Drug In Blood Plasma Research Articles

Sensitive Determination of Moxifloxacin HCl in Pharmaceuticals or Human Plasma Using Luminescence or Eye Vision

A new probe based on the complex of 1,2 dihydro-2-oxoquinoloine-4-carboxylic acid (DOCA) as a ligand with Europium (III) ion was developed for the quantitation of Moxifloxacin HCl (Moxi.HCl) in pharmaceuticals and human plasma using a luminescence method. The metal to ligand ratio of the complex is 1:2 as determined by a Job plot. The determination of Moxi.HCl is based on static quenching of the luminescence of the probe upon coordination of Moxi.HCl. The negative value for ΔG proves that this reaction is spontaneous. The calibration curve was constructed based on a Stern–Volmer equation and the quantitation range was 0.05–80 µg mL−1. This is low enough to determine the drug in blood plasma, even hours after administration, which is not feasible with the methods published so far. The LOD was 15 ng mL−1. The accuracy of the method was demonstrated by good recoveries of spiking experiments in tablets, ophthalmic eyedrops and human blood plasma, where the mean recovery was 99% with RSDs below 5%. The method was validated by closely matching concentrations of the drug found in all these real samples by HPLC. Additionally, Moxi.HCl can be assessed semi-quantitatively by eye vision upon excitation with a UV lamp at 365 nm by a gradual color shift from red to blue with increasing concentrations of Moxi.HCl.

Coating of silver nanoparticles (AgNPs) on glass fibers by a chemical method as plasmonic surface-enhanced Raman spectroscopy (SERS) sensors to detect molecular vibrations of Doxorubicin (DOX) drug in blood plasma

In the present study, Doxorubicin (DOX) drug in healthy blood plasma was the focus of the investigation by surface-enhanced Raman scattering (SERS). In recent years, chemotherapy has been the most popular treatment for various types of cancer; however, its adverse side effects on the patient's health have made a negative aspect regarding the use of this technique. DOX is the most common chemotherapy drug and is used for the treatment of an extensive range of human malignancies. The surface-enhanced Raman scattering (SERS) is a precise technique for the detection of chemicals and biomaterials with significantly low concentrations. The glass fiber substrates coated with silver nanoparticles (AgNPs) have been used to detect DOX. First, the Tollens' method was applied to prepare the AgNPs, and the characteristics of fabricated AgNPs were evaluated using ultraviolet–visible spectroscopy (UV–Vis) and X-ray diffraction (XRD). Then, AgNPs were coated on the glass fiber substrate by a chemical method. Finally, the enhancement of the Raman signal resulted from the molecular vibrations of DOX was evaluated using these SERS-active substrates as plasmonic and Raman spectroscopy sensors. Afterward, for making the sensors practical, the DOX in blood plasma were deposited on the fabricated sensors, and the Raman vibrations were evaluated. The SERS-active substrates, AgNPs deposited on glass fiber substrates, were fabricated for the detection of DOX in and out of the blood plasma; the limit of detection (LOD) for both was 10 −10 M, and the mean relative standard deviation at concentrations of 10 −10 M of DOX out of blood plasma, and 10 −10 M of DOX in blood plasma were obtained to be 3.76% and 3.61%, respectively for ten repeated measurements in which the AgNPs were SERS-active substrates of the biosensors for detecting the DOX. In addition, the enhancement factor was calculated both experimentally and via finite-difference time-domain (FDTD) simulation, which was 29.76 × 10 3 and 24.95 × 10 3 , respectively. Therefore, these SERS-active substrates can be used to develop microsensors and show positive results for SERS-based investigations.

5-Fluorouracil Loaded Orally Administered WGA-decorated Poly(lacticco- glycolic Acid) Nanoparticles for Treatment of Colorectal Cancer: In Vivo Evaluation

Background:: Several studies have suggested the potential aptitude of polylactic-co-glycolic acid (PLGA)-derived nanoparticles (NPs) to improve the antitumor efficacy of anticancer drugs against colon cancer. Further, conjugation of lectins over the surface of the NPs may ameliorate interaction and thus enhance the attachment of NPs with receptors. Objective:: The main goal of the study was to prepare and evaluate the targeting potential (in vivo) of the optimized NPs against colorectal cancer. Methods:: The 5-fluorouracil (5-FU) loaded and wheat germ agglutinin (WGA)-conjugated PLGA- NPs (WFUNPs) were prepared and then they were evaluated in vivo for targeting aptitude of formulation using gamma scintigraphy after oral delivery. The WGA-conjugated and non-conjugated optimized NPs were compared for any significant results. Further, optimized formulations were also assessed for different parameters such as radiolabeling efficiency, sodium pertechnetate uptake, stability of NPs, and organ distribution study. Results:: Findings suggested prolonged retention of 99mTc-tagged WFUNPs in the colonic region after 24 h study. Eventually, the outcome from conjugated formulation revealed enhanced bioavailability of the drug in blood plasma for up to 24 h. Conclusion:: In conclusion, WGA-conjugation to NPs could improve the performance of the PLGA- NPs in the treatment of colorectal cancer.

QbD-based design and characterization of mucoadhesive microspheres of quetiapine fumarate with improved oral bioavailability and brain biodistribution potential

The present work aims to discuss on Quality by Design based development and characterization of the sustained release mucoadhesive microspheres of quetiapine fumarate. The microspheres were prepared by non-aqueous solvent evaporation process. Factor screening study was carried out using fractional factorial design for identifying the influential factors. Systematic optimization of microspheres was accomplished by Box-Behnken design and characterized for particle size, entrapment efficiency, in vitro drug release and ex vivo mucoadhesion strength, which indicated that microspheres were consequence to be spherical and free flowing in nature. The microspheres exhibited high drug entrapment efficiency and in vitro drug release in a sustained manner, which was considered to be dependent on the concentration of rate controlling polymers. Ex vivo wash-off test on microspheres indicated good mucoadhesive property on excised goat intestinal mucosa. Out of all the accepted formulation, F6 was preferred as the optimized formulation. In vivo pharmacokinetic and brain biodistribution study revealed significant increase in the levels of drug in blood plasma and brain homogenates from the optimized formulation vis-à-vis the pure drug suspension. Overall, current study corroborated significant improvement in the biopharmaceutical attributes of quetiapine fumarate from mucoadhesive microspheres, which can be effectively used for management of depression and schizophrenia.

Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood.

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first-line treatment for HIV-infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric-adult, and 4 pediatric studies (age 6 weeks to 63years) with 3 formulations (gel-capsule, liquid, melt-extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP ) times hepatic extraction (EH ), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight-band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration-time curve (94.8 vs >107.4μghr/mL) and minimum observed concentration of drug in blood plasma (5.0vs> 7.1μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.

A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration-QTc (C-QTc) Analysis.

Most new chemical entities with systemic availability are required to be tested in a study specifically designed to exclude drug-induced corrected QT interval (QTc) effects, the so-called thorough QT/QTc study. Mirtazapine (Remeron™) is an antidepressant indicated for the treatment of episodes of major depression, which was originally approved in 1994 without a thorough QT study. To evaluate the proarrhythmic potential of mirtazapine, we performed a QT/QTc study with a novel design including implementation of an analysis of the relationship between drug concentration and the QTc interval as the primary assessment of proarrhythmic potential of mirtazapine. The least squares mean differences of the corrected QT interval between mirtazapine and placebo at the geometric mean maximum concentration of drug in blood plasma (90% confidence interval) were 2.39 milliseconds (0.70, 4.07) at the 45-mg dose and 4.00 milliseconds (1.18, 6.83) at the 75-mg dose level of mirtazapine. Modeling of the concentration/QTc relationship for moxifloxacin confirmed that the assay method was adequately sensitive. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45-mg and 75-mg doses of mirtazapine was not at a level generally considered to be clinically meaningful. This study further demonstrates that analysis of the relationship between drug concentration and the QTc interval may be a reasonable alternative to traditional TQT studies to assess risk of QT prolongation.

Clinical Pharmacokinetics and Drug‐Drug Interaction Potential for Coadministered SCY‐078, an Oral Fungicidal Glucan Synthase Inhibitor, and Tacrolimus

SCY-078 is an orally bioavailable triterpenoid glucan synthase inhibitor in clinical development as an intravenous and oral treatment of fungal infections caused by Candida and Aspergillus species. This was a sequential, single-center, open-label phase 1 study to assess the drug-drug interaction potential between SCY-078 and tacrolimus during concomitant administration in healthy subjects. In cohort 1, period 1, subjects received a single oral dose of tacrolimus 2mg in the fasted state. In period 2 after a ≥15 day washout, subjects received a single loading dose of SCY-078 1250mg on day 1 followed by maintenance doses of SCY-780 750mg on days 2 through 8. On day 3 of period 2, subjects also received a single dose of tacrolimus 2mg concurrent with SCY-078. In cohort 2, subjects received a loading dose of SCY-078 1250mg on day 1 followed by maintenance doses of SCY-780 750mg on days 2 and 3. Pharmacokinetic (PK) parameters were compared to assess both the impact of steady-state SCY-078 on tacrolimus and the impact of tacrolimus on the PK of steady-state SCY-078. The concurrent coadministration of tacrolimus and SCY-078 had no effect on the maximum blood levels of tacrolimus, as evidenced by no change in maximum concentration of drug in blood plasma and a 1.4-fold increase in total area under the plasma drug concentration-time curve. The concurrent coadministration of tacrolimus and SCY-078 resulted in a weaker interaction than typically observed with the azole class of antifungals. The current data indicate that an initial dose adjustment for tacrolimus may not be warranted when combined with SCY-078, as the modest increase in exposure is less than the therapeutic window, although tacrolimus monitoring, as with addition of any new medication, is recommended. These results support the coadministration of SCY-078 and tacrolimus.

Towards interference free HPLC-SERS for the trace analysis of drug metabolites in biological fluids

Sofosbuvir metabolite, 2′-deoxy-2′-fluoro-2′-C-methyluridine (PSI-6206) was studied for the first time by surface enhanced Raman spectroscopy (SERS) using the paper-based SERS substrate. The quantification limit of PSI-6206 by SERS was found to be 13ngL−1 (R2 value=0.959, RSD=5.23%). For the structural and quantitative analysis of PSI-6206 in blood plasma, an interference-free HPLC-SERS method was developed and compared to HPLC-DAD and HPLC–MS methods. The SERS quantification of the drug by the paper substrate was 4 orders of magnitude more sensitive than that by the diode array detector. In addition, the SERS detection provided unique structural identification of the drug in blood plasma, similar to Mass spectroscopy detector. Due to the disposable nature of the SERS substrate, the new method does not suffer from the known “memory effect” which is known to lead to false positive identification in traditional HPLC-SERS methods. Therefore, the presented HPLC-paper SERS platform holds great potential for the sensitive and cost effective determination of drugs and their metabolites in biological fluids.

Superparamagnetic anisotropic nano-assemblies with longer blood circulation in vivo: a highly efficient drug delivery carrier for leukemia therapy.

Leukemia, unlike solid tumors, has no definite shape and spreads throughout the whole circulatory system, therefore the therapy of leukemia requires medication to stay longer in the circulatory system. Anisotropic nanoparticles, showing longer blood circulating life than that of isotropic nanoparticles reported in previous research, meet the demands of leukemia therapy. Based on this strategy, superparamagnetic anisotropic nano-assemblies (SANs) were fabricated and loaded with vincristine (VCR) to form VCR-SANs. When compared to the same dose of VCR-loaded isotropic nano-assemblies (SINs), the decrease in the leukocytes count and the positive expression ratio of CD13 in the VCR-SANs group were 19.38% and 16.4%, respectively, which indicated the improved anti-leukemia activity of the VCR-SANs. From the results of the pharmacokinetics study, the VCR-SANs remarkably held the amount of drug removed from the whole body per unit time half of the isotropic group and the concentration of drug in blood plasma against time was 2.1 times the isotropic group, demonstrating the rapid and sustained release behavior and longer blood circulation when combined with the results of in vivo tissue distribution studies. In summary, anisotropic nano-assemblies were found to be more promising than isotropic nano-assemblies via our in vivo and in vitro examinations.

Monitoring the distribution of warfarin in blood plasma.

Warfarin is an anticoagulant drug extensively used in the treatment and prevention of thrombotic disorders. Previous studies have shown that warfarin binds extensively to blood plasma proteins and that only a small fraction of the drug is unbound and thus available for therapeutic function. Both warfarin's narrow therapeutic window and the susceptibility of anticoagulant function to patient-dependent factors necessitate regular monitoring. In this study, we have shown that the lifetimes for each of the various bound and free forms of the drug in blood plasma can be quantified in situ by time-correlated single-photon counting fluorescence spectroscopy over the clinically significant concentration range. A relationship between the blood coagulation and the distribution of fluorescence lifetimes was observed. The in situ detection of clinically relevant concentrations of warfarin in its respective bound and unbound forms could provide a prognostic tool for use in patient treatment.

Low-level detection of anti-cancer drug in blood plasma using microwave-treated gold-polystyrene beads as surface-enhanced Raman scattering substrates

We report on a low-level detection of anti-cancer drug (paclitaxel) in blood plasma using microwave-treated gold (Au) film-polystyrene (PS) beads as surface-enhanced Raman scattering (SERS) substrates. SERS spectra of paclitaxel can be acquired within 10 s at a concentration of 1 × 10 −8 M in blood plasma adsorbed on the modified Au-PS SERS substrates. The concentrations of paclitaxel ranging from 1.0 × 10 −8 to 1.0 × 10 −7 M in blood plasma can be well estimated with an accuracy of ∼3.8 × 10 −9 M using SERS technique. This work shows the promise of applying microwave-modified Au-PS as SERS substrates for rapid and accurate monitoring of the anti-cancer drug in blood plasma for immediate treatment decisions during cancer therapy.

A Bayesian Approach for Dose-Escalation in a Phase I Clinical Trial Incorporating Pharmacodynamic Endpoints

Bayesian decision procedures have already been proposed for and implemented in Phase I dose-escalation studies in healthy volunteers. The procedures have been based on pharmacokinetic responses reflecting the concentration of the drug in blood plasma and are conducted to learn about the dose-response relationship while avoiding excessive concentrations. However, in many dose-escalation studies, pharmacodynamic endpoints such as heart rate or blood pressure are observed, and it is these that should be used to control dose-escalation. These endpoints introduce additional complexity into the modeling of the problem relative to pharmacokinetic responses. Firstly, there are responses available following placebo administrations. Secondly, the pharmacodynamic responses are related directly to measurable plasma concentrations, which in turn are related to dose. Motivated by experience of data from a real study conducted in a conventional manner, this paper presents and evaluates a Bayesian procedure devised for the simultaneous monitoring of pharmacodynamic and pharmacokinetic responses. Account is also taken of the incidence of adverse events. Following logarithmic transformations, a linear model is used to relate dose to the pharmacokinetic endpoint and a quadratic model to relate the latter to the pharmacodynamic endpoint. A logistic model is used to relate the pharmacokinetic endpoint to the risk of an adverse event.

Binding of trazodone hydrochloride with human serum albumin: A spectroscopic study

The binding of trazodone hydrochloride (TZH) to human serum albumin (HSA) was investigated by spectroscopic techniques. Various binding parameters have been evaluated. Negative enthalpy and positive entropy values indicated that both hydrogen bond and hydrophobic forces played a major role in the binding of TZH to HSA. The distance, r between donor (HSA) and acceptor (TZH) was found to be 2.16 nm based on the Förster's theory of non-radiation energy transfer. The circular dichroism data indicated that the α-helicity of HSA decreased upon interaction with TZH. The binding constant of HSA–TZH was found to decrease in presence of common ions and hence, shortened the stored time of drug in blood plasma.

Markov Chain Monte Carlo Techniques for Studying Interoccasion and Intersubject Variability: Application to Pharmacokinetic Data

SUMMARY Values of pharmacokinetic parameters may seem to vary randomly between dosing occasions. An accurate explanation of the pharmacokinetic behaviour of a particular drug within a population therefore requires two major sources of variability to be accounted for, namely interoccasion variability and intersubject variability. A hierarchical model that recognizes these two sources of variation has been developed. Standard Bayesian techniques were applied to this statistical model, and a mathematical algorithm based on a Gibbs sampling strategy was derived. The accuracy of this algorithm’s determination of the interoccasion and intersubject variation in pharmacokinetic parameters was evaluated from various population analyses of several sets of simulated data. A comparison of results from these analyses with those obtained from parallel maximum likelihood analyses (NONMEM) showed that, for simple problems, the outputs from the two algorithms agreed well, whereas for more complex situations the NONMEM approach may be less accurate. Statistical analyses of a multioccasion data set of pharmacokinetic measurements on the drug metoprolol (the measurements being of concentrations of drug in blood plasma from human subjects) revealed substantial interoccasion variability for all structural model parameters. For some parameters, interoccasion variability appears to be the primary source of pharmacokinetic variation.

Automated Column Liquid Chromatographic Determination of a Basic Drug in Blood Plasma Using the Supported Liquid Membrane Technique for Sample Pretreatment

The determination of the basic drug Amperozide, one of its main metabolites, and a third related compound in human blood plasma is described. All three compounds include an amine functionality. The process is governed by a modified ASTED instrument (Gilson). The dialysis unit is exchanged for a supported liquid membrane (SLM), which gives a simultaneous cleanup and enrichment of the analytes. The ASTED is coupled to column liquid chromatographic equipment with UV detection

Rationale for rate-controlled drug delivery of cardiovascular drugs by the transdermal route

If the therapeutic effects of a drug are to be maximized and maintained while the side effects are minimized, an optimal concentration of drug in blood plasma must be sustained continuously. Conventional dosage forms such as tablest, capsules, or elixirs describe a peak-and-valley curve when their dosage intervals are charted, demonstrating great fluctuations in the safety and effectiveness of a drug during the dosage interval. The need for certain drugs to be delivered at a constant, or zero-order, rate has led to the development of rate-controlled drug delivery systems, which by definition deliver drug in precise quantities over time. One such system uses the transdermal route, which is discussed here in terms of convenience, compliance, reliability, and potential as a vehicle for cardiovascular agents.

Residues of Drugs in Eggs After Medication of Laying Hens for Eight Days

Drug residues in blood plasma, egg-white and -yolk have been measured for 3 weeks after 8 days of continuous treatment with sulphanilamide, sulphadimidine, sulphaquinoxaline and pyrimethamine. The results are discussed with reference to physiological data concerning eggwhite and -yolk formation. From this, it is concluded that a withdrawal period of at least 10 days after the disappearance of drug in blood plasma is necessary to avoid residues of drugs in eggs from treated hens.

Spectrophotofluorometric Determination of Methyltestosterone in Plasma or Serum

For determination of the relative bioavailability of methyltestosterone in man, a spectrophotofluorometric procedure was developed, based on fluorescence induced by hydrochloric acid and stabilized by ascorbic acid. The method is essentially specific and capable of assaying nanograms per milliliter amounts of unchanged drug in blood plasma or serum. The variability of determinations is associated with a relative standard deviation of less than 12%. The procedure was tested in a pilot study involving two healthy human volunteers, each administered a single 10-mg. methyltestosterone tablet. Serum concentrations in these subjects attained a maximum of about 30 ng./ml. within 1-2 hr. following administration of drug and then declined biphasically, with half-lives of approximately 1 hr. initially and changing to approximately 3.5 hr. within 3-4 hr. of dosage.

Effect of terephthalic acid upon the sulfadimethoxine content of blood plasma.

The effect of terephthalic acid (TPA) upon sulfadimethoxine contents in blood plasma was studied. The drug contents in blood plasma were increased by TPA feeding both in the rat and in the rabbit. The maximum contents of the drug in blood plasma were not so affected. However, 24 and 48 hr. after a single administration, they showed significant increases from that of the control. The drug excretion amounts in the urine of the TPA group was lower than those of the control and the plasma half-life of the drug was elongated by TPA administration, about 1.5 times in the rat and 1.9 times in the rabbit. Absorption of the drug through the gastrointestinal tract decreased with TPA administration and high contents of TPA might have a hindering effect on drug absorption from the small intestine. The contests of N4-acetate of the drug were increased by TPA administration. This increasing effect of TPA upon sulfadimethoxine seems to be concerned with excretion from the kidney. As a result, it is supposed that the plasma half-life of the drug is elongated.