Pharmacokinetics of pentamidine in Sprague-Dawley rats in late pregnancy

To our knowledge, placental transfer of pentamidine has not been previously studied in vivo. In the present study, the pharmacokinetics of pentamidine were analyzed in late gestation (18 days) among Sprague-Dawley rats. Pentamidine's kinetics were assessed in the following maternal compartments over a 12-hour period in 16 timed-pregnant rats: serum, liver, and kidney. Placentas were also analyzed for pentamidine concentration as were fetal brain, liver, and kidney tissues. Significant placental transfer of the drug was found, with pentamidine reaching all fetal compartments studied. Notably, by the twelfth hour fetal brain tissue achieved pentamidine concentrations that were not significantly different from those of maternal serum at the second hour of the experiment. This is an interesting observation because adult mouse and rat brains were found to be unexposed to the drug.     

Acute profound dystonia in infants with glutaric acidemia

Acute profound dystonia developed in three previously well infants who were found to have glutaryl-CoA dehydrogenase deficiency in cultured skin fibroblasts. Two patients had excessive urinary excretion of glutaric acid, but one did not. Neuroradiologic studies performed in all three patients at the onset of their illnesses revealed large CSF-containing spaces both within the sylvian fissures and anterior to the temporal lobes. Pathologic examination of the brain of one patient demonstrated cerebral and cerebellar atrophy, shrinkage of the putamen, and white matter vacuolation. Glutaric acidemia may be a common cause of acquired persistent dystonia or choreoathetosis in infancy.     

Embryofetal effects of pentamidine isethionate administered to pregnant Sprague-Dawley rats

The effects of pentamidine isethionate on the developing embryo and fetus have not been previously published. Pregnant Sprague-Dawley rats were given various doses of pentamidine during the period of embryogenesis. Animals were killed on days 18 to 20 of pregnancy and their fetuses were removed by hysterectomy. Autopsies were performed on all fetuses. There were significant differences among groups with regard to maternal weight gain and pregnancy resorption. More pregnancy resorptions were noted in the group that received normal human doses (4 mg/kg/day) of pentamidine than in the control group (p less than 0.05). One structural anomaly consisting of unilateral renal agenesis was noted in the 711 fetuses examined. Skeletal survey of fetal rats was unremarkable. Pentamidine was without teratogenic effects in rats when administered in doses similar to those recommended for adult humans; however, it appears to have an embryocidal effect when given in those same doses during embryogenesis.     

Trisomy 18 with Ectopia Cordis, Omphalocele, and Ventricular Septal Defect: Case Report

A case of thoracoabdominal ectopia cordis was diagnosed by ultrasonography at 21 week's gestation. Chromosomal analysis showed full trisomy 18. This case supports the associationl of thoracoabdominal ectopia cordis (Cantrell's pentad) with chromosomal errors, specifically trisomy 18.     

Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: evidence for secondary insufficiency of l-carnitine

Concentrations of l-carnitine and acylcarnitines have been determined in urine from patients with disorders of organic acid metabolism associated with an intramitochondrial accumulation of acyl-CoA intermediates. These included propionic acidemia, methylmalonic aciduria, isovaleric acidemia, multicarboxylase deficiency, 3-hydroxy-3-methylglutaric aciduria, methylacetoacetyl-CoA thiolase deficiency, and various dicarboxylic acidurias including glutaric aciduria, medium-chain acyl-CoA dehydrogenase deficiency, and multiple acyl-CoA dehydrogenase deficiency. In all cases, concentrations of acylcarnitines were greatly increased above normal with free carnitine concentrations ranging from undetectable to supranormal values. The ratios of acylcarnitine/carnitine were elevated above the normal value of 2.0 +/- 1.1. l-Carnitine was given to three of these patients; in each case, concentrations of plasma and urine carnitines increased accompanied by a marked increase in concentrations of short-chain acylcarnitines. These acylcarnitines have been examined using fast atom bombardment mass spectrometry in some of these diseases and have been shown to be propionylcarnitine in methylmalonic aciduria and propionic acidemia, isovalerylcarnitine in isovaleric acidemia, and hexanoylcarnitine and octanoylcarnitine in medium-chain acyl-CoA dehydrogenase deficiency. The excretion of these acylcarnitines is compatible with the known accumulation of the corresponding acyl-CoA esters in these diseases. In this group of disorders, the increased acylcarnitine/carnitine ratio in urine and plasma indicates an imbalance of mitochondrial mass action homeostasis and, hence, of acyl-CoA/CoA ratios. Despite naturally occurring attempts to increase endogeneous l-carnitine biosynthesis, there is insufficient carnitine available to restore the mass action ratio as demonstrated by the further increase in acylcarnitine excretion when patients were given oral l-carnitine.(ABSTRACT TRUNCATED AT 250 WORDS)     

An oral (gavage) control embryo-fetal development study in the Wistar Hannover rat

Many of the studies conducted to examine the developmental and reproductive toxicity potential of candidate pharmaceuticals use the Sprague-Dawley rat as the animal model. This is due in part to the large database for this outbred rat available for comparison of litter data, and the low incidence of fetal malformations and variations. The following study was conducted to generate information on potential embryo-fetal developmental defects and litter data in another outbred stock of rat, the Wistar Hannover. One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WIfBR) were dosed orally once per day with distilled water from Gestation Days (GD) 6 through 17 covering the time from implantation to closure of the hard palate (GD0 = day of insemination). Caesarean sections were performed on Day 20 of gestation. All fetuses were examined for external, visceral and skeletal malformations and variations. Macroscopic and histomorphologic examinations were also completed for the F0 females at termination. The percent pregnant (88%) and litter size (average 10.6) were found to be lower than that commonly reported for the Sprague-Dawley rat (Crl:CD (SD)BR; 95.4% and 14.6, respectively). Pre-implantation loss (14.1%), post-implantation loss (7.4%) and percent resorptions (7.2%) occurred at a higher incidence than typically seen in the Sprague-Dawley rat (5.9, 5.6 and 5.1%, respectively). The average fetal body weights for both the female and male rats were lower than those typically seen in the Sprague-Dawley rat. External, visceral and skeletal examination of the F1 fetuses revealed numerous malformations and variations which also occurred at higher incidences than those reported for the Sprague-Dawley rat. Routine macroscopic and histomorphologic examination showed there were no changes that would be interpreted to have impaired mating performance, fertility or gestation. Thus, this study provides information on the reproductive effects and the background incidence of embryo-fetal development defects that could be used for comparison to those identified when using this outbred rat for developmental and reproductive toxicity studies, as well as for comparison to the more commonly used rat stock, the Sprague-Dawley rat. For the parameters evaluated, the Wistar Hannover rat had greater variability and an increased incidence of spontaneous malformations as compared to the Crl:CD (SD)BR Sprague-Dawley rat. These findings should be considered if this stock of rat is selected in the conduct of developmental and reproductive toxicity studies.     

Effects of food ration on survival and sublethal responses of lake chubsuckers (Erimyzon sucetta) exposed to coal combustion wastes

Study organisms in chronic toxicological bioassays are often provided with excessive resources to remove food limitations as a confounding experimental variable. Under more ecologically realistic situations, resources are often less abundant and such restrictions may alter the responses of organisms to environmental contaminants. Here, we investigated the interaction between resource level and sediment toxicity in the lake chubsucker, Erimyzon sucetta. For 78 days we fed fish one of three ration levels (1X, 2X, 4X; uncontaminated food) that was grazed directly from either clean sand or coal ash-contaminated sediments. Despite provision of uncontaminated food, fish exposed to the contaminated sediments accumulated significant whole body concentrations of As, Se, Sr, and V. Food ration affected the pattern of Se accumulation, with lowest concentrations accumulated by fish supplied with the lowest rations (1X). Paradoxically, fish in the 1X-ash treatment were most adversely effected by ash-exposure, despite having Se burdens much lower than fish in the 2X- and 4X-ash treatments. Fish in the 1X-ash treatment exhibited higher mortality, lower proportional growth, and increased incidence of fin erosion compared to fish provided with higher rations. Such results may, in part, be explained by the apparent inability of fish with reduced rations to maintain positive energy balance, as evidenced by their higher standard metabolic rates compared to control fish fed similar rations. Our results underscore the importance of considering resource quantity and nutritional factors in chronic bioassays in order to draw more ecologically realistic conclusions about contaminant effects.     

Comparative efficacy of Adderall and methylphenidate in attention-deficit/hyperactivity disorder: a meta-analysis

Because methylphenidate is currently the most widely prescribed medication for attention-deficit/ hyperactivity disorder, several studies have used it as the active comparator medication for evaluating the efficacy of a newer stimulant, Adderall. These prior studies show Adderall to be superior to placebo and suggest it is at least as effective as the standard-release form of methylphenidate and has a longer duration of action. Although these initial studies provide useful information for clinicians treating children with attention-deficit/hyperactivity disorder, they are difficult to interpret because findings vary among studies and among the different types of measures used within each study. To provide a clearer picture of what conclusions can be drawn from these studies, we performed a meta-analysis. Data from the four available studies suggest that Adderall has a small but statistically significant advantage over the standard-release form of methylphenidate. This advantage was observed for both symptom measures and global ratings but was strongest for global ratings. The effect of Adderall was significant for clinician and parent ratings but not for teacher ratings and was significant for both fixed-dose and best-dose designs.     

Portion size of food affects energy intake in normal-weight and overweight men and women

BACKGROUND: Large portions of food may contribute to excess energy intake and greater obesity. However, data on the effects of portion size on food intake in adults are limited. OBJECTIVES: We examined the effect of portion size on intake during a single meal. We also investigated whether the response to portion size depended on which person, the subject or the experimenter, determined the amount of food on the plate. DESIGN: Fifty-one men and women were served lunch 1 d/wk for 4 wk. Lunch included an entrée of macaroni and cheese consumed ad libitum. At each meal, subjects were presented with 1 of 4 portions of the entrée: 500, 625, 750, or 1000 g. One group of subjects received the portion on a plate, and a second group received it in a serving dish and took the amount they desired on their plates. RESULTS: Portion size significantly influenced energy intake at lunch (P < 0.0001). Subjects consumed 30% more energy (676 kJ) when offered the largest portion than when offered the smallest portion. The response to the variations in portion size was not influenced by who determined the amount of food on the plate or by subject characteristics such as sex, body mass index, or scores for dietary restraint or disinhibition. CONCLUSIONS: Larger portions led to greater energy intake regardless of serving method and subject characteristics. Portion size is a modifiable determinant of energy intake that should be addressed in connection with the prevention and treatment of obesity.