Differential changes in maternal proinflammatory IL6 plasmalevels as a putatively surrogate marker of candidacy andclinical utility during mid- and late pregnancy hyperglycemia:interventional impact of clinical pharmacist on maternal andneonatal outcomes in a randomized clinical trial / Cambios diferenciales en los niveles plasmáticos de IL6 proinflamatoria materna como un marcador supuestamente sustituto de candidatura y utilidad clínica durante la hiperglucemia a mitad y final del embarazo: impacto intervencionista del farmacéutico clínico en los resultados maternos y neonatales en un ensayo clínico aleatorizado

Background/methods: The impact of clinical pharmacist on undiagnosed pregnancy hyperglycemia (PHG) in mid- and late- pregnancy as a major preventable cause of maternal and neonatal (M/N) complications is investigated. This longitudinal randomized controlled study of changes in plasma levels of predictive/prognostic/diagnostic biomarkers of oxytocin, thrombospondin, MCP1, IL6, MIF, insulin and LAR and undesirable M/N pregnancy outcomes in women with/out PHG (pregnancy normoglycemia; PNG) following the implementation of clinical pharmacist interventions were investigated. Results: A total of 68 PHG (36 intervention vs. 32 non-intervention) vs. 21 PNG participants were enrolled at 20–28 weeks and followed up till delivery. BMI of intervention PHG (unlike non-intervention) was greater (p=0.036) compared to PNG’s. LAR and insulin, oxytocin, thrombospondin1, adiponectin and MCP1 plasma levels and their differences between 2nd and 3rd pregnancy trimesters lacked discrepancies in participants. Both PHG groups in mid pregnancy had substantially greater HbA1c %, FPG and IL6 levels vs. PNG, while PHG non-intervention’ leptin was greater than PNG’s. In late pregnancy, greater SBP, IL6 and MIF levels between either PHG groups vs. PNG’s were observed. Unlike PHG non-intervention and PNG; IL6 level in PHG intervention group decreased (-2.54±6.61; vs. non-intervention PHG’s 4.26±5.28; p<0.001 and vs. PNG’s 2.30±4.27; p=0.023). None of the assessed M/N outcomes was found of differential significance between any of the three study groups. Conclusions: Proinflammatory IL6 as a robust and generalizable cardiometabolic risk-based and related pharmacotherapy biomarker in mid and late hyperglycemic pregnancy with likely implications of novel therapeutic targets was delineated by clinical pharmacist interventions.(AU)

Effects of ginger (Zingiber officinale) supplementation on testicular histology, semen characteristic, blood plasma parameters and reproductive performance in aged broiler breeder roosters.

Higher long-chain polyunsaturated fatty acids contents in roosters' sperm plasma membrane along with age-related decrease in antioxidant defense make the spermatozoa very susceptible to lipid peroxidation. Ginger root contains abundant amounts of gingerol, shogaols, gingerdiol and other active compounds, which known as antioxidant compounds to enhance semen quality. The goal of the study was to evaluate the effect of dietary supplementation of ginger root on semen quality, blood chemistry, immune response, testicular histology and reproductive performance of Ross-308 breeder roosters from 47 to 60 weeks of age. The feeding of ginger root resulted in an increase in parameters related to sperm forward motility and seminal total antioxidant capacity (TAC), and following there was a tendency to increase and decrease in seminal superoxide dismutase activity and malondialdehyde concentration, respectively; however, sperm concentration was not affected. There was an increase and tendency to increase in blood total protein and TAC in the supplemented group respectively. The roosters fed ginger supplemented diet had a higher spermiation index; and following there was tendency to increase seminal tubes spermatozoids number (p = 0.056) and repopulation index (p = 0.058). Despite the improved seminal antioxidant status and a tendency to lower embryonic mortality in the ginger-received group, the fertility and hatchability rate of roosters were statistically insignificant. Supplementations of ginger root in ageing rooster's diet had a beneficial effect on sperm motility, seminal antioxidant status and testicular spermiation index.

The Effect of Low Doses of Zearalenone (ZEN) on the Bone Marrow Microenvironment and Haematological Parameters of Blood Plasma in Pre-Pubertal Gilts.

The aim of this study was to determine whether low doses of zearalenone (ZEN) influence the carry-over of ZEN and its metabolites to the bone marrow microenvironment and, consequently, haematological parameters. Pre-pubertal gilts (with a body weight of up to 14.5 kg) were exposed to daily ZEN doses of 5 µg/kg BW (group ZEN5, n = 15), 10 µg/kg BW (group ZEN10, n = 15), 15 µg/kg BW (group ZEN15, n = 15), or were administered a placebo (group C, n = 15) throughout the entire experiment. Bone marrow was sampled on three dates (exposure dates 7, 21, and 42-after slaughter) and blood for haematological analyses was sampled on 10 dates. Significant differences in the analysed haematological parameters (WBC White Blood Cells, MONO-Monocytes, NEUT-Neutrophils, LYMPH-Lymphocytes, LUC-Large Unstained Cells, RBC-Red Blood Cells, HGB-Haemoglobin, HCT-Haematocrit, MCH-Mean Corpuscular Volume, MCHC-Mean Corpuscular Haemoglobin Concentrations, PLT-Platelet Count and MPV-Mean Platelet Volume) were observed between groups. The results of the experiment suggest that exposure to low ZEN doses triggered compensatory and adaptive mechanisms, stimulated the local immune system, promoted eryptosis, intensified mycotoxin biotransformation processes in the liver, and produced negative correlations between mycotoxin concentrations and selected haematological parameters.

A Genus-Wide Bioactivity Analysis of Daboia (Viperinae: Viperidae) Viper Venoms Reveals Widespread Variation in Haemotoxic Properties.

The snake genus Daboia (Viperidae: Viperinae; Oppel, 1811) contains five species: D. deserti, D. mauritanica, and D. palaestinae, found in Afro-Arabia, and the Russell's vipers D. russelii and D. siamensis, found in Asia. Russell's vipers are responsible for a major proportion of the medically important snakebites that occur in the regions they inhabit, and their venoms are notorious for their coagulopathic effects. While widely documented, the extent of venom variation within the Russell's vipers is poorly characterised, as is the venom activity of other species within the genus. In this study we investigated variation in the haemotoxic activity of Daboia using twelve venoms from all five species, including multiple variants of D. russelii, D. siamensis, and D. palaestinae. We tested the venoms on human plasma using thromboelastography, dose-response coagulometry analyses, and calibrated automated thrombography, and on human fibrinogen by thromboelastography and fibrinogen gels. We assessed activation of blood factors X and prothrombin by the venoms using fluorometry. Variation in venom activity was evident in all experiments. The Asian species D. russelii and D. siamensis and the African species D. mauritanica possessed procoagulant venom, while D. deserti and D. palaestinae were net-anticoagulant. Of the Russell's vipers, the venom of D. siamensis from Myanmar was most toxic and D. russelli of Sri Lanka the least. Activation of both factor X and prothrombin was evident by all venoms, though at differential levels. Fibrinogenolytic activity varied extensively throughout the genus and followed no phylogenetic trends. This venom variability underpins one of the many challenges facing treatment of Daboia snakebite envenoming. Comprehensive analyses of available antivenoms in neutralising these variable venom activities are therefore of utmost importance.

Inflammatory phenotype modulation in the respiratory tract and systemic circulation of e-cigarette users: a pilot study.

Over 40 million people use e-cigarettes worldwide, but the impact of chronic e-cigarette use on health has not been adequately defined. In particular, effects of e-cigarette aerosol inhalation on inflammation and host defenses across the body are not fully understood. We conducted a longitudinal cohort pilot study to explore changes in the inflammatory state and monocyte function of e-cigarette users (n = 20) versus healthy controls (n = 13) and to evaluate effects of e-cigarette use reduction on the same. Saliva, sputum, and blood were obtained from e-cigarette users at baseline and after a 2-wk intervention of decreased e-cigarette use. Overall, across 38 proteins quantified by multiplex, airway samples from e-cigarette users tended to have decreased levels of immunomodulatory proteins relative to healthy controls, whereas levels of cytokines, chemokines, and growth factors in the circulation tended to be elevated. Specifically, e-cigarette users had lower levels of IL-1 receptor antagonist (IL-1Ra) in saliva (P < 0.0001), with higher IL-1Ra and growth-regulated oncogene (GRO) levels in sputum (P < 0.01 and P < 0.05, respectively), and higher levels of both TNFß (P < 0.0001) and VEGF (P < 0.0001) in plasma. Circulating monocytes from e-cigarette users had alterations in their inflammatory phenotype in response to reduced e-cigarette use, with blunted IL-8 and IL-6 release upon challenge with bacterial lipopolysaccharide (P < 0.001 and P < 0.05, respectively), suggesting a decreased ability to appropriately respond to bacterial infection. Based on these findings, chronic inhalation of e-cigarette aerosols alters the inflammatory state of the airways and systemic circulation, raising concern for the development of both inflammatory and infectious diseases in chronic users of e-cigarettes.

Stability and Safety of Inhibitor Cystine Knot Peptide, GTx1-15, from the Tarantula Spider Grammostola rosea.

Inhibitor cystine knot (ICK) peptides are knotted peptides with three intramolecular disulfide bonds that affect several types of ion channels. Some are proteolytically stable and are promising scaffolds for drug development. GTx1-15 is an ICK peptide that inhibits the voltage-dependent calcium channel Cav3.1 and the voltage-dependent sodium channels Nav1.3 and Nav1.7. As a model molecule to develop an ICK peptide drug, we investigated several important pharmaceutical characteristics of GTx1-15. The stability of GTx1-15 in rat and human blood plasma was examined, and no GTx1-15 degradation was observed in either rat or human blood plasma for 24 h in vitro. GTx1-15 in blood circulation was detected for several hours after intravenous and intramuscular administration, indicating high stability in plasma. The thermal stability of GTx1-15 as examined by high thermal incubation and protein thermal shift assays indicated that GTx1-15 possesses high heat stability. The cytotoxicity and immunogenicity of GTx1-15 were examined using the human monocytic leukemia cell line THP-1. GTx1-15 showed no cytotoxicity or immunogenicity even at high concentrations. These results indicate that GTx1-15 itself is suitable for peptide drug development and as a peptide library scaffold.

Snake Venom Proteomics, Immunoreactivity and Toxicity Neutralization Studies for the Asiatic Mountain Pit Vipers, Ovophis convictus, Ovophis tonkinensis, and Hime Habu, Ovophis okinavensis.

Snakebite envenomation is a serious neglected tropical disease, and its management is often complicated by the diversity of snake venoms. In Asia, pit vipers of the Ovophis species complex are medically important venomous snakes whose venom properties have not been investigated in depth. This study characterized the venom proteomes of Ovophis convictus (West Malaysia), Ovophis tonkinensis (northern Vietnam, southern China), and Ovophis okinavensis (Okinawa, Japan) by applying liquid chromatography-tandem mass spectrometry, which detected a high abundance of snake venom serine proteases (SVSP, constituting 40-60% of total venom proteins), followed by phospholipases A2, snake venom metalloproteinases of mainly P-III class, L-amino acid oxidases, and toxins from other protein families which were less abundant. The venoms exhibited different procoagulant activities in human plasma, with potency decreasing from O. tonkinensis > O. okinavensis > O. convictus. The procoagulant nature of venom confirms that consumptive coagulopathy underlies the pathophysiology of Ovophis pit viper envenomation. The hetero-specific antivenoms Gloydius brevicaudus monovalent antivenom (GbMAV) and Trimeresurus albolabris monovalent antivenom (TaMAV) were immunoreactive toward the venoms, and cross-neutralized their procoagulant activities, albeit at variably limited efficacy. In the absence of species-specific antivenom, these hetero-specific antivenoms may be useful in treating coagulotoxic envenomation caused by the different snakes in their respective regions.

Association between the donor to recipient ICG-PDR variation rate and the functional recovery of the graft after orthotopic liver transplantation: A case series.

BACKGROUND: Despite current advances in liver transplant surgery, post-operative early allograft dysfunction still complicates the patient prognosis and graft survival. The transition from the donor has not been yet fully understood, and no study quantifies if and how the liver function changes through its transfer to the recipient. The indocyanine green dye plasma disappearance rate (ICG-PDR) is a simple validated tool of liver function assessment. The variation rate between the donor and recipient ICG-PDR still needs to be investigated. MATERIALS AND METHODS: Single-center retrospective study. ICG-PDR determinations were performed before graft retrieval (T1) and 24 hours after transplant (T2). The ICG-PDR relative variation rate between T1 and T2 was calculated to assess the graft function and suffering/recovering. Matched data were compared with the MEAF model of graft dysfunction. OBJECTIVE: To investigate whether the variation rate between the donor ICG-PDR value and the recipient ICG-PDR measurement on first postoperative day (POD1) can be associated with the MEAF score. RESULTS: 36 ICG-PDR measurements between 18 donors and 18 graft recipients were performed. The mean donor ICG-PDR was 22.64 (SD 6.35), and the mean receiver's ICG-PDR on 1st POD was 17.68 (SD 6.60), with a mean MEAF value of 4.51 (SD 1.23). Pearson's test stressed a good, linear inverse correlation between the ICG-PDR relative variation and the MEAF values, correlation coefficient -0.580 (p = 0.012). CONCLUSION: The direct correlation between the donor to recipient ICG-PDR variation rate and MEAF was found. Measurements at T1 and T2 showed an up- or downtrend of the graft performance that reflect the MEAF values.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

ABSTRACT: High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Isavuconazole for treatment of refractory coccidioidal meningitis with concomitant cerebrospinal fluid and plasma therapeutic drug monitoring.

Coccidioidal meningitis (CM) is a life-threatening infection with limited treatment options. Small series have reported success with isavuconazole; however, limited data exist on cerebrospinal fluid (CSF) penetration. Paired plasma and CSF isavuconazole concentrations were measured. Eleven CSF levels were tested, (7 ventricular, 4 lumbar) in three CM patients. Ventricular CSF levels were undetectable despite detectable plasma levels. All lumbar CSF levels were detectable (mean 1.00 µg/ml). Three pairs of lumbar CSF/plasma concentrations taken within 1 h of each other yielded a mean CSF/plasma ratio of 0.31. Isavuconazole was detectable in lumbar but not ventricular CSF in three patients treated for refractory CM. LAY SUMMARY: Isavuconazole is a triazole antifungal that has been used as salvage therapy in the treatment of coccidioidal meningitis (CM). Few data exist characterizing its concentration in the cerebrospinal fluid (CSF). We report tandem plasma and CSF concentrations of isavuconazole in three patients with CM.

Global biochemical analysis of plasma, serum and whole blood collected using various anticoagulant additives.

INTRODUCTION: Analysis of blood for the evaluation of clinically relevant biomarkers requires precise collection and sample handling by phlebotomists and laboratory staff. An important consideration for the clinical application of metabolomics are the different anticoagulants utilized for sample collection. Most studies that have characterized differences in metabolite levels in various blood collection tubes have focused on single analytes. We define analyte levels on a global metabolomics platform following blood sampling using five different, but commonly used, clinical laboratory blood collection tubes (i.e., plasma anticoagulated with either EDTA, lithium heparin or sodium citrate, along with no additive (serum), and EDTA anticoagulated whole blood). METHODS: Using an untargeted metabolomics platform we analyzed five sample types after all had been collected and stored at -80°C. The biochemical composition was determined and differences between the samples established using matched-pair t-tests. RESULTS: We identified 1,117 biochemicals across all samples and detected a mean of 1,036 in the sample groups. Compared to the levels of metabolites in EDTA plasma, the number of biochemicals present at statistically significant different levels (p<0.05) ranged from 452 (serum) to 917 (whole blood). Several metabolites linked to screening assays for rare diseases including acylcarnitines, bilirubin and heme metabolites, nucleosides, and redox balance metabolites varied significantly across the sample collection types. CONCLUSIONS: Our study highlights the widespread effects and importance of using consistent additives for assessing small molecule levels in clinical metabolomics. The biochemistry that occurs during the blood collection process creates a reproducible signal that can identify specimens collected with different anticoagulants in metabolomic studies. IMPACT STATEMENT: In this manuscript, normal/healthy donors had peripheral blood collected using multiple anticoagulants as well as serum during a fasted blood draw. Global metabolomics is a new technology being utilized to draw clinical conclusions and we interrogated the effects of different anticoagulants on the levels of biochemicals from each of the donors. Characterizing the effects of the anticoagulants on biochemical levels will help researchers leverage the information using global metabolomics in order to make conclusions regarding important disease biomarkers.

Plasma pooling in combination with amotosalen/UVA pathogen inactivation to increase standardisation and safety of therapeutic plasma units.

OBJECTIVES: Assessment of the impact of pooling five single-donor plasma (SDP) units to obtain six pathogen-reduced therapeutic plasma (PTP) units on standardisation and the retention of labile coagulation factors. BACKGROUND: SDP shows a high inter-donor variability with potential implications for the clinical treatment outcome. Additionally, there is still an existing risk for window-period transmissions of blood borne pathogens including newly emerging pathogens. METHODS/MATERIALS: Five ABO-identical SDP units were pooled, treated with the INTERTCEPT™ Blood System (Cerus Corporation, U.S.A.) and split into six PTP units which were frozen and thawed after 30 days. The variability in volume, labile coagulation factor retention and activity was assessed. RESULTS: The variability of volumes between the PTP units was reduced by 46% compared to SDP units. The variability in coagulation factor content between the PTP units was reduced by 63% compared to SDP units. Moderate, but significant losses of coagulation factors (except for vWF) were observed in PTPs compared to SDPs. CONCLUSION: The pooling of five SDP units to obtain six PTP units significantly increases product standardisation with potential implications for safety, economics as well as transfusion-transmitted pathogen safety, making it an interesting alternative to quarantine SDP (qSDP) and pathogen-reduced SDP.

Direct Oral Anticoagulants Plasma Levels Measurement: Clinical Usefulness from Trials and Real-World Data.

Measurement of direct oral anticoagulants (DOACs) activity is not routinely necessary. Indeed, evaluation of DOACs plasmatic concentration is discouraged for the majority of patients, due to the lack of outcome data supporting this approach. Nevertheless, DOAC measurements may be useful in emergency situations such as serious bleeding events, need for urgent invasive procedures, and acute ischemic stroke or in managing anticoagulation in "special populations" not adequately studied in clinical trials, for example the very elderly or those at the extremes of body weight. The aim of this review is to describe and summarize the methods for DOACs activity evaluation and the settings in which their plasma level measurement may be indicated, analyzing indications from scientific societies and evidence from clinical trials, as well as real world data on the usefulness of DOACs plasma levels "monitoring."

Pulmonaria obscura and Pulmonaria officinalis Extracts as Mitigators of Peroxynitrite-Induced Oxidative Stress and Cyclooxygenase-2 Inhibitors-In Vitro and In Silico Studies.

The Pulmonaria species (lungwort) are edible plants and traditional remedies for different disorders of the respiratory system. Our work covers a comparative study on biological actions in human blood plasma and cyclooxygenase-2 (COX-2) -inhibitory properties of plant extracts (i.e., phenolic-rich fractions) originated from aerial parts of P. obscura Dumort. and P. officinalis L. Phytochemical profiling demonstrated the abundance of phenolic acids and their derivatives (over 80% of the isolated fractions). Danshensu conjugates with caffeic acid, i.e., rosmarinic, lithospermic, salvianolic, monardic, shimobashiric and yunnaneic acids were identified as predominant components. The examined extracts (1-100 µg/mL) partly prevented harmful effects of the peroxynitrite-induced oxidative stress in blood plasma (decreased oxidative damage to blood plasma components and improved its non-enzymatic antioxidant capacity). The cellular safety of the extracts was confirmed in experimental models of blood platelets and peripheral blood mononuclear cells. COX-2 inhibitor screening evidently suggested a stronger activity of P. officinalis (IC50 of 13.28 and 7.24 µg/mL, in reaction with synthetic chromogen and physiological substrate (arachidonic acid), respectively). In silico studies on interactions of main components of the Pulmonaria extracts with the COX-2 demonstrated the abilities of ten compounds to bind with the enzyme, including rosmarinic acid, menisdaurin, globoidnan A and salvianolic acid H.

Exhaled Propofol Concentrations Correlate With Plasma and Brain Tissue Concentrations in Rats.

BACKGROUND: Propofol can be measured in exhaled gas. Exhaled and plasma propofol concentrations correlate well, but the relationship with tissue concentrations remains unknown. We thus evaluated the relationship between exhaled, plasma, and various tissue propofol concentrations. Because the drug acts in the brain, we focused on the relationship between exhaled and brain tissue propofol concentrations. METHODS: Thirty-six male Sprague-Dawley rats were anesthetized with propofol, ketamine, and rocuronium for 6 hours. Animals were randomly assigned to propofol infusions at 20, 40, or 60 mg·kg·h (n = 12 per group). Exhaled propofol concentrations were measured at 15-minute intervals by multicapillary column-ion mobility spectrometry. Arterial blood samples, 110 µL each, were collected 15, 30, and 45 minutes, and 1, 2, 4, and 6 hours after the propofol infusion started. Propofol concentrations were measured in brain, lung, liver, kidney, muscle, and fat tissue after 6 hours. The last exhaled and plasma concentrations were used for linear regression analyses with tissue concentrations. RESULTS: The correlation of exhaled versus plasma concentrations (R = 0.71) was comparable to the correlation of exhaled versus brain tissue concentrations (R = 0.75) at the end of the study. In contrast, correlations between plasma and lung and between lung and exhaled propofol concentrations were poor. Less than a part-per-thousand of propofol was exhaled over 6 hours. CONCLUSIONS: Exhaled propofol concentrations correlate reasonably well with brain tissue and plasma concentrations in rats, and may thus be useful to estimate anesthetic drug effect. The equilibration between plasma propofol and exhaled gas is apparently independent of lung tissue concentration. Only a tiny fraction of administered propofol is eliminated via the lungs, and exhaled quantities thus have negligible influence on plasma concentrations.

Predictive Value of FMO3 Variants on Plasma Disposition and Adverse Reactions of Oral Voriconazole in Febrile Neutropenia.

BACKGROUND AND OBJECTIVES: With the increasing number of patients with febrile neutropenia (FN), voriconazole (VRC) has been widely used in hospitals for first-line treatment of FN. The study was designed for evaluating the influence of FMO3 mutation on the plasma disposition and adverse reactions of VRC in FN. MATERIALS AND METHODS: A single-center observational study was conducted in the inpatient ward for 4 years. The genotypes of FMO3 and cytochrome P450 (CYP) 2C19 were detected by PCR-restriction fragment length polymorphism. Patients with neutropenia were screened according to the CYP2C19 metabolic phenotype and other inclusion criteria. Five days after empirical administration of VRC, blood concentrations of VRC and nitrogen oxides in patients' blood were determined by liquid chromatography-electrospray tandem mass spectrometry (LC-ESI MS/MS). Serum parameters and clinical adverse reaction symptoms in the medical records were collected and statistically analyzed. RESULTS: A total of 165 patients with neutropenia with the intermediate metabolic phenotype of CYP2C19 were screened. At the initial stage of oral VRC treatment, patients with the FMO3 E308G genotype had a poorer plasma disposal ability to VRC than those with the wide type of FMO3 (WT) genotype (p = 0.0005). Moreover, patients with the FMO3 E308G genotype were more likely to have adverse drug reactions and abnormal serum parameters after receiving VRC treatment. For example, the serum potassium level in the FMO3 E308G genotype group was significantly lower than that in the WT group (p = 0.028), the abnormal level of total bilirubin in the FMO3 E308G genotype group was significantly higher than that in the WT group (p = 0.049), and the aspartate aminotransferase level in the E308G group was significantly higher than that in the WT group (p = 0.05). The incidence of atopic dermatitis and visual impairment in the FMO3 E308G genotype group was 67 and 75%, respectively, and the incidences of peripheral neuroedema, headache, and diarrhea were 57, 50, and 60%, respectively, which were significantly different from those in the WT group. CONCLUSION: FMO3 E308G reduces the activity of the FMO3 enzyme by decreasing the metabolic ability of VRC, which increases the plasma concentration of VRC and may also lead to adverse reactions in patients with FN.

Gender differences in plasma pharmacokinetics and hepatic metabolism of geissoschizine methyl ether from Uncaria hook in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Geissoschizine methyl ether (GM), an indole alkaloid from Uncaria hook, is an active ingredient in the traditional Japanese Kampo medicine yokukansan, which is used to treat neurosis, insomnia, irritability, and night crying in children. AIM OF THE STUDY: Recent our pharmacokinetic studies suggested that there may be gender differences in the plasma concentrations of GM in rats, but not in humans. However, the details of this difference remain unverified. The purpose of this study was to clarify the reasons for the gender differences in rats. MATERIALS AND METHODS: GM plasma pharmacokinetics was compared in male and female rats orally administered yokukansan (4 g/kg). To confirm the involvement of cytochrome P450 (CYP) in GM liver metabolism, GM was incubated with male and female rat liver S9 fraction in the absence or presence of 1-aminobenzotriazole (a nonspecific CYP inhibitor). CYP isoforms involved in GM metabolism were estimated using recombinant rat CYP isoforms and anti-rat CYP antibodies. RESULTS: The maximum GM plasma concentrations were significantly higher in female than in male rats. When GM was incubated with rat liver S9 fractions, GM reduction was more striking in male S9 (69.3%) than that in female S9 (10.0%) and was completely blocked with nonspecific CYP inhibitor 1-aminobenzotriazole. Screening experiments using recombinant rat cytochrome P450 (CYP) isoforms showed that CYP1A1, CYP2C6, CYP2C11, CYP2D1, and CYP3A2 were involved in GM metabolism. Of these CYP isoforms, the use of anti-rat CYP antibodies indicated that male-dependent CYP2C11 and CYP3A2 were predominantly involved in the liver microsomal GM metabolism with gender differences. CONCLUSIONS: These results suggest that the cause of gender differences in plasma GM pharmacokinetics in rats is most likely because of male-dependent CYP2C11 and CYP3A2, and provide also useful information to further evaluate the pharmacological and toxicological effects in future. This study is the first to demonstrate that the gender differences in plasma GM pharmacokinetics in rats are caused by the gender-dependent metabolism of GM.

Influence of exogenous phytase supplementation on phytate degradation, plasma inositol, alkaline phosphatase, and glucose concentrations of broilers at 28 days of age.

Inositol is the final product of phytate degradation, which has the potential to serve as an indicator of phytase efficacy. An experiment was conducted to evaluate effects of supplementing broiler diets with phytase on phytate degradation and plasma inositol concentrations at 28 d of age. Twenty-four Ross × Ross 708 male chicks were placed in battery cages (4 birds per cage) from 1 to 21 d of age and individually from 22 to 28 d of age. At 27 d of age, a catheter was placed in the brachial vein of broilers to avoid repeated puncture of the vein during blood collection. At 28 d of age, broilers received 1 of 3 experimental diets formulated to contain 0, 400, or 1,200 phytase units (FTU)/kg, respectively, in diet 1, 2, and 3. Blood was collected 1 h before feeding experimental diets and from 20 to 240 min after feeding experimental diets at 20-min intervals with a final blood collection at 480 min to determine plasma inositol concentrations. Inositol phosphate (IP) ester degradation was determined in gizzard contents and ileal digesta. Broilers provided the 1,200 FTU/kg phytase diet had 60% less (P < 0.01) IP6 concentration in gizzard content (1,264 vs. 4,176 nmol/g) and ileal digesta (13,472 vs. 33,244 nmol/g) than birds fed the 400 FTU/kg diet. Adding phytase at 1,200 FTU/kg increased (P < 0.01) inositol concentrations in gizzard content and ileal digesta of broilers by 2.5 (2,703 vs. 1,071 nmol/g) and 3.5 (16,485 vs. 4,667 nmol/g) fold, respectively, compared with adding 400 FTU/kg. Plasma inositol concentration of broilers was not different (P = 0.94) among the dietary treatments at each collection time. Inositol liberation in the digesta of broilers fed diets with 1,200 FTU/kg phytase did not translate to increased plasma inositol concentrations, which warrants further investigation.

Effects of embryonic exposure to chromium (VI) on blood parameters and liver microstructure of 1-day-old chickens.

Hexavalent chromium (Cr(VI)) has carcinogenic, nephrotoxic, hepatotoxic, and neurotoxic effects. Exposure to Cr(VI) can also lead to hematological alterations and blood biochemical changes. The literature on Cr(VI) toxicity concerns mostly adult forms of vertebrates. In this study, an attempt was made to determine the effect on the developing chicken embryo of Cr(VI) in ovo administration. It was observed that chromium affected the hatchability of chicks in a dose-dependent manner. At a dose from 25 to 250 µg per egg, Cr(VI) resulted in a statistically significant reduction of hatchability. Chromium administrated at lower doses (1.56 and 2.5 µg per egg) caused a statistically insignificant increase of hatchability. However, chromium at a level of LD50 (15.6 µg per egg) or 1/10 LD50 (1.56 per egg) did not cause major changes in hematological parameters or plasma biochemical indices in newly hatched chicks. The same doses did not lead to any histopathological changes in the liver.

21-Day dermal exposure to aircraft engine oils: effects on esterase activities in brain and liver tissues, blood, plasma, and clinical chemistry parameters for Sprague Dawley rats.

This dermal study tested the potential toxicity of grade 3 (G3) and 4 (G4) organophosphate-containing aircraft engine oils in both new (G3-N, G4-N) and used states (G3-U, G4-U) to alter esterase activities in blood, brain and liver tissues, clinical chemistry parameters, and electrophysiology of hippocampal neurons. A 300 µl volume of undiluted oil was applied in Hill Top Chamber Systems®, then attached to fur-free test sites on backs of male and female Sprague Dawley rats for 6 hr/day, 5 days/week for 21 days. Recovery rats received similar treatments and kept for 14 days post-exposure to screen for reversibility, persistence, or delayed occurrence of toxicity. In brain, both versions of G3 and G4 significantly decreased (32-41%) female acetylcholinesterase (AChE) activity while in males only G3-N and G4-N reduced (33%) AChE activity. Oils did not markedly affect AChE in liver, regardless of gender. In whole blood, G3-U decreased female AChE (29%) which persisted during recovery (32%). G4-N significantly lowered (29%) butyrylcholinesterase (BChE) in male plasma, but this effect was resolved during recovery. For clinical chemistry indices, only globulin levels in female plasma significantly increased following G3-N or G4-N exposure. Preliminary electrophysiology data suggested that effects of both versions of G3 and G4 on hippocampal function may be gender dependent. Aircraft maintenance workers may be at risk if precautions are not taken to minimize long-term aircraft oil exposure.