a modified Ussing chamber. We also performed semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to detect and quantify transport proteins. RESULTS: The spontaneous I(sc) in the ascending colon was found to be greater than that in the rectum (P<0.01), whereas isobutylmethylxanthine/forskolin and carbachol (CCh) induced a greater rise in I(sc) in the rectum than in the ascending colon (P<0.05). When coupled with indomethacin pretreatment, the increase in Delta I(sc) after the addition of CCh and forskolin was significant as compared to that observed without pretreatment (P<0.05). However, in the rectum, the secretory response to CCh and forskolin was abolished to a significant degree by indomethacin (P<0.05). Moreover, these indomethacin-induced changes were reversed by the addition of PGE2. Upon semiquantitative RT-PCR analysis, the amounts of cystic fibrosis transmembrane regulator, KCNQ1, and CLCA1 mRNAs were not found to be different between the two segments. CONCLUSION: There was a clear segmental heterogeneity with regard to electrogenic secretion in the human colon, and this difference can be explained by differences in the ascending colon and rectum.

Metabolism of isbufylline in humans. Isolation, identification, and synthesis of plasma and urine metabolites.

Isbufylline metabolism after oral administration to humans was studied. The main metabolites detected by the HPLC method, in plasma, were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-hydroxy-2-methyl-propyl) xanthine (II), and 1-methyl-7-(2-methyl-propyl) xanthine (III). The main metabolites detected in urine were 1-methyl-7-(2-hydroxy-2-methyl-propyl) xanthine (I), 1,3-dimethyl-7-(2-carboxy-propyl) xanthine (IV), and 1,3-dimethyl-7-(2-hydroxymethyl-propyl) xanthine glucuronic acid (V)-Gluc. They were isolated by HPLC, identified by GC/MS, HPLC/MS, or HPLC/MS/MS, and finally synthesized. Recovery of these metabolites, along with the absence of unmetabolized isbufylline in the urine, indicated biotransformation and renal excretion as the main routes of isbufylline elimination in humans. HPLC quantitation of the characterized urine metabolites revealed that 49% of the drug was eliminated as (I), 9% as (V)-Gluc, and 5% as (IV).

Pharmacology of phosphodiesterase-5 inhibitors.

The clinical properties (efficacy and safety profile) of a medicine are related not only to its mode of action, but also to its selectivity for its target (usually a receptor or enzyme) and are also influenced by its pharmacokinetic properties (absorption, distribution, metabolism and elimination). The growing number of phosphodiesterase inhibitors that are selective for phosphodiesterase-5 (PDE5) represent a promising new class of compounds that are useful for the treatment of erectile dysfunction and perhaps other disorders. Some of the basic pharmacodynamic and pharmacokinetic parameters that describe drug action are discussed with regard to the new PDE5 inhibitors. Central topics reviewed are the concentration that produces a given in vitro response, or potency (IC50), maximum plasma concentration (Cmax), time to Cmax (Tmax), half-life (t 1/2), area under the curve (AUC), bioavailability, onset and duration of action, and the balance to achieve optimum safety and efficacy. To illustrate these concepts, a group of inhibitors with varying selectivities and potencies for PDE5 (theophylline, IBMX, zaprinast, sildenafil, tadalafil and vardenafil) are discussed. Each drug has its own set of unique pharmacological characteristics based on its specific molecular structure, enzyme inhibition profile and pharmacokinetic properties. Each PDE5 inhibitor has a distinct selectivity that contributes to its safety profile. As with all new drugs, and especially those in a new class, careful evaluation will be necessary to ensure the optimal use of the PDE5 inhibitors.

Chronic effects of xanthines on levels of central receptors in mice.

1. Chronic ingestion of caffeine causes a significant increase in levels of A1-adenosine, nicotinic and muscarinic receptors, serotonergic receptors, GABAA receptors and L-type calcium channels in cerebral cortical membranes from mice NIH Swiss strain mice. 2. Chronic theophylline and paraxanthine had effects similar to those of caffeine except that levels of L-type channels were unchanged. Chronic theobromine, a weak adenosine antagonist, and 1-isobutyl-3-methylxanthine (IBMX), a potent adenosine antagonist and phosphodiesterase inhibitor, caused only an increase in levels of A1-adenosine receptors. A combination of chronic caffeine and IBMX had the same effects on receptors as caffeine alone. Chronic 3,7-dimethyl-1-propargylxanthine (DMPX), a somewhat selective A2A-antagonist, caused only an increase in levels of A1-adenosine receptors. Pentoxifylline, an adenosine-uptake inhibitor inactive at adenosine receptors, had no effect on receptor levels or calcium channels. 3. A comparison of plasma and brain levels of xanthines indicated that caffeine penetrated more readily and attained somewhat higher brain levels than theophylline or theobromine. Penetration and levels were even lower for IBMX, paraxanthine, DMPX, and pentoxyfylline. 4. The results suggest that effective blockade of both A1 and A2A-adenosine receptors is necessary for the full spectrum of biochemical changes elicited by chronic ingestion of xanthines, such as caffeine, theophylline, and paraxanthine.

Chocolate, café, té y otros estimulantes: bebidas energéticas avant la lettre (I) / No disponible

Las bebidas estimulantes naturales con metilxantinas (chocolate, café y té entre otras) vienen usándose desde la más remota antigüedad por sus propiedades para eliminar la fatiga, aumentar la alerta y combatir el sueño. En el presente artículo se revisan las principales características botánicas, historia, composición, procesamiento, formas de uso y efectos sobre la salud de estas bebidas, así como los principales aspectos farmacodinámicos, farmacocinéticos y toxicológicos del principio activo responsable de sus efectos estimulantes, la cafeína. Dado que los polifenoles juegan también un papel importante en los efectos sobre la salud de estas bebidas, se hace también hincapié en su relevancia en la prevención de enfermedades crónicas (AU)

Natural stimulant beverages containing methylxanthines (chocolate, coffee and tea, among others) have been used since earliest times because of their properties for avoiding fatigue, enhancing alertness and fi ghting sleepiness. In this paper we review the main botanical characteristics, the history, composition, processing, use and health effects of these natural beverages as well as the main pharmacodynamic, pharmacokinetic and toxicological aspects of caffeine, the active ingredient responsible for their stimulant effects. Polyphenols play an important role in the health effects of these beverages, attention is also paid to their relevance in chronic disease prevention (AU)