Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2mg/kg single i.p dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis was similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters was unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response.

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Cytochrome P4501A1 (CYP1A1), an important drug metabolizing enzyme, is expressed in human placenta throughout gestation as well as in fetal liver. Obesity, a chronic inflammatory condition, is known to alter CYP enzyme expression in non-placental tissues. In the present study, we test the hypothesis that maternal obesity alters the distribution of CYP1A1 activity in feto-placental unit. Placentas were collected from non-obese (BMI<30) and obese (BMI>30) women at term. Livers were collected from gestation day 130 fetuses of non-human primates fed either control diet or high-fat diet (HFD). Cytosol and microsomes were collected using differential centrifugation, and incubated with 7-Ethoxyresorufin. The CYP1A1 specific activity (pmoles of resorufin formed/min/mg of protein) was measured at excitation/emission wavelength of 530/590nm. Placentas of obese women had significantly reduced microsomal CYP1A1 activity compared to non-obese women (0.046 vs. 0.082; p<0.05); however no such effect was observed on cytosolic activity. Similarly, fetal liver from HFD fed mothers had significantly reduced microsomal CYP1A1 activity (0.44±0.04 vs. 0.20±0.10; p<0.05), with no significant difference in cytosolic CYP1A1 activity (control, 1.23±0.20; HFD, 0.80±0.40). Interestingly, multiple linear regression analyses of placental efficiency indicates cytosolic CYP1A1 activity is a main effect (5.67±2.32 (β±SEM); p=0.022) along with BMI (−0.57±0.26; p=0.037), fetal gender (1.07±0.26; p<0.001), and maternal age (0.07±0.03; p=0.011). In summary, while maternal obesity affects microsomal CYP1A1 activity alone, cytosolic activity along with maternal BMI is an important determinant of placental efficiency. Together, these data suggest that maternal lifestyle could have a significant impact on CYP1A1 activity, and hints at a possible role for CYP1A1 in feto-placental growth and thereby well-being of fetus.

Oral contraceptives have been in wide use for more than 50 years. Levonorgestrel, a commonly employed progestin component of combined oral contraceptives, was implicated in drug-drug interactions mediated via CYP2C9. Although in vitro studies refuted this interaction, there are no confirmatory in vivo studies. In the current study, we examined the phenotypic status of CYP2C9 using low-dose (125 mg) tolbutamide before and after oral contraceptive use in reproductive age women. Blood was collected 24 hours after the tolbutamide oral dose was administered, plasma was isolated, and tolbutamide concentration (C 24 ) was measured using liquid chromatography-mass spectrometry. The natural logarithm of tolbutamide C 24 , a metric for CYP2C9 phenotype, was found to be equivalent (within 80%-125% equivalency boundaries) before and after oral contraceptive use. In conclusion, levonorgestrel-containing oral contraceptives, the most commonly used form of oral contraception, do not affect the status of the CYP2C9 enzyme. This suggests that it is safe to coadminister levonorgestrel-containing oral contraceptives and CYP2C9 substrates, which include a wide array of drugs.

Adult individuals born with intrauterine growth restriction (IUGR) have physiological maladaptations that significantly increase risk of chronic disease. We suggested that such abnormalities in organ function would alter pharmacokinetics throughout life, exacerbated by environmental mismatch. Pregnant and lactating rats were fed either a purified control diet (18% protein) or low-protein diet (9% protein) to produce IUGR offspring. Offspring were weaned onto either laboratory chow (11% fat) or highfat diet (45% fat). Adult offspring (5 months old) were dosed with furosemide (10 mg/kg i.p.) and serum and urine collected. The overall exposure profile in IUGR males was significantly reduced due to a~35% increase in both clearance and volume of distribution. Females appeared resistant to the IUGR phenotype. The effects of the high-fat diet trended in the opposite direction to that of IUGR, with increased drug exposure due to decreases in both clearance (31% males, 46% females) and volume of distribution (24% males, 44% females), with a 10% longer half-life in both genders. The alterations in furosemide pharmacokinetics and pharmacodynamics were explained by changes in the expression of renal organic anion transporters 1 and 3, and sodiumpotassium-chloride cotransporter-2. In summary, this study suggests that IUGR and diet interact to produce subpopulations with similar body-weights but dissimilar pharmacokinetic profiles; this underlines the limitation of one-size-fits-all dosing which does not account for physiological differences in body composition resulting from IUGR and diet.An adverse intrauterine environment -one where nutrient flow to the developing foetus is suppressed -produces suboptimal growth and development of foetal organ systems, now called 'intrauterine growth restriction' (IUGR) [1]. Robust evidence in human and animal models demonstrates a link between IUGR and increased risk of cardiovascular disease and the metabolic syndrome [2]; thus, this predisposition for chronic disease increases the likelihood that IUGR individuals will need to be treated with pharmaceutical agents over their life-time. However, it is not clear whether one-size-fits-all dosing will be sufficient to optimize pharmacotherapy in this population.The IUGR phenotype in human beings and animals is consistently associated with decreased (30%) numbers of nephrons and cardiomyocytes, leading to elevated risks of renal and cardiac dysfunction. These deficits also contribute to an increased risk of hypertension and many forms of cardiovascular disease [3][4][5][6]. In our model of IUGR, pregnant rats were fed a low-protein diet during gestation and lactation resulting in offspring with low birthweight and stunted postnatal growth [7][8][9][10]. The IUGR offspring had a reduced urinary excretion of the loop diuretic, furosemide, compared to rats that had a normal birthweight [11]. These experiments led to the studies reported here.The primary objective of the current study was to examine whether pharmacokinetic factors are a...

Category: Other; Ankle; Midfoot/Forefoot Introduction/Purpose: Closure of high-tension surgical wounds is a challenge frequently encountered during surgical procedures. The use of a novel adhesive augmentation device, HEMIGARD, has been proposed to decrease tension on wound closure and thereby increase the amount of force needed for suture pullout. In principle, this may help prevent wound dehiscence, skin edge necrosis and the sequelae thereof. We hypothesized that HEMIGARD augmentation of suture placement would require more force for suture pullout from human cadaveric lower extremity skin when compared to suture alone. Methods: In this study, HEMIGARD with suture was compared to suture alone on leg and foot measurements from four cadavers. One side of the incision was used to test the HEMIGARD according to the manufacturer's instructions. The other side of the same incision was used to test the same suture material, passed without HEMIGARD, to allow for direct comparison. A force gauge was used to measure the Newtons of force required for suture pullout. A total of 30 measurements were recorded per cadaver; 15 using HEMIGARD and 15 using suture alone. Results: No difference was observed between HEMIGARD and suture alone in the amount of force required for suture pullout. When excluding instances of HEMIGARD adhesive failure, which occurred in 67% of measurements, the HEMIGARD was found to be superior to suture alone in the cadaveric foot, but not in the leg. Conclusion: The amount of force required for suture pullout from human cadaveric lower extremity skin did not significantly differ when using HEMIGARD augmentation of suture placement versus using suture alone. However, when excluding instances of HEMIGARD adhesive failure, the HEMIGARD may be superior to suture alone in the cadaveric foot, but not in the cadaveric leg.

Dear Editor,With great enthusiasm we read a report of long-term programming of cytochrome P450 enzyme activities into adulthood as a result of early life insult (Sohi et al., 2013). It is likely that birth weight, a surrogate for early life environment, coupled with postnatal growth could explain part of the variability in CYP enzyme activities. Greater understanding of interindividual variability in CYP activities would further enable optimization of pharmacotherapies. Although the article covered a comprehensive analysis of select CYP enzymes, we were surprised at the statement that there are no prior studies evaluating the effects of low birth weight in preclinical species or humans. We would like to bring to the authors' attention published studies that have evaluated the programming effects of maternal low-protein diet on adulthood CYP enzyme status.First, Cherala et al. (2007) examined the effects of two different compositions of low-protein diets administered to pregnant and lactating rat dams on the activities of the five most relevant hepatic CYP isozymes and CYP reductase in adult offspring. The findings of the study by Sohi et al. corroborate the V max data reported by Cherala et al. and further characterize intrinsic clearance. Interestingly, Sohi et al. speculate that the elevated intrinsic clearance could translate into higher clearance of drugs metabolized by the select CYP isozymes examined in this study. However, Cherala et al. (2007) showed that the rate of metabolism of hexobarbital, a drug predominantly metabolized by CYP2C11 and CYP2C12 in male and female rats, respectively, is unaltered in rat offspring. Second, in a recent report, in vivo clearance of midazolam (a CYP3A marker) was lower in both extremes of birth weight, although only women were examined .Together, these studies suggest that the in vitro intrinsic clearance data do not correlate with in vivo clearance. As Sohi et al. point out in their discussion, other pharmacokinetic processes such as protein binding and transporters might be confounding in vitro-in vivo correlation. Preliminary data from our research group are supportive of confounding factors (Dubois et al., 2013). We could not agree more with the authors that there is a need for prospective studies to elucidate the effects of perinatal environment on pharmacokinetics during adulthood. Authorship ContributionsWrote or contributed to the writing of the manuscript: Cherala, Pearson, Dubois, Mahmood. Department of Pharmacy