scholarly journals Lung Microdialysis Study of Levofloxacin in Rats following Intravenous Infusion at Steady State

2008 ◽  
Vol 52 (9) ◽  
pp. 3074-3077 ◽  
Author(s):  
Sandrine Marchand ◽  
Denis Frasca ◽  
Claire Dahyot-Fizelier ◽  
Céline Breheret ◽  
Olivier Mimoz ◽  
...  
Keyword(s):  
Steady State ◽  
Intravenous Infusion ◽  
High Performance ◽  
Drug Infusion ◽  
Dose Administration ◽  
Muscle Tissues ◽  
Interesting Approach ◽  
Microdialysis Study

ABSTRACT Lung microdialysis has been used with rats to investigate antibiotic distribution after single-dose administration. However, conducting such experiments after intravenous infusion at steady state would constitute a more convenient alternative, which was evaluated here, using levofloxacin (LVX) as a test compound. Microdialysis probes were inserted in blood and muscle, used as a comparator, between 9:00 a.m. and 11:00 a.m. Intravenous LVX infusion was started 6 h later and maintained until the end of the experiment at a rate of 1.0 mg·h−1. Lung microdialysis probes were inserted on the morning of the next day. Rats were kept anesthetized during dialysate collection. In vivo probe recoveries were estimated by retrodialysis using a calibrator method, with ciprofloxacin (CIP) as the calibrator. LVX and CIP were analyzed in dialysates by high-performance liquid chromatography. The steady-state tissue-to-blood unbound-drug concentration ratios were 1.00 ± 0.15 in muscle tissues and 1.06 ± 0.40 in lungs, suggesting passive distribution of LVX in tissue. Although providing no information on rate of distribution, microdialysis investigations following drug infusion at steady state appear to be an interesting approach for characterization of antibiotic distribution in rat lungs.

Computer Control of Drug Delivery by Continuous Intravenous Infusion

2015 ◽  
Vol 122 (3) ◽  
pp. 647-658 ◽  
Author(s):  
Michael J. Parker ◽  
Mark A. Lovich ◽  
Amy C. Tsao ◽  
Abraham E. Wei ◽  
Matthew G. Wakim ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Steady State ◽  
Intravenous Infusion ◽  
Computer Control ◽  
Dead Volume ◽  
Dominant Factor ◽  
Drug Infusion ◽  
Temporal Lags

Abstract Background: Intravenous drug infusion driven by syringe pumps may lead to substantial temporal lags in achieving steady-state delivery at target levels when using very low flow rates (“microinfusion”). This study evaluated computer algorithms for reducing temporal lags via coordinated control of drug and carrier flows. Methods: Novel computer control algorithms were developed based on mathematical models of fluid flow. Algorithm 1 controlled initiation of drug infusion and algorithm 2 controlled changes to ongoing steady-state infusions. These algorithms were tested in vitro and in vivo using typical high and low dead volume infusion system architectures. One syringe pump infused a carrier fluid and a second infused drug. Drug and carrier flowed together via a manifold through standard central venous catheters. Samples were collected in vitro for quantitative delivery analysis. Parameters including left ventricular max dP/dt were recorded in vivo. Results: Regulation by algorithm 1 reduced delivery delay in vitro during infusion initiation by 69% (low dead volume) and 78% (high dead volume). Algorithmic control in vivo measuring % change in max dP/dt showed similar results (55% for low dead volume and 64% for high dead volume). Algorithm 2 yielded greater precision in matching the magnitude and timing of intended changes in vivo and in vitro. Conclusions: Compared with conventional methods, algorithm-based computer control of carrier and drug flows can improve drug delivery by pump-driven intravenous infusion to better match intent. For norepinephrine infusions, the amount of drug reaching the bloodstream per time appears to be a dominant factor in the hemodynamic response to infusion.

scholarly journals Functional characterization of the human tRNA methyltransferases TRMT10A and TRMT10B

2020 ◽  
Vol 48 (11) ◽  
pp. 6157-6169 ◽  
Author(s):  
Elisa Vilardo ◽  
Fabian Amman ◽  
Ursula Toth ◽  
Annika Kotter ◽  
Mark Helm ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Steady State ◽  
Human Genome ◽  
Functional Significance ◽  
Functional Characterization ◽  
Trna Methyltransferase ◽  
Steady State Levels

Abstract The TRM10 family of methyltransferases is responsible for the N1-methylation of purines at position 9 of tRNAs in Archaea and Eukarya. The human genome encodes three TRM10-type enzymes, of which only the mitochondrial TRMT10C was previously characterized in detail, whereas the functional significance of the two presumably nuclear enzymes TRMT10A and TRMT10B remained unexplained. Here we show that TRMT10A is m1G9-specific and methylates a subset of nuclear-encoded tRNAs, whilst TRMT10B is the first m1A9-specific tRNA methyltransferase found in eukaryotes and is responsible for the modification of a single nuclear-encoded tRNA. Furthermore, we show that the lack of G9 methylation causes a decrease in the steady-state levels of the initiator tRNAiMet-CAT and an alteration in its further post-transcriptional modification. Our work finally clarifies the function of TRMT10A and TRMT10B in vivo and provides evidence that the loss of TRMT10A affects the pool of cytosolic tRNAs required for protein synthesis.

scholarly journals Characterization of the PduS Cobalamin Reductase of Salmonellaenterica and Its Role in the Pdu Microcompartment

2010 ◽  
Vol 192 (19) ◽  
pp. 5071-5080 ◽  
Author(s):  
Shouqiang Cheng ◽  
Thomas A. Bobik
Keyword(s):  
Mass Spectrometry ◽  
High Performance ◽  
Cobalt Atom ◽  
Flavin Mononucleotide ◽  
Vitamin B ◽  
Genetic Studies ◽  
Coenzyme B ◽  
Assimilation System

ABSTRACT Salmonella enterica degrades 1,2-propanediol (1,2-PD) in a coenzyme B12 (adenosylcobalamin, AdoCbl)-dependent fashion. Salmonella obtains AdoCbl by assimilation of complex precursors, such as vitamin B12 and hydroxocobalamin. Assimilation of these compounds requires reduction of their central cobalt atom from Co3+ to Co2+ to Co+, followed by adenosylation to AdoCbl. In this work, the His6-tagged PduS cobalamin reductase from S. enterica was produced at high levels in Escherichia coli, purified, and characterized. The anaerobically purified enzyme reduced cob(III)alamin to cob(II)alamin at a rate of 42.3 ± 3.2 μmol min−1 mg−1, and it reduced cob(II)alamin to cob(I)alamin at a rate of 54.5 ± 4.2 nmol min−1 mg−1 protein. The apparent K m values of PduS-His6 were 10.1 ± 0.7 μM for NADH and 67.5 ± 8.2 μM for hydroxocobalamin in cob(III)alamin reduction. The apparent K m values for cob(II)alamin reduction were 27.5 ± 2.4 μM with NADH as the substrate and 72.4 ± 9.5 μM with cob(II)alamin as the substrate. High-performance liquid chromatography (HPLC) and mass spectrometry (MS) indicated that each monomer of PduS contained one molecule of noncovalently bound flavin mononucleotide (FMN). Genetic studies showed that a pduS deletion decreased the growth rate of Salmonella on 1,2-PD, supporting a role in cobalamin reduction in vivo. Further studies demonstrated that the PduS protein is a component of the Pdu microcompartments (MCPs) used for 1,2-PD degradation and that it interacts with the PduO adenosyltransferase, which catalyzes the terminal step of AdoCbl synthesis. These studies further characterize PduS, an unusual MCP-associated cobalamin reductase, and, in conjunction with prior results, indicate that the Pdu MCP encapsulates a complete cobalamin assimilation system.

Phase I clinical and pharmacokinetic evaluation of high-dose mitoxantrone in combination with cytarabine in patients with acute leukemia.

1993 ◽  
Vol 11 (10) ◽  
pp. 2002-2009 ◽  
Author(s):  
E J Feldman ◽  
D S Alberts ◽  
Z Arlin ◽  
T Ahmed ◽  
A Mittelman ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Phase I ◽  
Intravenous Infusion ◽  
High Performance ◽  
Lymphoblastic Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Advanced Phase

PURPOSE To determine the maximally tolerated dose of mitoxantrone in combination with cytarabine in patients with acute leukemia and advanced phases of chronic myelogenous leukemia (CML), and to assess the pharmacokinetics of high-dose mitoxantrone in this patient population. PATIENTS AND METHODS In a phase I study, 68 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and accelerated- and blastic-phase CML received induction therapy consisting of cytarabine 3 g/m2 by infusion over 3 hours daily for 5 days, with escalating doses of mitoxantrone 40 to 80 mg/m2 over 1 to 2 days by intravenous infusion over 15 minutes. Mitoxantrone pharmacokinetics were evaluated by high-performance liquid chromatography (HPLC) in 15 patients given a single dose of mitoxantrone ranging from 40 to 80 mg/m2 in combination with cytarabine. RESULTS Severe, but reversible hyperbilirubinemia (> three times normal) was considered the dose-limiting toxicity, and was observed in 25% of all patients and in 35% of those who received 70 to 80 mg/m2 of mitoxantrone. Other extramedullary toxicity, including cardiac dysfunction, was mild. Myelosuppression was universal and the median time to complete remission (CR) was 28 days (range, 19 to 77). The CR rate for previously untreated and relapsed patients with AML was 85% (17 of 20) and 38% (seven of 18), respectively. Eighty-three percent (15 of 18) of patients with ALL achieved a CR, including all patients with previously untreated disease. Eight of 12 patients with advanced-phase CML achieved a CR. No significant changes in mean mitoxantrone plasma elimination rates (ie, terminal plasma half-life and total-body clearance rate) occurred as the mitoxantrone dose doubled, indicating linear pharmacokinetics. CONCLUSIONS The recommended phase II dose of mitoxantrone is 80 mg/m2 administered over 15 minutes as a single intravenous infusion in combination with cytarabine 3 g/m2/d for 5 days. At this dose, high concentrations of mitoxantrone are achievable in vivo to levels that have been shown to be extremely cytotoxic in vitro.

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