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BACKGROUND: Conivaptan is a nonpeptide vasopressin V(1A)/V(2)-receptor antagonist that produces a controlled increase in serum sodium concentration in hospitalized patients with euvolemic or hyper-volemic hyponatremia. OBJECTIVE: This study evaluated the pharmacokinetics of conivaptan in patients with euvolemic or hypervolemic hyponatremia and with or without underlying congestive heart failure who were participating in an efficacy and tolerability clinical trial. METHODS: Data from an open-label, multicenter study were used to evaluate the pharmacokinetics of conivaptan in hyponatremic patients. Patients received a 20-mg loading dose intravenously over 30 minutes, followed by a continuous 4-day infusion of 20 or 40 mg/d. In the entire cohort, plasma conivaptan concentrations were determined at baseline, at the end of the loading dose (0.5 hour), at 24 hours, on days 3 and 4, and at the follow-up visit on day 11. A subset of patients at 2 study sites (the 'pharmacokineticrich' subset) provided additional samples for pharmacokinetic analysis on day 1 at 1, 4, and 24 hours; on day 2 at 24 hours; and on day 5 at 1, 2, 7, 12, and 24 hours. RESULTS: Plasma conivaptan concentrations were evaluated in 31 patients who received conivaptan 20 mg/d (mean [SD] age, 73.1 [14.3] years; weight, 68.1 [17.2] kg; 71.0% female; 87.1% white, 9.7% black, 3.2% other) and 172 patients who received co-nivaptan 40 mg/d (mean [SD] age, 71.5 [14.4] years; weight, 65.6 [15.9] kg; 64.0% female; 90.1% white, 6.4% black, 3.5% other). The pharmacokinetic-rich subset included 8 patients who received conivap-tan 20 mg/d (mean [SD] age, 76.3 [12.4] years; weight, 71.5 [14.7] kg; 87.5% female; 100% white) and 8 who received conivaptan 40 mg/d (mean [SD] age, 78.3 [7.9] years; weight, 71.3 [15.6] kg; 37.5% female; 100% white). In the overall patient group, plasma conivaptan concentrations were the highest after the 30-minute (C(0.5h)) loading dose (mean [SD] C(0.5h) = 733 [323] and 701 [343] ng/mL with conivap-tan 20 and 40 mg/d, respectively) and then declined during day 1 to concentrations (C(24h)) (mean [SD] C(24h) = 84 [78] and 215 [129] ng/mL with conivaptan 20 and 40 mg/d, respectively) that were maintained by the continuous infusion of 20 or 40 mg/d. At the end of infusion (96 hours), the mean (SD) plasma conivaptan concentrations were 176 (196) and 308 (321) ng/mL for conivaptan 20 and 40 mg/d, respectively. A ratio of 1.75 indicated near dose proportionality; however, interpatient variability was evident. No apparent differences in plasma conivaptan concentrations measured at 0.5 or 96 hours were observed between patients with euvolemic or hypervolemic hypona-tremia or between patients with or without congestive heart failure. In the pharmacokinetic-rich subset, for conivaptan 20 and 40 mg/d, respectively, conivaptan clearance was 18.7 and 9.5 L/h, the elimination t1/2 was 5.3 and 10.2 hours, and exposure to conivaptan in terms of AUC(infinity) was 6996 and 30,771 ng . h/mL. CONCLUSION: The results of this study suggest that the pharmacokinetics of conivaptan 20 and 40 mg/d do not differ by volume status or the presence or absence of congestive heart failure. [ABSTRACT FROM AUTHOR]

Sclerotinia sclerotiorum (Ss) is one of the most devastating fungal pathogens, causing huge yield loss in multiple economically important crops including oilseed rape. Plant resistance to Ss pertains to quantitative disease resistance (QDR) controlled by multiple minor genes. Genome-wide identification of genes involved in QDR to Ss is yet to be conducted. In this study, we integrated several assays including genome-wide association study (GWAS), multi-omics co-localization, and machine learning prediction to identify, on a genome-wide scale, genes involved in the oilseed rape QDR to Ss. Employing GWAS and multi-omics co-localization, we identified seven resistance-associated loci (RALs) associated with oilseed rape resistance to Ss. Furthermore, we developed a machine learning algorithm and named it Integrative Multi-Omics Analysis and Machine Learning for Target Gene Prediction (iMAP), which integrates multi-omics data to rapidly predict disease resistance-related genes within a broad chromosomal region. Through iMAP based on the identified RALs, we revealed multiple calcium signaling genes related to the QDR to Ss. Population-level analysis of selective sweeps and haplotypes of variants confirmed the positive selection of the predicted calcium signaling genes during evolution. Overall, this study has developed an algorithm that integrates multi-omics data and machine learning methods, providing a powerful tool for predicting target genes associated with specific traits. Furthermore, it makes a basis for further understanding the role and mechanisms of calcium signaling genes in the QDR to Ss., Competing Interests: The authors declare no conflicts of interest.

Purpose: ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose., Patients and Methods: Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly., Results: Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia., Conclusions: ARO-HIF2 downregulated HIF2α in advanced ccRCC-inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner., (©2024 The Authors; Published by the American Association for Cancer Research.)

Premature infants are prone to dyspnea after birth due to immature development, and some infants require respiratory assistance. However, the risk factors for respiratory assistance in premature infants are rarely reported. The present study enrolled 3,394 premature infants (665 infants had been provided with respiratory assistance and 2,729 had not used respiratory assistance) to retrospectively analyze the risk factors associated with respiratory aid. The multivariate logistic regression analysis demonstrated that placental abnormality [odds ratio (OR)=1.284; P=0.048], the male sex (OR=0.696; P=0.001), delivery via cesarean section (OR=1.538; P<0.001), low 1-min Apgar score (OR=0.727; P<0.001), low birth weight (OR=0.999; P=0.005) and low gestational age (OR=0.616; P<0.001) were independent risk factors for respiratory assistance in premature infants. Overall, a number of risk factors, including placental abnormality, cesarean section, low 1-min Apgar score, low birth weight and small gestational age, were identified for respiratory assistance in premature infants. By conducting a risk assessment of risk factors at birth and using this information to provide timely respiratory assistance, the survival rates of premature infants may increase., (Copyright: © Li et al.)

The unusual endoperoxide bridge is believed to be the active center for artemisinin activations. Our Raman study indicated that the active center endoperoxide bridge is more significantly influenced by impurity than other parts in artemisinin molecule. This phenomenon provides a Raman spectroscopy method for quantitative measurement of impurity content basing on the relative intensity ratio analysis of characteristic vibrational modes. The proposed Raman method can be a good alternative to high performance liquid chromatography, which is a commonly applied technique for measuring impurity content. Also, the Raman method can provide additional information of impurity homogeneity. In addition, Raman imaging is presented for easy visualization of impurity content and homogeneity in artemisinin simultaneously., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Parkinson disease is an age-related disorder of the central nervous system principally due to loss of dopamine-producing cells in the midbrain. Levodopa, in combination with carbidopa, is widely regarded as an effective treatment for the symptoms of Parkinson disease. A dose-response relationship is established for carbidopa-levodopa extended-release capsules (IPX066) in levodopa-naive Parkinson disease patients using a disease progression model. Unified Parkinson Disease Rating Scale (UPDRS) part II plus part III scores from 171 North American patients treated with placebo or IPX066 for approximately 30 weeks from a double-blind, parallel-group, dose-ranging study were used to develop the pharmacodynamic model. The model comprised 3 components: a linear function describing disease progression, a component describing placebo (or nonlevodopa) effects, and a component to describe the effect of levodopa. Natural disease progression in early Parkinson disease as measured by UPDRS was 11.6 units/year and faster in patients with more severe disease (Hoehn-Yahr stage 3). Maximum placebo/nonlevodopa response was 23.0% of baseline UPDRS. Maximum levodopa effect from IPX066 was 76.7% of baseline UPDRS, and the ED50 was 450 mg levodopa. Equilibration half-life for the effect compartment was 62.8 days. Increasing age increased and being female decreased equilibration half-life. The quantitative model allowed description of the entire time course of response to clinical trial intervention., (© 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Cryptochromes (CRY) are blue-light photoreceptors that mediate various light responses in plants and animals. It has long been demonstrated that Arabidopsis CRY (CRY1 and CRY2) C termini (CCT1 and CCT2) mediate light signaling through direct interaction with COP1. Most recently, CRY1 N terminus (CNT1) has been found to be involved in CRY1 signaling independent of CCT1, and implicated in the inhibition of gibberellin acids (GA)/brassinosteroids (BR)/auxin-responsive gene expression. Here, we performed RNA-Seq assay using transgenic plants expressing CCT1 fused to β-glucuronidase (GUS-CCT1, abbreviated as CCT1), which exhibit a constitutively photomorphogenic phenotype, and compared the results with those obtained previously from cry1cry2 mutant and the transgenic plants expressing CNT1 fused to nuclear localization signal sequence (NLS)-tagged YFP (CNT1-NLS-YFP, abbreviated as CNT1), which display enhanced responsiveness to blue light. We found that 2903 (67.85%) of the CRY-regulated genes are regulated by CCT1 and that 1095 of these CCT1-regulated genes are also regulated by CNT1. After annotating the gene functions, we found that CCT1 is involved in mediating CRY1 regulation of phytohormone-responsive genes, like CNT1, and that about half of the up-regulated genes by GA/BR/auxin are down-regulated by CCT1 and CNT1, consistent with the antagonistic role for CRY1 and these phytohormones in regulating hypocotyl elongation. Physiological studies showed that both CCT1 and CNT1 are likely involved in mediating CRY1 reduction of seedlings sensitivity to GA under blue light. Furthermore, protein expression studies demonstrate that the inhibition of GA promotion of HY5 degradation by CRY1 is likely mediated by CCT1, but not by CNT1. These results give genome-wide transcriptome information concerning the signaling mechanism of CRY1, unraveling possible involvement of its C and N termini in its regulation of response of GA and likely other phytohormones.

Chemotherapy is the primary treatment for both resectable and advanced gastric carcinoma, yet multiple drug resistance (MDR) of gastric carcinoma remains a significant therapeutic obstacle. The development of novel strategies to reduce MDR in gastric carcinoma would yield a better outcome following chemotherapy. ING4, a member of the inhibitor of growth (ING) tumor-suppressor family, possesses antitumor and radiosensitization or chemosensitization effects in a variety of human cancers. The present study investigated the effects and possible mechanisms of action of adenovirus-mediated ING4 (AdVING4) on the reversion of human gastric carcinoma cell MDR in vitro and in vivo in nude mouse xenografts. The data showed that the expression of ING4 mRNA and protein was dramatically downregulated (or lost) in gastric carcinoma SGC7901/CDDP cells after CDDP-induced MDR phenotype and in the parental SGC7901 cells. AdVING4‑induced ING4 expression reversed MDR and induced apoptosis of SGC7901/CDDP cells in vitro and in vivo in the SGC7901/CDDP xenograft tumors. Furthermore, AdVING4 substantially downregulated the expression of MDR-related proteins P-gp and MRP1 and apoptosis‑related proteins Bcl-2 and survivin, but upregulated the expression of apoptosis-related protein Bax in the SGC7901/CDDP xenograft tissues. The reversion effects elicited by AdVING4 on gastric cancer cell MDR were closely associated with the downregulation of ATP-binding cassette transporters and activation of apoptotic pathways. Thus, these findings suggest that AdVING4 may be a feasible modulator for the MDR phenotype of gastric carcinoma cells.

Vernakalant hydrochloride is a novel, predominantly atrial-selective antiarrhythmic drug that effectively and rapidly terminates atrial fibrillation (AF). Plasma vernakalant concentration data from 5 phase 2 and 3 clinical trials of vernakalant in patients with AF or atrial flutter and a phase 1 study in healthy volunteers were used to construct a population pharmacokinetic model. Plasma vernakalant concentration-time data were best fit by a 2-compartment mammillary model, with rapid first-order elimination from the central compartment. Median systemic clearance was 0.35 L/h/kg (or 28 L/h for an 80-kg patient), with intersubject variability estimated to be 40%. Clearance was significantly influenced by CYP2D6 genotype, age, serum creatinine concentration, and subject status (patient vs volunteer). The intercompartmental clearance was also influenced by subject status, whereas the volumes of the central compartment and peripheral compartment were unaffected by any covariates. Based on the final pharmacokinetic model, the area under the plasma vernakalant concentration-time curve from 0 to 90 minutes was estimated to be 15% higher in CYP2D6 poor metabolizers than extensive metabolizers, with age and serum creatinine having much smaller influences on exposure. These data suggest that dose adjustments based on patient characteristics, including use of concomitant drugs, are unnecessary for intravenous vernakalant.

Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [(14)C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [(14)C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC(0-∞); IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [(14)C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion., (©2011 Bentham Science Publishers Ltd.)

Vernakalant hydrochloride injection (RSD1235) is a relatively atrial-selective antiarrhythmic agent that converts atrial fibrillation rapidly to sinus rhythm. The pharmacokinetics of vernakalant were explored in healthy volunteers and in patients with atrial fibrillation or atrial flutter in 4 clinical studies. Key pharmacokinetic parameters analyzed were the maximum plasma concentration and the area under the plasma concentration-time curve. Vernakalant exhibited linear pharmacokinetics over the dose range of 0.1 mg/kg to 5.0 mg/kg in healthy subjects, and generally showed dose proportionality in patients with atrial fibrillation or atrial flutter who received 1 or 2 vernakalant infusions. Vernakalant was metabolized rapidly via 4-O-demethylation by cytochrome P450 (CYP)2D6 to its major metabolite RSD1385, which then circulated predominantly as an inactive glucuronide conjugate. In most patients, the maximum plasma concentration of RSD1385 glucuronide exceeded that of vernakalant. Unconjugated RSD1385 was found at low levels in all patients demonstrating either a cytochrome P450 CYP2D6 "extensive metabolizer" or "poor metabolizer" phenotype or genotype; however, CYP2D6 poor metabolizers had even lower levels of unconjugated RSD1385. The impact of CYP2D6 metabolizer status on vernakalant exposure was explored in patients with atrial fibrillation or atrial flutter who received a therapeutic regimen (3 mg/kg initially via 10-minute intravenous infusion followed by a second 2 mg/kg 10-minute infusion if atrial fibrillation persisted after a 15-minute observation period). In the subset that received 2 vernakalant infusions, there was little difference in vernakalant maximum plasma concentration or area under the plasma concentration-time curve from the start of the first infusion to 90 minutes between CYP2D6 poor metabolizers and extensive metabolizers or between those who did or did not receive concomitant CYP2D6-inhibitor medications. Gender, age, and renal function did not have a clinically significant influence on the pharmacokinetics of vernakalant. These results suggest that an assessment of CYP2D6 expression may not be needed when vernakalant is administered acutely and intravenously to patients with atrial fibrillation.

Purpose: To study the effect of protein and calorie malnutrition on in vitro drug metabolism of protein and calorie malnourished juvenile and adult rats., Method: Microsomal incubation was used as a means of monitoring drug metabolism changes, HPLC was employed to quantify metabolites and enzyme immunoassay (EIA) was used for rat growth hormone (rGH) monitoring., Results: Protein and calorie malnutrition significantly decreased levels of microsomal protein and total P450. Microsome of protein and calorie malnourished rats showed impaired testosterone 16alpha- and 2alpha- hydroxylation (CYP2C11), testosterone 6beta-hydroxylation (CYP3A), and testosterone 7alpha-hydroxylation (CYP2A1). Testosterone 16beta-hydroxylation (CYP2B1) did not show any significant change, neither in capacity nor affinity. The quantity and the secretion pattern of rGH were not altered in protein and calorie malnourished rats compared to those in healthy animals., Conclusions: Serum albumin is not a good indicator of malnutrition. The capacity and affinity of CYP2C11, CYP3A and CYP2A1 were compromised by protein and calorie malnutrition. The impairment of drug metabolism in protein and calorie malnourished rats was not caused by the alteration of rGH.