VOC and trace gas measurements and ozone chemistry over the Chesapeake Bay during OWLETS-2, 2018.

The Ozone Water-Land Environmental Transition Study, 2018 (OWLETS-2) measured total non-methane hydrocarbons (TNMHC) and EPA PAMS Volatile Organic Compounds (VOCs) on an island site in the northern Chesapeake Bay 2.1 and 3.4 times greater in concentration, respectively, than simultaneous measurements at a land site just 13 km away across the land-water interface. Many PAMS VOCs had larger concentrations at the island site despite lower NEI emissions over the water, but most of the difference comprised species generally consistent with gasoline vapor or exhaust. Sharp chemical differences were observed between the island and mainland and the immediate air ~300 m above the water surface observed by airplane. Ozone formation potential over land was driven by propene and isoprene but toluene and hexane were dominant over the water with little isoprene observed. VOC concentrations over the water were noted to increase diurnally with an inverse pattern to land resulting in increasing NOx sensitivity over the water. Total reactive nitrogen was lower over the water than the nearby land site, but reservoir compounds (NOz) were greater. Ozone production rates were generally slow (~5 ppb hr-1) both at the surface and aloft over the water, even during periods of high ozone (>70 ppbv) at the water surface. However, specific events showed rapid ozone production >40 ppb hr-1 at the water's surface during situations with high VOCs and sufficient NOx. VOC and photochemistry patterns at the island site were driven by marine sources south of the island, implicating marine traffic, and indicate ozone abatement strategies over land may not be similarly applicable to ozone over the water.Implications: Measured chemical properties and patterns driven primarily by marine traffic sources over water during ozone conducive conditions were starkly different to immediately adjacent land sites, implying ozone abatement strategies over land may not be similarly applicable to ozone over the water.

Pharmacokinetics of Anakinra in Subjects of Heavier vs. Lighter Body Weights.

This trial (20010168) studied how body weight (BW) and body mass index (BMI) influenced the pharmacokinetics (PK) of anakinra. Subjects (n = 32) were assigned to four groups (n = 8) according to BW and BMI. Randomization was according to a four-treatment, four-period, four-sequence crossover design. The four anakinra injections were 100, 150, and 300 mg s.c. and 100 mg i.v. Plasma samples were measured by enzyme-linked immunosorbent assay and noncompartmental PK parameters estimated. BW demonstrated the following effects: after i.v. administration, significant effects (P < 0.05) were observed for exposure (area under the concentration-time curve from zero to infinity (AUC0-∞ )), peak plasma concentration (Cmax ), volume of distribution at steady state, and clearance; whereas after s.c. administration, significant effects (P < 0.05) were observed for Cmax , AUC0-∞ , terminal half-life, and estimated apparent clearance. Mean AUC was reduced 24% and 33% for heavier (BW ≥ 100 kg) vs. lighter subjects (BW ≤ 90 kg) after i.v. and s.c. administration, respectively. BMI increased clearance for heavier subjects. For example, mean (SD) plasma clearance of i.v. anakinra increased from 1.17 ± 0.29 to 1.62 ± 0.24 mL/minute/kg (P < 0.05) for larger (> 100 kg) obese (BMI > 36) vs. larger (> 100 kg) less obese (BMI < 35) subjects, respectively. Similarly, results following s.c. supported those after i.v. administration. Derived half-lives increased with higher BW and higher BMI ranging from 3.63 hour for less obese, lighter-weight subjects to 7.62 hour for obese, heavier-weight subjects. Absolute bioavailability ranged from 80-92% and was unrelated to BW or BMI. Anakinra exposure is statistically significantly related to BW and to a lesser extent BMI.

An integrated analysis of safety and tolerability of etelcalcetide in patients receiving hemodialysis with secondary hyperparathyroidism.

BACKGROUND: Calcimimetics have been shown to be effective and safe therapies for the treatment of secondary hyperparathyroidism (sHPT), a serious complication of disordered mineral metabolism associated with dialysis-dependent chronic kidney disease. Etelcalcetide, a recently approved intravenous calcimimetic, reduces serum parathyroid hormone (PTH), calcium, phosphorus, and fibroblast growth factor-23 concentrations. Here we report the first integrated safety profile of etelcalcetide using pooled data from five pivotal clinical trials. METHODS: This analysis included data from patients receiving hemodialysis with moderate to severe sHPT enrolled in two randomized, placebo-controlled trials; a randomized active-controlled (with cinacalcet) trial; and two single-arm, open-label extension trials. Patients initially received etelcalcetide intravenously 5 mg three times weekly (TIW) after hemodialysis; with potential dose increases of 2.5 or 5 mg at 4-week intervals to a maximum dose of 15 mg TIW, depending on serum PTH and calcium levels. The nature, frequency, and severity of treatment-emergent adverse events (AEs) and changes in laboratory parameters were assessed. RESULTS: Overall, we evaluated 1023 patients from the placebo-controlled trials, 683 from the active-controlled trial, and 1299 from open-label extensions. The frequency and nature of common treatment-emergent AEs reported for the etelcalcetide arm were consistent among the placebo-controlled and active-controlled trials. The most common AEs were those related to mineral metabolism (decreased blood calcium, hypophosphatemia, muscle spasms) or gastrointestinal abnormalities (diarrhea, nausea, vomiting). Hypocalcemia leading to discontinuation of either calcimimetic was experienced in ≤ 1% of patients. CONCLUSIONS: This integrated safety assessment of etelcalcetide across placebo- and active-controlled trials showed an overall favorable risk/benefit profile, with safety similar to that of cinacalcet. Consistent with its mechanism of action, the most important risks associated with etelcalcetide were serum calcium reductions and hypocalcemia-related AEs; no new safety findings were identified in the pooled long-term extension trials.

Pathogen-associated molecular patterns activate expression of genes involved in cell proliferation, immunity and detoxification in the amebocyte-producing organ of the snail Biomphalaria glabrata.

The anterior pericardial wall of the snail Biomphalaria glabrata has been identified as a site of hemocyte production, hence has been named the amebocyte-producing organ (APO). A number of studies have shown that exogenous abiotic and biotic substances, including pathogen associated molecular patterns (PAMPs), are able to stimulate APO mitotic activity and/or enlarge its size, implying a role for the APO in innate immunity. The molecular mechanisms underlying such responses have not yet been explored, in part due to the difficulty in obtaining sufficient APO tissue for gene expression studies. By using a modified RNA extraction technique and microarray technology, we investigated transcriptomic responses of APOs dissected from snails at 24 h post-injection with two bacterial PAMPs, lipopolysaccharide (LPS) and peptidoglycan (PGN), or with fucoidan (FCN), which may mimic fucosyl-rich glycan PAMPs on sporocysts of Schistosoma mansoni. Based upon the number of genes differentially expressed, LPS exhibited the strongest activity, relative to saline-injected controls. A concurrent activation of genes involved in cell proliferation, immune response and detoxification metabolism was observed. A gene encoding checkpoint 1 kinase, a key regulator of mitosis, was highly expressed after stimulation by LPS. Also, seven different aminoacyl-tRNA synthetases that play an essential role in protein synthesis were found to be highly expressed. In addition to stimulating genes involved in cell proliferation, the injected substances, especially LPS, also induced expression of a number of immune-related genes including arginase, peptidoglycan recognition protein short form, tumor necrosis factor receptor, ficolin, calmodulin, bacterial permeability increasing proteins and E3 ubiquitin-protein ligase. Importantly, significant up-regulation was observed in four GiMAP (GTPase of immunity-associated protein) genes, a result which provides the first evidence suggesting an immune role of GiMAP in protostome animals. Moreover, altered expression of genes encoding cytochrome P450, glutathione-S-transferase, multiple drug resistance protein as well as a large number of genes encoding enzymes associated with degradation and detoxification metabolism was elicited in response to the injected substances.

Altered Gene Expression in the Schistosome-Transmitting Snail Biomphalaria glabrata following Exposure to Niclosamide, the Active Ingredient in the Widely Used Molluscicide Bayluscide.

In view of the call by the World Health Organization (WHO) for elimination of schistosomiasis as a public health problem by 2025, use of molluscicides in snail control to supplement chemotherapy-based control efforts is likely to increase in the coming years. The mechanisms of action of niclosamide, the active ingredient in the most widely used molluscicides, remain largely unknown. A better understanding of its toxicology at the molecular level will both improve our knowledge of snail biology and may offer valuable insights into the development of better chemical control methods for snails. We used a recently developed Biomphalaria glabrata oligonucleotide microarray (31K features) to investigate the effect of sublethal exposure to niclosamide on the transcriptional responses of the snail B. glabrata relative to untreated snails. Most of the genes highly upregulated following exposure of snails to niclosamide are involved in biotransformation of xenobiotics, including genes encoding cytochrome P450s (CYP), glutathione S-transferases (GST), and drug transporters, notably multi-drug resistance protein (efflux transporter) and solute linked carrier (influx transporter). Niclosamide also induced stress responses. Specifically, six heat shock protein (HSP) genes from three super-families (HSP20, HSP40 and HSP70) were upregulated. Genes encoding ADP-ribosylation factor (ARF), cAMP response element-binding protein (CREB) and coatomer, all of which are involved in vesicle trafficking in the Golgi of mammalian cells, were also upregulated. Lastly, a hemoglobin gene was downregulated, suggesting niclosamide may affect oxygen transport. Our results show that snails mount substantial responses to sublethal concentrations of niclosamide, at least some of which appear to be protective. The topic of how niclosamide's lethality at higher concentrations is determined requires further study. Given that niclosamide has also been used as an anthelmintic drug for decades and has been found to have activity against several types of cancer, our findings may be of relevance in understanding how both parasites and neoplastic cells respond to this compound.

Fucoidan stimulates cell division in the amebocyte-producing organ of the schistosome-transmitting snail Biomphalaria glabrata.

Adult Salvador (schistosome-resistant) strain Biomphalaria glabrata snails were injected with 5 µl of 10 mg/ml solutions of the sulfated polysaccharides λ carageenan, dextran sulfate, fucoidan, and heparin, the nonsulfated polysaccharide laminarin, and the monosaccharides L-fucose and L-galactose, and mitotic activity in the amebocyte-producing organ (APO) was measured in histological sections at 24 h post injection. Among the substances tested, only fucoidan induced elevated mitotic activity. Desulfated fucoidan was not mitogenic, indicating that sulfate groups are required for activity. Schistosome-susceptible M-line snails possessed minimal or no hematopoietic tissue in their APO, which did not respond to fucoidan. Immersion of juvenile Salvador snails in 1 or 10 mg/ml solutions of fucoidan for 3 h did not elevate mitotic activity at 24 h post immersion, suggesting that the external and digestive tract epithelia of B. glabrata are impermeable to this molecule. These results provide support for the hypothesis that fucosylated glycans on the tegument and in excretory-secretory products of sporocysts of Schistosoma mansoni are in part responsible for increased mitotic activity in the APO of B. glabrata infected with this trematode or injected with its extracts.

Lipochitin oligosaccharides immobilized through oximes in glycan microarrays bind LysM proteins.

Glycan microarrays have emerged as novel tools to study carbohydrate-protein interactions. Here we describe the preparation of a covalent microarray with lipochitin oligosaccharides and its use in studying proteins containing LysM domains. The glycan microarray was assembled from glycoconjugates that were synthesized by using recently developed bifunctional chemoselective aminooxy reagents without the need for transient carbohydrate protecting groups. We describe for the first time the preparation of a covalent microarray with lipochitin oligosaccharides and its use for studying proteins containing LysM domains. Lipochitin oligosaccharides (also referred to as Nod factors) were isolated from bacterial strains or chemoenzymatically synthesized. The glycan microarray also included peptidoglycan-related compounds, as well as chitin oligosaccharides of different lengths. In total, 30 ligands were treated with the aminooxy linker molecule. The identity of the glycoconjugates was verified by mass spectrometry, and they were then immobilized on the array. The presence of the glycoconjugates on the array surface was confirmed by use of lectins and human sera (IgG binding). The functionality of our array was tested with a bacterial LysM domain-containing protein, autolysin p60, which is known to act on the bacterial cell wall peptidoglycan. P60 showed specific binding to Nod factors and to chitin oligosaccharides. Increasing affinity was observed with increasing chitin oligomer length.

Legume receptors perceive the rhizobial lipochitin oligosaccharide signal molecules by direct binding.

Lipochitin oligosaccharides called Nod factors function as primary rhizobial signal molecules triggering legumes to develop new plant organs: root nodules that host the bacteria as nitrogen-fixing bacteroids. Here, we show that the Lotus japonicus Nod factor receptor 5 (NFR5) and Nod factor receptor 1 (NFR1) bind Nod factor directly at high-affinity binding sites. Both receptor proteins were posttranslationally processed when expressed as fusion proteins and extracted from purified membrane fractions of Nicotiana benthamiana or Arabidopsis thaliana. The N-terminal signal peptides were cleaved, and NFR1 protein retained its in vitro kinase activity. Processing of NFR5 protein was characterized by determining the N-glycosylation patterns of the ectodomain. Two different glycan structures with identical composition, Man(3)XylFucGlcNAc(4), were identified by mass spectrometry and located at amino acid positions N68 and N198. Receptor-ligand interaction was measured by using ligands that were labeled or immobilized by application of chemoselective chemistry at the anomeric center. High-affinity ligand binding was demonstrated with both solid-phase and free solution techniques. The K(d) values obtained for Nod factor binding were in the nanomolar range and comparable to the concentration range sufficient for biological activity. Structure-dependent ligand specificity was shown by using chitin oligosaccharides. Taken together, our results suggest that ligand recognition through direct ligand binding is a key step in the receptor-mediated activation mechanism leading to root nodule development in legumes.

Effect of crude lipopolysaccharide from Escherichia coli O127:B8 on the amebocyte-producing organ of Biomphalaria glabrata (Mollusca).

Lipopolysaccharide (LPS) is a pathogen associated molecular pattern (PAMP) to which the internal defense system (IDS) of both vertebrates and invertebrates responds. We measured the mitotic response of the hematopoietic tissue of the schistosome-transmitting snail, Biomphalaria glabrata, to crude LPS from Escherichia coli 0127:B8. In a dose-response study, snails were injected with a range of concentrations of crude LPS, and mitotic figures were enumerated in histological sections of amebocyte-producing organ (APO) fixed at 24h post-injection (PI) following a 6h treatment with 0.1% colchicine. In APOs from Salvador strain snails, which are genetically resistant to infection with Schistosoma mansoni, LPS concentrations of 0.01 mg/ml and above triggered a large increase in mitotic activity, whereas in APOs from schistosome-susceptible NIH albino snails, concentrations of 0.1mg/ml elicited a much smaller, but statistically significant increase. A time course study, without colchicine treatment, revealed that in Salvador APOs the mitotic response to 0.1mg/ml occurred by 18 h PI, peaked at 24h, and returned to control levels by 72 h; NIH albino APOs showed no detectible response. When Salvador APOs were exposed to crude LPS in vitro, no increase in mitotic activity occurred, a result suggesting the possible requirement for a peripheral tissue or hemolymph factor. The increased cell proliferation induced by crude LPS represents a novel systemic response of an invertebrate IDS to one or more PAMPs from a Gram-negative bacterium.

A retrospective study of positive antibody screens at delivery in Rh-negative parturients.

PURPOSE: Rhesus- (Rh-) negative women receiving anti-D antibodies antenatally often have a positive antibody screen at delivery. We investigated the incidence of positive antibody screens at delivery in this population and examined how the presence of positive antibody screens affected the time required to obtain type and screen or type and crossmatch results. METHODS: Records of parturients who had type and screen or type and crossmatch done upon presentation for delivery from June to October 2007 were examined to determine estimated gestational age at admission, Rh-status, the presence of positive antibody screens, and the time interval from receipt of specimen in the blood bank to the availability of antibody screen results. RESULTS: Of the 480 specimens sent for type and screen or type and crossmatch, 20% of parturients were Rh-negative, with 57% of those demonstrating a positive antibody screen compared with 4% of the Rh-positive parturients (P < 0.01). In the Rh-negative group, 100% (95% CI 98-102) of positive antibody screens were anti-D antibodies. There was a longer median laboratory time for Rh-negative vs Rh-positive parturients (146 vs 65 min), for antibody positive vs antibody negative parturients (243 vs 65 min) (P < 0.001 for both), but not for Rh-positive/antibody positive vs Rh-negative/antibody positive patients (312 vs 218 min) (P = 0.09). The antibody screen was positive in 100% of Rh-negative parturients until 37 weeks gestation, after which there was a decline. CONCLUSIONS: Rh-negative parturients who receive anti-D antibodies antenatally have a higher incidence of positive antibody screens at delivery than Rh-positive parturients due to the presence of anti-D antibodies.

Involvement of protein kinase C signalling and mitogen-activated protein kinase in the amebocyte-producing organ of Biomphalaria glabrata (Mollusca).

Mechanisms that regulate hemocyte production in molluscs, at either the organismal or cellular levels, are not well understood. In the present study, 24-h saline cultures of the amebocyte-producing organ (APO) of the schistosome-transmitting snail Biomphalaria glabrata were used to test for the potential involvement of protein kinase C (PKC) signalling in hematopoiesis. Exposure to phorbol myristate acetate (PMA), an activator of PKC, resulted in an increase in the number of dividing hematopoietic cells in APOs from schistosome-resistant Salvador snails. PMA-induced cell division was blocked by treatment with U0126, an inhibitor of the mitogen-activated protein kinase kinase, MEK1/2. These results suggest that PKC-induced activation of the mitogen-activated protein kinase, ERK1/2, is involved in cell division in the APO.

In vitro mitotic responses of the amebocyte-producing organ of Biomphalaria glabrata to extracts of Schistosoma mansoni.

Amebocyte-producing organs (APOs) of Biomphalaria glabrata were maintained in nonnutritive saline with, or without, extracts of miracidia and adults of Schistosoma mansoni, and examined histologically. The hematopoietic cells remained viable and showed measurable mitotic activity for up to 6 days, with little evidence of tissue death. APOs accumulated fluid and became swollen by as soon as 24 hr, but no cell exomigration was observed. Parasite extracts elicited an increase in the number of dividing cells in the APO, suggesting that the extract may directly stimulate a response from the hematopoietic cells by providing either nutrients or mitogenic growth factors.

Postoperative hypoxemia in morbidly obese patients with and without obstructive sleep apnea undergoing laparoscopic bariatric surgery.

INTRODUCTION: The increased incidence of morbid obesity has resulted in an increase of bariatric surgical procedures. Obstructive sleep apnea (OSA) is a commonly encountered comorbidity in morbidly obese patients. Sedatives, analgesics, and anesthetics alter airway tone, and airway obstruction and death have been reported in patients with OSA after minimal doses of sedatives and anesthetics, yet there is a lack of consensus regarding the care of these patients. In this study, we sought to determine whether obese patients with polysomnography-confirmed diagnosis of OSA were at significantly greater risk for postoperative hypoxemic episodes in the first 24 h after laparoscopic bariatric surgery than morbidly obese patients without a diagnosis of OSA. METHODS: Adult subjects (Body Mass Index, 35-75 kg/m(2)) scheduled to undergo laparoscopic bariatric surgery were studied. A finger pulse oximetry probe was placed preoperatively and oxygen saturation (Spo(2)) was recorded continuously. All subjects underwent preoperative polysomnography testing within 4 wk of surgery. Anesthetic management was standardized, using propofol for induction and desflurane and remifentanil for maintenance of anesthesia. Patient-controlled analgesia programmed to deliver morphine, 1 mg. every 10 minutes, was used for pain management postoperatively. Hypoxemic episodes were scored as Spo(2) >4% below the polysomnography study baseline and lasting for more than 10 s. RESULTS: Eight men and 32 women were enrolled and 1 subject had incomplete data. Thirty-one of the 40 subjects had polysomnography-confirmed OSA. Eight subjects used home continuous positive airway pressure devices nightly, and six of these used their device postoperatively. Preoperatively, subjects with OSA had lower nadir Spo(2) during the polysomnography study and a larger number had an apnea/hypopnea index >10 episodes per hour compared with the non-OSA group. In the first 24 h postoperatively, there was no difference in the median Spo(2) with and without oxygen therapy, between OSA and non-OSA groups. The number of episodes of oxygen desaturation >4% below the polysomnography study baseline value and the mean number of desaturation episodes per hour did not differ between the groups. CONCLUSIONS: In morbidly obese subjects, in the first 24 h after laparoscopic bariatric surgery, OSA does not seem to increase the risk of postoperative hypoxemia. Our data confirm that morbidly obese subjects, with or without OSA, experience frequent oxygen desaturation episodes postoperatively, despite supplemental oxygen therapy suggesting that perioperative management strategies in morbidly obese patients undergoing laparoscopic bariatric surgery should include measures to prevent postoperative hypoxemia.

Cinacalcet does not affect the pharmacokinetics or pharmacodynamics of warfarin.

BACKGROUND AND OBJECTIVE: Cinacalcet HCl (cinacalcet), approved for secondary hyperparathyroidism and parathyroid carcinoma-associated hypercalcaemia, may be coadministered with warfarin. The purpose of this study was to determine the pharmacokinetics/pharmacodynamics and tolerability of warfarin during cinacalcet coadministration. SUBJECTS AND METHODS: In this phase 1, randomised, double-blind, placebo-controlled, two-treatment, two-period crossover study, 21 healthy subjects received oral cinacalcet (30 mg) or placebo twice a day for 7 days and once on day 8, with a single warfarin dose (25mg) on day 5. After a 3-week washout, subjects received the alternative treatment. Samples for warfarin pharmacokinetics/pharmacodynamics were obtained until 144 hours post-dose. RESULTS: Single-dose administration of warfarin to subjects receiving cinacalcet did not demonstrate altered pharmacodynamics of either the R- or S-enantiomer. Geometric means ratio (90% CIs) for R- and S-warfarin were 1.01 (0.95, 1.07) and 1.00 (0.94, 1.04), respectively, for the area under the plasma concentration-time curve from time 0 to infinity (AUC(infinity)) and 0.90 (0.84, 0.96) and 0.88 (0.83, 0.94), respectively, for observed maximum plasma concentrations (C(max)). Additionally, the pharmacokinetic profiles of R- or S-warfarin were similar for all subjects. The ratio for the AUC from time 0 to the last measurable concentration (AUC(t)) for prothrombin time and factor VII were 1.03 (1.01, 1.04) and 0.97 (0.93, 1.01), respectively. The maximum rise (R(max)) and maximum change (Delta(max)) were 1.04 (1.02, 1.05) and 1.00 (0.96, 1.03), respectively. All treatment-emergent and treatment-related adverse events were mild to moderate in severity. There were no obvious differences in adverse events according to treatment. CONCLUSION: Warfarin pharmacokinetics/pharmacodynamics were not affected in subjects treated with warfarin 25mg who received cinacalcet 30 mg twice daily, thus suggesting that dose adjustment is not required.

Population pharmacokinetics of darbepoetin alfa in healthy subjects.

AIM: To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. METHODS: PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 microg kg(-1), or either 80 or 500 microg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. RESULTS: The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose-exposure relationship at the 8.0 microg kg(-1)-dose relative to the 0.75 microg kg(-1)-dose may reflect changing relative bioavailability, which increased from approximately 48% at 0.75 microg kg(-1) to 78% at 8.0 microg kg(-1). The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. CONCLUSION: The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.

Sublethal effects of ultraviolet b radiation on miracidia and sporocysts of Schistosoma mansoni: intramolluscan development, infectivity, and photoreactivation.

Schistosoma mansoni occurs in tropical regions where levels of ultraviolet B (UVB; 290-320 nm) light are elevated. However, the effects of UVB on parasite transmission are unknown. This study examines effects of UVB on the miracidia and sporocysts of S. mansoni, focusing specifically on intramolluscan development, infectivity, and the ability to photoreactivate (repair DNA damage using visible light). Histology revealed that miracidia irradiated with 861 J x m(-2) underwent abnormal development after penetrating Biomphalaria glabrata snails. Total number of sporocysts in snail tissues decreased as a function of time postinfection (PI), among both nonirradiated and irradiated parasites; however, this decrease was greater in the latter. Moreover, whereas the proportion alive of nonirradiated sporocysts increased PI, that of irradiated sporocysts, i.e., derived from irradiated miracidia, decreased. Irradiation of miracidia with UVB resulted in decreased prevalence of patent infection (defined by presence of daughter sporocysts) in a dose-dependent manner, and no infections occurred at a dose of 861 J x m(-2). Like many aquatic organisms, including the snail host, parasites were able to photoreactivate if exposed to visible light following UVB irradiation, even subsequent to penetrating snails. These photoreactivation results suggest cyclobutane-pyrimidine dimers in DNA as the primary mechanism of UVB damage, and implicate photoreactivation, rather than nucleotide excision, as the main repair process in S. mansoni.

Pharmacokinetics, pharmacodynamics, and safety assessment of palifermin (rHuKGF) in healthy volunteers.

BACKGROUND: Palifermin is a recombinant human keratinocyte growth factor approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies who received myelotoxic therapy requiring hematopoietic stem cell support. METHODS: This randomized, double-blind, placebo-controlled study investigated the pharmacokinetics, pharmacodynamics, and safety of palifermin in healthy volunteers after single, escalating doses (60 to 250 mug/kg). Pharmacodynamic measurements (Ki67 staining) assessing buccal mucosal epithelial proliferation were performed at baseline and at 48 or 72 hours after dosing. RESULTS: Exposure to palifermin increased approximately dose proportionally, with a 3-fold increase observed for a 4-fold increase in dose. Palifermin concentrations decreased sharply during the first 0.5 to 1.5 hours after dosing, slightly increased or plateaued between 1.5 and 6 hours, and subsequently decreased. The overall mean systemic clearance and volume of distribution at steady state were 590 mL/h/kg and 2000 mL/kg, respectively. The mean half-life ranged from 4.5 to 6 hours across the dose levels. The mean and SD ratio of Ki67 staining at 48 hours after dosing to baseline was 1.19 (0.24) for placebo, 2.02 (0.60) for 60 mug/kg, 3.04 (1.13) for 120 mug/kg, and 4.66 (0.77) for 250 mug/kg-treated groups. CONCLUSION: Palifermin exhibited linear pharmacokinetics and caused dose-dependent epithelial proliferation.

Bioequivalence of liquid and reconstituted lyophilized etanercept subcutaneous injections.

The objective of this study was to compare the pharmacokinetics of liquid and reconstituted lyophilized etanercept. This single-center, open-label study had a 2-period crossover design in which 36 healthy subjects were randomly assigned in a 1:1 ratio to etanercept (liquid/lyo or lyo/liquid). The treatments were separated by 28 days. Blood samples were obtained predose and at 10 predetermined time points postdose. Serum concentrations were determined by enzyme-linked immunosorbent assay. Noncompartmental pharmacokinetic parameters were analyzed using a standard crossover analysis of variance model. Thirty-three subjects completed both treatment periods. Geometric mean values (adjusted) of area under the serum drug concentration-time curve from time zero to the time of the final quantifiable sample, area under the serum drug concentration-time curve from time zero to infinity, and maximum concentration obtained with the 50-mg/mL liquid etanercept injection were 93.0%, 90.7%, and 98.5% of the respective parameters for 2 injections of 25 mg/mL reconstituted formulation. All associated confidence intervals were within the predefined equivalence interval of 80% to 125%. No differences in safety profiles of the 2 formulations were apparent. Liquid etanercept was bioequivalent to the reconstituted lyophilized etanercept formulation.

Pharmacokinetics of darbepoetin alfa after intravenous or subcutaneous administration in patients with non-myeloid malignancies undergoing chemotherapy.

BACKGROUND AND OBJECTIVE: The pharmacokinetics of darbepoetin alfa after intravenous (IV) administration in the oncology setting have not been previously reported. The objective of this study was to evaluate the pharmacokinetics of IV or subcutaneous (SC) darbepoetin alfa in patients with non-myeloid malignancies undergoing multicycle chemotherapy. METHODS: Fifty-six patients (haemoglobin