Low-level nutrient enrichment during thermal stress delays bleaching and ameliorates calcification in three Hawaiian reef coral species.

Terrestrial-based nutrient pollution has emerged as one of the most detrimental factors to coral health in many reef habitats. Recent studies have shown that excessive dissolved inorganic nutrients can reduce coral thermal tolerance thresholds and even exacerbate bleaching during thermal stress, yet the effects of minor nutrient enrichment under heat stress have not been extensively studied. In this study, Lobactis scutaria, Montipora capitata, and Pocillopora acuta colonies under heated conditions (~30.5 °C) were exposed to low and balanced nitrogen and phosphorous concentrations over a 31-day heating period. Coral colonies were collected from Kane'ohe Bay, O'ahu, which has a unique history of nutrient pollution, and held in mesocosms that allowed for environmental manipulation yet are also influenced by local field conditions. Principal findings included delays in the bleaching of nutrient-enriched heated colonies as compared to heated-only colonies, in addition to relatively greater calcification rates and lower proportions of early-stage paling. Species-specific outcomes were prevalent, with L. scutaria demonstrating no difference in calcification with enrichment under heat stress. By the end of the heating stage, however, many heated colonies were at least partially impacted by bleaching or mortality. Despite this, our findings suggest that low levels of balanced nutrient enrichment may serve as a mitigative force during thermal events. Further field-based studies will be required to assess these results in different reef habitats.

Rebounds, regresses, and recovery: A 15-year study of the coral reef community at Pila'a, Kaua'i after decades of natural and anthropogenic stress events.

Pila'a reef on the north shore of Kaua'i, Hawai'i was subjected to a major flood event in 2001 that deposited extensive sediment on the reef flat, resulting in high coral mortality. To document potential recovery, this study replicated benthic and sediment surveys conducted immediately following the event and 15 years later. Coral cores were analyzed to determine coral growth rates and density. Our results suggest that significant reduction in terrigenous sediments has led to partial ecosystem recovery based on coral species and colony increases, more balanced size frequency distributions, improved coral condition, and enhanced coral recruitment despite lack of recovery of large dead coral colonies. However, within this 15-year period, episodic storms and a bleaching event impeded the recovery process, preventing full recovery and continuously threatening the coral reef community. As climate change progresses, the intensity and frequency of these disturbances are predicted to increase.

Prognosis of patients with gastric variceal bleeding after endoscopic variceal obturation according to the type of varices.

BACKGROUND AND AIMS: This study was performed to evaluate the treatment efficacy of endoscopic variceal obturation (EVO) in patients with gastric variceal bleeding (GVB) according to the type of varices. PATIENTS AND METHODS: All patients who were treated with EVO for bleeding from gastric varices (GVs) were included. Patients with a previous history of endoscopic treatment for GVB and those with accompanying portal vein invasion by hepatocellular carcinoma or other malignancy were excluded. RESULTS: Ninety-one patients with GVB were included. Mean age was 59.4±12.4 years and 72 (79.1%) patients were men. The types of varices were gastroesophageal varices (GOV) type 1 (GOV1), GOV2, and isolated gastric varices type 1 (IGV1) in 30 (33.3%), 35 (38.5%), and 26 (28.6%) patients, respectively. Hemostasis and GV obliteration were achieved in 88 (96.7%) and 81 (89.0%) patients, respectively. Among 81 patients with GV obliteration, GV recurred in 26 (32.1%) patients. The GV recurrence rate was significantly lower in patients with GOV1 than in those with GOV2 (P=0.007), while it was comparable between patients with GOV1 and IGV1 (P=0.111) and between patients with GOV2 and IGV1 (P=0.278). Variceal rebleeding occurred in 11 (13.6%) patients. GVB recurrence rate was significantly higher in patients with GOV2 than in those with GOV1 (P=0.034) and IGV1 (P=0.018), while it was comparable between patients with GOV1 and IGV1 (P=0.623). Mortality rate was comparable among the three groups. CONCLUSIONS: EVO was very effective in patients with GVB. GV recurrence and GV rebleeding were significantly lower in patients with GOV1 than in those with GOV2.

Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans.

BACKGROUND: The gut hormone motilin stimulates gastrointestinal motility by inducing gastric phase III of the migrating motor complex (MMC) and enhancing the rate of gastric emptying. Camicinal (GSK962040), a small molecule motilin receptor agonist, has been shown to increase gastrointestinal motility. METHODS: In this proof of concept study the effects of camicinal on MMC activity, esophageal and gastric pH was evaluated in eight healthy volunteers as a secondary endpoint. Doses of 50 and 150 mg were compared to placebo for a period of 24 hours in a double-blinded randomized crossover trial. KEY RESULTS: The 50 mg dose (n=4) of camicinal had no significant impact on gastroduodenal manometry or pH parameters. A single dose of 150 mg (n=4) induced a gastric phase III after 0:34 h (0:25-0:58), which was significantly faster compared to placebo (18:15 h (4:32-22:16); P=.03). Moreover, the high dose significantly increased the occurrence of gastric phase III contractions compared to placebo (12% vs 39%; P=.0003). This increase in gastric phase III contractions during a period of 24 hour was due to an increased occurrence of gastric phases III during the daytime (5% vs 50%; P=.0001). The same dose however did not affect small bowel manometry parameters or esophageal and gastric pH. CONCLUSIONS AND INFERENCES: Considering its stimulating effect on the MMC and gastric emptying, camicinal is an attractive candidate for the treatment of gastroparesis and gastroesophageal reflux disease. This trial was registered at clinicaltrials.gov as NCT00562848.

Safety profile of the 9-valent human papillomavirus vaccine: assessment in prior quadrivalent HPV vaccine recipients and in men 16 to 26 years of age.

A 9-valent HPV (9vHPV) vaccine has been developed to protect against HPV type 6/11/16/18/31/33/45/52/58-related infection and disease. Previous safety analyses from 7 clinical trials conducted in 9vHPV vaccine recipients 9-26 years of age, including comparisons of 9vHPV and quadrivalent HPV (qHPV) vaccines in girls and women 16-26 years of age, showed that the 9vHPV vaccine was generally well tolerated. Additional safety analyses were conducted to include the results of new clinical studies. The safety profile of the 9vHPV vaccine in prior qHPV vaccine recipients (n = 3756 from 1 randomized controlled trial and 2 open-label extension studies) and young men (n = 248 9vHPV and n = 248 qHPV vaccine recipients from 1 randomized controlled trial) was evaluated. Vaccine was administered as a 3-dose regimen (at Day 1 and Months 2 and 6), and adverse events (AEs) were monitored. The most common AEs were injection-site events (91.1% and 79.0% in prior qHPV vaccine recipients and young men, respectively), the majority of which were mild. Discontinuations due to an AE were rare (0.2% and 0.0% among prior qHPV vaccine recipients and young men, respectively). In young men, the AE profile of the 9vHPV vaccine was generally similar to that of the qHPV vaccine. Overall, the 9vHPV vaccine was generally well tolerated in prior qHPV vaccine recipients and in young men, with an AE profile generally consistent with that previously reported with the broader clinical program.

Single-Dose and Multiple-Dose Pharmacokinetics of Vaniprevir in Healthy Men.

Vaniprevir is an inhibitor of the hepatitis C virus (HCV) NS3/4A protease. The aim of these double-blind, placebo-controlled phase I studies was to evaluate the safety and pharmacokinetics of vaniprevir in healthy male volunteers. The primary objective for both studies was the safety and tolerability of vaniprevir. Single-dose and steady-state pharmacokinetics were also assessed. In both studies, there was no apparent relationship between the frequency or intensity of adverse events and vaniprevir dose. At single doses >20 mg, the plasma area under the curve (AUC)0-∞ and maximum concentration (Cmax ) increased in a greater-than-dose-proportional manner. The geometric mean ratios (GMRs; fed/fasted) were 1.22 and 0.79 for AUC0-∞ and Cmax , respectively. Following multiple doses, GMR accumulations for AUC0-12h and Cmax (day 14/day 1) ranged from 1.53 to 1.90 and from 1.41 to 1.92, respectively. These data support the use of vaniprevir with peginterferon and ribavirin in patients with HCV infection.

TRPV1 dysfunction in cystinosis patients harboring the homozygous 57 kb deletion.

Cystinosis is a rare autosomal recessive disorder characterized by lysosomal cystine accumulation due to loss of function of the lysosomal cystine transporter (CTNS). The most common mutation in cystinosis patients of Northern Europe consists of a 57-kb deletion. This deletion not only inactivates the CTNS gene but also extends into the non-coding region upstream of the start codon of the TRPV1 gene, encoding the capsaicin- and heat-sensitive ion channel TRPV1. To evaluate the consequences of the 57-kb deletion on functional TRPV1 expression, we compared thermal, mechanical and chemical sensitivity of cystinosis patients with matched healthy controls. Whereas patients heterozygous for the 57-kb deletion showed normal sensory responses, homozygous subjects exhibited a 60% reduction in vasodilation and pain evoked by capsaicin, as well as an increase in heat detection threshold. Responses to cold, mechanical stimuli or cinnamaldehyde, an agonist of the related nociceptor channel TRPA1, were unaltered. We conclude that cystinosis patients homozygous for the 57-kb deletion exhibit a strong reduction of TRPV1 function, leading to sensory deficiencies akin to the phenotype of TRPV1-deficient mice. These deficits may account for the reported sensory alterations and thermoregulatory deficits in these patients, and provide a paradigm for life-long TRPV1 deficiency in humans.

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, After Single and Multiple Doses in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid, and food did not influence single-dose PK. Accumulation was minimal, and steady state was reached after 2 to 3 weeks. Weekly (area under the curve) AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ∼2 L/h. DPP-4 inhibition ranged from ∼77% to 89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ∼2-fold increases in weighted average postprandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profiles support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study predicted a low risk of QTc prolongation within the likely clinical dose range, a finding later confirmed in a thorough QT trial.

Post-ischemic treatment of WIB801C, standardized Cordyceps extract, reduces cerebral ischemic injury via inhibition of inflammatory cell migration.

ETHNOPHARMACOLOGICAL RELEVANCE: Anti-inflammatory therapy has been intensively investigated as a potential strategy for treatment of cerebral stroke. However, despite many positive outcomes reported in animal studies, anti-inflammatory treatments have not proven successful in humans as yet. Although immunomodulatory activity and safety of Cordyceps species (Chinese caterpillar fungi) have been proven in clinical trials and traditional Asian prescriptions for inflammatory diseases, its anti-ischemic effect remains elusive. AIM OF THE STUDY: In the present study, therefore, we investigated the potential therapeutic efficacy of WIB801C, the standardized extract of Cordyceps militaris, for treatment of cerebral ischemic stroke. MATERIALS AND METHODS: The anti-chemotactic activity of WIB801C was assayed in cultured rat microglia/macrophages. Sprague-Dawley rats were subjected to ischemic stroke via either transient (1.5-h tMCAO and subsequent 24-h reperfusion) or permanent middle cerebral artery occlusion (pMCAO for 24-h without reperfusion). WIB801C was orally administered twice at 3- and 8-h (50mg/kg each) after the onset of MCAO. Infarct volume, edema, blood brain barrier and white matter damages, neurological deficits, and long-term survival rates were investigated. The infiltration of inflammatory cells into ischemic lesions was assayed by immunostaining. RESULTS: WIB801C significantly decreased migration of cultured microglia/macrophages. This anti-chemotactic activity of WIB-801C was not mediated via adenosine A3 receptors, although cordycepin, the major ingredient of WIB801C, is known as an adenosine receptor agonist. Post-ischemic treatment with WIB801C significantly reduced the infiltration of ED-1-and MPO-positive inflammatory cells into ischemic lesions in tMCAO rats. WIB801C-treated rats exhibited significantly decreased infarct volume and cerebral edema, less white matter and blood-brain barrier damages, and improved neurological deficits. WIB801C also improved survival rates over 34 days after ischemia onset. A significant reduction in infarct volume and neurobehavioral deficits by WIB801C was also observed in rats subjected to pMCAO. CONCLUSIONS: In summary, post-ischemic treatment of WIB801C reduced infiltration of inflammatory cells into ischemic lesions via inhibition of chemotaxis, which confers long-lasting histological and neurological protection in ischemic brain. WIB801C may be a promising anti-ischemic drug candidate with clinically relevant therapeutic time window and safety.

Comparison of single and blend acidifiers as alternative to antibiotics on growth performance, fecal microflora, and humoral immunity in weaned piglets.

The banning of the use of antibiotics as feed additive has accelerated investigations of alternative feed additives in animal production. This experiment investigated the effect of pure citric acid or acidifier blend supplementation as substitute for antibiotic growth promoters on growth performance, fecal microbial count, and humoral immunity in weaned piglets challenged with Salmonella enterica serover Typhimurium and Escherichia coli KCTC 2571. A total of 60 newly weaned piglets (crossbred, 28-d-old; average 8 kg initial weight) were randomly assigned to four dietary treatments in a completely randomized design. Dietary treatments included NC (negative control; basal diet), PC (positive control; basal diet+0.002% apramycin), T1 (basal diet+0.5% pure citric acid), and T2 (basal diet+0.4% acidifier blend). All piglets were orally challenged with 5 mL of culture fluid containing 2.3×10(8) cfu/mL of E. coli KCTC 2571 and 5.9×10(8) cfu/mL of S. typhimurium at the beginning of the experiment. The PC group showed the highest ADG and ADFI, whereas gain:feed was improved in the PC and T1 group (p<0.05). All dietary treatments showed significant reduction in fecal counts of Salmonella and E. coli, compared to NC (p<0.05), with PC being better than T1 and T2. Significant elevation in fecal Lactobacillus spp. counts was shown by treatments with T1, T2, and PC, whereas Bacillus spp. counts were increased by treatment with T1 and T2 compared to NC and PC diet (p<0.05). Serum IgG concentration was increased by T1 diet (p<0.05), whereas IgM and IgA were not significantly affected by any of the dietary treatments (p>0.05). From these above results, it can be concluded that, as alternatives to antibiotics dietary acidification with pure citric acid or acidifiers blend did not fully ameliorate the negative effects of microbial challenges in respect of growth performance and microbial environment, however improved immunity suggested further research with different dose levels.

Estradiol and weight are covariates of paracetamol clearance in young women.

AIM: Paracetamol clearance differs between pregnant and non-pregnant women and between women with or without specific oral contraceptives (OCs). However, an association between female sex hormones and paracetamol clearance has never been explored. METHODS: In total, 49 women at delivery, 8 female control subjects without OC use, historical data of 14 women taking OCs, and 15 postpartum observations with and without OCs were pooled to explore covariates of paracetamol clearance. All received a single intravenous 2-gram paracetamol dose, and blood samples were collected up to 6 h after dosing. High-performance liquid chromatography was used to quantify paracetamol. The area under the curve to time infinity (AUC0-∞) was determined and clearance (l/h·m(2)) was calculated by dose/ AUC0-∞. In addition, estradiol and progesterone were quantified by ELISA with electro-chemiluminescence. RESULTS: Median paracetamol clearance at delivery was significantly higher when compared to postpartum or non-pregnant women (11.9 vs. 6.42 and 8.4 l/h·m(2), at least p < 0.05), while an association between paracetamol clearance and estradiol was observed (R = 0.494, p < 0.0001). In non-pregnant subjects, there was no impact of OC exposure on paracetamol clearance. Multiple regression revealed a linear association (Radj = 0.41, p < 0.001) between paracetamol clearance and weight (p = 0.0462) and estradiol (p < 0.0001). CONCLUSION: Estradiol and weight in part explain the variation in paracetamol clearance in young women.

Weight, pregnancy and oral contraceptives affect intravenous paracetamol clearance in young women.

OBJECTIVES: Because of the extensive variability in paracetamol clearance in young women, published data were pooled with newly collected observations in search of covariates of paracetamol pharmacokinetics (PK) within this specific population. SUBJECTS AND METHODS: PK estimates and clinical characteristics [pregnant, weight, exposure to oral contraceptives (OC)] in young women following IV loading dose (2 g paracetamol) were pooled, using a non-compartmental linear disposition model in individual time-concentration profiles. Data were reported by median and range. Rank correlation was used to link clearance (l/h) to weight, Mann Whitney U test to compare clearance (l/h.m-2) between subgroups (pregnant, OC exposure). Finally, a multiple regression model with clearance (l/h) in all women and all non-pregnant women was performed. RESULTS: Based on 73 paracetamol PK estimates, a 8-fold variability in clearance (range 7.1-62.2 l/h) was documented, in part explained by a correlation (r2=0.36) between clearance (l/h) and weight. Clearance (l/h and l/h.m-2) and distribution volume (l) at delivery (n=36) were higher compared to non-pregnant observations. In non-pregnant women, women on OC (n=20) had a higher paracetamol clearance (l/h.m-2) compared to women (n=17) not on OC (p = 0.023). Weight (p = 0.0043) and pregnancy (p = 0.02) were independent variables (r=0.56) of paracetamol clearance (l/h). In non-pregnant women, weight (p = 0.009) and OC exposure (p = 0.03) were independent variables (r=0.51). CONCLUSIONS: Weight, pregnancy and OC result in higher clearance of IV paracetamol in young women. Besides compound specific relevance, these findings also unveil covariates of drug metabolism in young women.

Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates.

OBJECTIVES: Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. METHODS: Thirty-six neonates [median birth body weight 2720 (range 540-4200) g, current body weight (cBW) 2755 (830-4200) g and postnatal age (PNA) 9 (1-30) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (>60% of the time) in all patients. RESULTS: A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (Bmax) of 136 mg/L and a dissociation constant (KD) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for Bmax, explaining 50%, 58% and 41% of inter-individual variability in V, clearance and Bmax, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. CONCLUSIONS: A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates.

Development of an experimental model to study trigeminal nerve-mediated vasodilation on the human forehead.

BACKGROUND: During migraine, trigeminal sensory nerve terminals release calcitonin gene-related peptide (CGRP), inducing nociception and vasodilation. Applied on the skin, capsaicin activates the transient receptor potential vanilloid type 1 (TRPV1) channel and releases CGRP from sensory nerve terminals, thus increasing dermal blood flow (DBF). Using capsaicin application and electrical stimulation of the forehead skin, a trigeminal nerve-innervated dermatome, we aimed to develop a model to measure trigeminal nerve-mediated vasodilation in humans. METHODS: Using laser Doppler imaging, forehead DBF responses to application of capsaicin (0.06 mg/ml and 6.0 mg/ml) and saline, with and without iontophoresis, were studied in healthy subjects. The within-subject coefficient of variation (WCV) of repeated DBF measurements was calculated to assess reproducibility. RESULTS: Maximal DBF responses to 6.0 mg/ml capsaicin with and without iontophoresis did not differ (Emax 459 ± 32 and 424 ± 32 arbitrary units (a.u.), WCV 6 ± 4%). In contrast, DBF responses to 0.06 mg/ml capsaicin were significantly larger with than without iontophoresis (Emax 307 ± 60 versus 187 ± 21 a.u., WCV 21 ± 13%). Saline with iontophoresis significantly increased DBF (Emax: 245 ± 26 a.u, WCV 11 ± 8%), while saline application without iontophoresis did not affect DBF. CONCLUSION: Topical application of capsaicin and electrical stimulation induce reproducible forehead DBF increases and therefore are suitable to study trigeminal nerve-mediated vasodilation in humans.

Pharmacokinetics of intravenous ketorolac following caesarean delivery.

BACKGROUND: Drug disposition is altered by pregnancy and the peripartum period but data on intravenous ketorolac pharmacokinetics following caesarean delivery have not been previously reported. METHODS: At the end of caesarean delivery, women received an intravenous bolus of ketorolac tromethamine 30 mg (immediate postpartum, Group IP). Plasma samples were collected at 1, 2, 4, 6 and 8h. A similar pharmacokinetic study was repeated in a subgroup of these women 4-5 months after delivery (late postpartum, Group LP) and in a group of unrelated, healthy non-pregnant female volunteers (controls, Group C). A non-compartmental linear disposition model was applied to analyse individual ketorolac time-concentration profiles. Results at delivery were compared with controls using unpaired or paired statistics as appropriate. Covariates of pharmacokinetic estimates at delivery were examined. RESULTS: Thirty-nine women were studied at caesarean delivery, of whom eight were re-evaluated 4-5 months later. In addition, eight volunteers were studied. Clearance in Group IP was higher compared to Groups LP and C (2.11 vs. 1.43 and 1.07 L/h·m(2) respectively, P<0.05). Volume of distribution was also increased in Group IP compared to Groups LP and C (0.24 vs. 0.16 and 0.17 L/kg respectively, P<0.05). No significant covariates of pharmacokinetic estimates, including gestational age, preterm vs. term, twin vs. singleton and maternal co-morbidity, were seen in Group IP. CONCLUSIONS: Ketorolac clearance and distribution volume are significantly increased following caesarean delivery. These data provide pharmacokinetic estimates on which to base studies on post caesarean analgesia.

Cefazolin plasma protein binding and its covariates in neonates.

Cefazolin (CFZ) is highly and saturably bound to human serum albumin (HSA) in adults. We aim to describe CFZ protein binding and its covariates in neonates. In neonates to whom intravenous CFZ (50 mg/kg) was administered prior to a surgical procedure, total and unbound CFZ plasma concentrations (mg/l) were determined at 0.5, 2, 4 and 8 h after CFZ administration. Linear and multiple regression analyses were used to document covariates of unbound CFZ fraction. The Wilcoxon signed-rank test was used for the paired analysis of unbound CFZ fractions. In 40 patients with a median weight of 2,767 (range 830-4,200) g and a postmenstrual age (PMA) of 39 (25-45) weeks, 131 samples were collected. The median unbound CFZ fraction was 0.39 (0.10-0.73). Linear regression of unbound CFZ fraction versus unbound CFZ plasma concentration (R (2) = 0.39) had a slope significantly different from zero (p < 0.001). In a multiple regression analysis, albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA resulted in an R (2) value of 0.496. The median unbound CFZ fraction at the peak concentration (0.46, range 0.28-0.69) was significantly higher compared to the trough level (0.36, range 0.17-0.73) (p < 0.001). The between- and within-patient saturability of CFZ plasma protein binding were documented in neonates. The median unbound CFZ fraction in neonates is higher than in adults and depends partly on albuminaemia, total CFZ concentration, indirect bilirubinaemia and PMA. Integration of CFZ protein binding in future pharmacokinetic/pharmacodynamic research is warranted in order to optimise neonatal CFZ dosing. We recommend protein binding assessment in the neonatal pharmacokinetic evaluation of highly protein-bound or clinically relevant drugs.

Equivalent dynamic human brain NK1-receptor occupancy following single-dose i.v. fosaprepitant vs. oral aprepitant as assessed by PET imaging.

The type 1 neurokinin receptor (NK1R) antagonist aprepitant and its i.v. prodrug fosaprepitant have been approved for prevention of acute and delayed nausea and vomiting associated with chemotherapy. This study evaluated the magnitude and duration of brain NK1R occupancy over a period of 5 days after single-dose i.v. infusion of 150-mg fosaprepitant and single-dose oral administration of 165-mg aprepitant, using serial [(18)F]MK-0999 positron emission tomography (PET) in 16 healthy subjects. Each subject underwent three scans. Brain NK1R occupancy rates after i.v. fosaprepitant at time to peak concentration (T(max); ~30 min), 24, 48, and 120 h after the dose were 100, 100, ≥97, and 41-75%, respectively. After aprepitant, NK1R occupancy rates at these time points (T(max) ~4 h) were ≥99, ≥99, ≥97, and 37-76%, respectively. Aprepitant plasma concentration profiles were comparable for the two dosage forms. The study illustrates the utility of PET imaging in determining central bioequivalence in a limited number of subjects.

Pharmacokinetics of a loading dose of intravenous paracetamol post caesarean delivery.

BACKGROUND: The postpartum period affects drug disposition, but data of intravenous paracetamol loading dose pharmacokinetics immediately following caesarean delivery have not yet been reported. METHODS: Immediately following caesarean delivery, women received a 2-g loading dose of intravenous paracetamol. Plasma samples were collected at 1, 2, 4 and 6 h. Individual pharmacokinetics were calculated assuming a linear one-compartment model with instantaneous input and first-order output. Data were reported using median and range. RESULTS: Twenty-eight patients undergoing caesarean delivery were recruited (age 31.5 [20-42] years, weight 79 [57-110] kg, body surface area 1.9 [1.5-2.4]m(2)). Median paracetamol plasma concentrations after 1, 2, 4 and 6 h were 22.5, 15.25, 7.9, and 3.9 mg/L respectively. Paracetamol clearance was 20.3 (11.8-62.8) L/h or 10.9 (7-23.8)L/hm(2), distribution volume 58.3 (42.9-156) L or 0.72 (0.52-1.56) L/kg. CONCLUSION: Pharmacokinetics of intravenous paracetamol have been estimated following caesarean delivery. Although limited to a loading dose shortly after surgery, the results are clinically relevant since this is the first description in this patient population. These data provide evidence on which to base further integrated pharmacokinetic/pharmacodynamic studies in peripartum analgesia.

MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans.

MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant GABA(A) receptors with comparable high affinity (0.21-0.40 nM). However, MRK-409 has greater agonist efficacy at the α3 compared with α1 subtypes (respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This compound readily penetrates the brain in rats and occupies the benzodiazepine site of GABA(A) receptors, measured using an in vivo [(3)H]flumazenil binding assay, with an Occ(50) of 2.2 mg/kg p.o. and a corresponding plasma EC(50) of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409 produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of anxiety with minimum effective doses corresponding to occupancies, depending on the particular model, ranging from ∼35% to 65% yet there were minimal overt signs of sedation at occupancies greater than 90%. In humans, however, safety and tolerability studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a C(max) plasma concentration of 28 ng/mL, which, based on the rodent plasma EC(50) for occupancy of 115 ng/mL, suggested that sedation in humans occurs at low levels of occupancy. This was confirmed in human positron emission tomography studies, in which [(11)C]flumazenil uptake following a single dose of 1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of GABA(A) receptor benzodiazepine binding sites by MRK-409 was below the limits of detection (i.e. <10%). Taken together, these data show that MRK-409 causes sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably less than those predicted from rodent models to be required for anxiolytic efficacy (∼35-65%). Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted.