A Signal Processing Approach to Pharmacokinetic Data Analysis.

The connection between pharmacokinetic models and system theory has been established for a long time. In this approach, the drug concentration is seen as the output of a system whose input is the drug administered at different times. In this article we further explore this connection. We show that system theory can be used to easily accommodate any therapeutic regime, no matter its complexity, allowing the identification of the pharmacokinetic parameters by means of a non-linear regression analysis. We illustrate how to exploit the properties of linear systems to identify non-linearities in the pharmacokinetic data. We also explore the use of bootstrapping as a way to compare populations of pharmacokinetic parameters and how to handle the common situation of using multiple hypothesis tests as a way to distinguish two different populations. Finally, we demonstrate how the bootstrap values can be used to estimate the distribution of derived parameters, as can be the allometric scale factors.

La responsabilidad obstétrica en la miocardiopatía dilatada periparto / The obstetrical responsability in the peripartum dilated myocardiopathy

Dos casos surgidos en nuestro centro son ocasión para considerar las implicaciones del ginecólogo en la miocardiopatía dilatada periparto (MCDP). Según publicaciones consultadas, aproximadamente 35% de los casos se presentaron antes del parto, mientras las gestantes eran pacientes obstétricas. El 32%, en la primera semana postparto, todavia dependientes del ginecólogo y el 16% a lo largo del primer mes, pudiendo éstas recalar indistintamente en urgencias de maternidad o generales. Sólo un 16% se presentaron lejos del parto, por lo que ellas no relacionan su problema con el embarazo, acudiendo, principalmente, a urgencias generales. Así que la mayoría de los casos de MCDP se presentan cuando las mujeres son pacientes del ginecólogo-obstetra y nos compete y compromete su diagnóstico

Two cases that arose in our hospital provide an opportunity to consider the gynecological implications of dilated myocardiopathy both during and atter the birth. According to publications we have consulted, approximately 35% of the cases presented before the birth, and these were obstetric patients. 32%, in the first week postpartam, still depended on the gynecologist and during the first month another 16% were able to attend the general emergency room or casualty in the maternity hospital. Only 16% presented a long time after the birth, and as they did not relate their problem to their pregnancy, they tended to go to the general emergency room of the hospital. Thus, the majority of MCDP cases present when women are still patients of the gynecologist/ obstetrician and we are therefore responsible for the diagnosis of their disease

Embarazo y patología de la cavidad bucal / Oral pathology during pregnancy

Se subraya la importancia que tiene para la embarazada optimizar su salud oral, la cual merece ser orientada por parte del obstetra. El odontólogo considera a la gestante una paciente especial, tanto por las adaptaciones que experimenta su organismo como por tener que asumir la presencia del feto. Se repasan las modificaciones que tienen lugar en la cavidad bucal, al abrigo de los cambios hormonales, inmunológicos, vasculares y bacterianos del embarazo, que estarían implicados en el aumento de la morbilidad. Señalamos las patologías más comunes, reconociendo la necesidad de implantar programas de vigilancia odontológica para las embarazadas y la conveniencia de recomendarles el control preconcepcional (AU)

Embarazo después de trasplante hepático / Pregnancy after liver transplant

Paciente de 27 años de edad, embarazada 2 años después de haber sufrido trasplante hepático, funcionalmente estabilizado, en tratamiento con tacrolimus. El embarazo cursó de forma completamente fisiológica. El parto se presentó a término, eutócico, y el feto fue normal (AU)

Hippocampal AgNOR activity after chronic alcohol consumption and alcohol deprivation in rats.

Chronic alcohol consumption induces morphological changes in the central nervous system and withdrawal does not reverse these changes. It is well known that the hippocampal formation is one of the brain regions most sensitive to prolonged alcohol ingestion. The aim of our study was to evaluate the transcriptional neuronal activity by measuring the argyrophilic nucleolar organizer regions (AgNORs) in the dentate gyrus, CA3, and CA1 hippocampal areas from adult male rats receiving chronic administration of ethanol (ALC) and after withdrawal (WDL). The parameters evaluated were the number and area of AgNORs, together with the area of nucleus and the proportion between AgNOR and nuclear areas (ratio). The animals from ALC and WDL groups showed a reduction in the number of AgNOR per cell as compared to the control group. CA3 was the hippocampal area most affected by chronic alcohol intake. No improvement was observed in animals after withdrawal. Our data support the idea that the chronic intake of alcohol decreases protein synthesis in hippocampal neurons at an early age. This decrease may explain the memory impairment showed by rats receiving chronic treatment with alcohol because, both in humans and rats, it is associated with a reduction in the number of cholinergic neurons in the basal forebrain that would in turn affect the hippocampal function.

Selective and nonselective effects of 1-methyl-4-phenylpyridinium on oxygen consumption in rat striatal and hippocampal slices.

Insights into the etiology and pathophysiology of Parkinson's disease may derive from elucidation of the neurotoxic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite, 1-methyl-4-phenylpyridinium (MPP+). In previous studies, MPP+ provoked oxidation of cytochrome b and K+ leakage into the extracellular space of rat striatal slices. Magnitudes of these time-dependent responses were far greater than expected had the MPP+ effects been limited to dopaminergic terminals. To determine whether cytochromes become oxidized from K(+)-induced increases in ion transport activity or from electron transport inhibition at complex I, oxygen consumption was measured because this should be increased by the former and decreased by the latter mechanism. Low MPP+ concentrations (1 microM) decreased O2 consumption (approximately 40% in 3 h) in striatal slices. This decrease was diminished by mazindol and did not occur in hippocampal slices. High toxin concentrations (100 microM) inhibited oxygen consumption to a greater extent (approximately 60%) in striatal slices; this inhibition was still greater in hippocampal slices. These results support the hypothesis that acute effects of low ("selective") MPP+ concentrations require the presence of dopaminergic terminals to trigger a sequence of destructive metabolic events but that the metabolic consequences of MPP+ spread to neighboring cells. In contrast, high MPP+ concentrations nonselectively inhibit metabolic and ion transport activity without requiring the presence of dopaminergic terminals. These results also suggest that physiological effects of "selective" MPP+ concentrations extend to nondopaminergic cells.

Potassium-induced increases in oxygen consumption are diminished by age in rat hippocampal slices.

Previous reports showed that cytochrome alpha,alpha 3 responded to heightened brain activity with shifts toward oxidation in adult rats but toward reduction in aged animals. To determine whether this change indicates an age-associated limitation in mitochondrial respiratory capacity, the present study compared oxygen consumption in hippocampal slices of young adult (6 month, control) and aged (26 month) rats. Slices were used to insure that results were independent of cerebrovascular factors. Age was without effect on oxygen consumption under 'resting' conditions (i.e. with slices bathed at 3.5 mM K+), but oxygen consumption was not increased as much in hippocampal slices from aged rats under heightened energy demands (produced by raising the extracellular potassium ion activity [( K+]o to 50 mM). This lesser oxygen consumption response to enhanced metabolic demand suggests that there are age-associated limits to the brain's ability to increase its metabolic rate.

The pharmacokinetics, tissue distribution, and biotransformation of a new class of antitumor agents: mitonafide and pinafide.

The pharmacokinetics, biotransformation, protein binding and tissue distribution of mitonafide and pinafide were studied after single i.v. and oral administration of each drug (20 mg/Kg) in female rats. In pregnant rats a study of cross placental-barrier after i.v. administration of the two drugs was also performed. The drugs were absorbed fairly rapidly with a mean peak plasma level of 7.63 +/- 0.70 micrograms eq/ml for the 3H-mitonafide and with 6.16 +/- 0.77 micrograms eq/ml for the 3H-pinafide between 30 minutes and 1 hour after oral dosing. For both drugs, the pharmacokinetics can be described by a two-compartment open model. The mean elimination half-lives were 17.8 h and 47.5 h for 3H-mitonafide and 3H-pinafide, respectively. Two metabolites for each compound as well as unchanged drugs were identified in urine by TLC and GC/MS by comparison of their chromatographic properties with a number of reference compounds. Approximately 30% of the radioactive drug was excreted over a 48 h period for 3H-mitonafide and 24% for 3H-pinafide in urine, after i.v. administration. The cross placental-barrier studies showed that both 3H-mitonafide and 3H-pinafide were present in the 14-day fetuses.

Depression of primate spinothalamic tract neurons by iontophoretic application of 5-hydroxytryptamine.

The effects of iontophoretic applications of 5-hydroxytryptamine (5-HT) were tested upon primate spinothalamic tract neurons recorded extracellularly in the spinal cord of anesthetized monkeys. The activity of most high threshold and wide dynamic range spinothalamic tract cells was depressed. 5-HT also reduced the responses of the cells to glutamate pulses which by themselves had a powerful excitatory action. It is concluded that 5-HT has a depressant action upon the postsynaptic membranes of spinothalamic tract cells, although the action has a slow time course. The observations are consistent with, but by no means prove, the hypothesis that serotonergic pathways descending from the brain stem produce a postsynaptic inhibiton of spinothalamic tract neurons.