Journal articles on the topic 'Drug distribution ratios'
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Puanglamjeak, Mananya, Siriporn Pranee, and Samitthichai Seeyangnok. "Preparation of Crude Turmeric Extract Loaded Poly(Acrylamide-co-Acrylic Acid) Microspheres for Drug Release System." Materials Science Forum 990 (May 2020): 86–90. http://dx.doi.org/10.4028/www.scientific.net/msf.990.86.
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Crude turmeric extract (CTE), which is a natural substance, is obtained from Curcuma Longa L. This substance is widely used in pharmaceutical application because of its ability to treat various diseases. Dermatitis is one of the many diseases that can be treated by CTE due to their inhibition of gram-negative and gram-positive bacteria. CTE has short half-life and easy to degradation. Therefore, protection has to be applied on CTE to prevent from decomposition before applying to skin. This research mainly focuses on preparation of CTE loaded poly (acrylamide-co-acrylic acid) (PAMAA) hydrogel microspheres (HM) at 9:1, 8:2 and 7:3 mole ratios and investigation of the releasing profile of CTE from microsphere. The particle size distribution of PAMAA microsphere that is analyzed by SEM found that mole ratios of PAMAA with 9:1, 8:2 and 7:3 showed the narrow particle distribution with average particle size at 28.1±7.4, 25.5±6.6 and 23.2±5.5 respectively. Thermal decomposition property of PAMAA is confirmed by TGA and HM swelling ratios are confirmed by weight indicated that the percentage swelling ratios of PAMAA with 9:1, 8:2 and 7:3 mole ratios is 1500, 1230 and 780 respectively. CTE releasing profiles are confirmed by UV-Vis in the media solutions of PBS pH 8.5 and NaOH pH 12.
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Yatscoff, R. W., N. Honcharik, M. Lukowski, J. Thliveris, P. Chackowsky, and C. Faraci. "Distribution of cyclosporin G (NVa2 cyclosporin) in blood and plasma." Clinical Chemistry 39, no. 2 (February 1, 1993): 213–17. http://dx.doi.org/10.1093/clinchem/39.2.213.
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Abstract We report here on the distribution of cyclosporin G (CsG), an analog of cyclosporin A, in whole blood. CsG has a temperature-dependent distribution between erythrocytes (RBCs) and plasma. After 30 min at 37 degrees C, the plasma/whole blood and plasma/RBC ratios were relatively constant (0.7-0.8) up to CsG at 1000 micrograms/L. At 5000 micrograms/L, this ratio increased to 1.0-1.1 for plasma/whole blood and 1.7 for plasma/RBC. The primary CsG metabolites GM1 and GM9 were sequestered within RBCs to a greater extent than was the parent drug. In whole blood, approximately 2% of CsG was bound to granulocytes, 6% to lymphocytes, and 50-55% to RBC, and 35-40% was found in the plasma fraction. The free fraction of the drug as determined by ultracentrifugation was 5-6% and 13-17% of total drug at 37 and 4 degrees C, respectively. In plasma the drug was primarily associated with high-density lipoprotein (50-60%) and to a lesser degree with low-density (20-30%) and very-low-density (10%) lipoproteins.
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Chang, Hsuan Ping, Yuen Kiu Cheung, and Dhaval K. Shah. "Whole-Body Pharmacokinetics and Physiologically Based Pharmacokinetic Model for Monomethyl Auristatin E (MMAE)." Journal of Clinical Medicine 10, no. 6 (March 23, 2021): 1332. http://dx.doi.org/10.3390/jcm10061332.
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Monomethyl auristatin E (MMAE) is one of the most commonly used payloads for developing antibody–drug conjugates (ADC). However, limited studies have comprehensively evaluated the whole-body disposition of MMAE. Consequently, here, we have investigated the whole-body pharmacokinetics (PK) of MMAE in tumor-bearing mice. We show that while MMAE is rapidly eliminated from the plasma, it shows prolonged and extensive distribution in tissues, blood cells, and tumor. Highly perfused tissues (e.g., lung, kidney, heart, liver, and spleen) demonstrated tissue-to-plasma area under the concentration curve (AUC) ratios > 20, and poorly perfused tissues (e.g., fat, pancreas, skin, bone, and muscle) had ratios from 1.3 to 2.4. MMAE distribution was limited in the brain, and tumor had 8-fold higher exposure than plasma. A physiological-based pharmacokinetic (PBPK) model was developed to characterize the whole-body PK of MMAE, which accounted for perfusion/permeability-limited transfer of drug in the tissue, blood cell distribution of the drug, tissue/tumor retention of the drug, and plasma protein binding. The model was able to characterize the PK of MMAE in plasma, tissues, and tumor simultaneously, and model parameters were estimated with good precision. The MMAE PBPK model presented here can facilitate the development of a platform PBPK model for MMAE containing ADCs and help with their preclinical-to-clinical translation and clinical dose optimization.
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Ramesh, Yerikala, Abhilash Kaki Rohan, Balasaradhi Koorapati, and P. Sudarsanam. "Formulation and evaluation of almotriptan controlled release pellets." Journal of Drug Delivery and Therapeutics 9, no. 1-s (February 15, 2019): 312–18. http://dx.doi.org/10.22270/jddt.v9i1-s.2355.
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Abstract: The aim of the present study was to formulate and evaluate Almotriptan pellets. Almotriptan controlled release pellets were prepared by Solution layering technique by using croscarmellose and povidone in former case and three different polymers HPMC K 100, Ethyl cellulose and Eudragit RS 100 as rate controlling polymer in three different ratios like 1:1, 1:1.5 and 1:2 to achieve desired release in later case. Evaluation was performed according to the Pharmacopoeia standards including Drug excipients compatibility, Percentage yield, Particle size distribution, Drug content analysis and in-vitro release study. The best results were found to be using Almotriptan and Eudragit RS 100 in 1:2 ratios. A broad variety of drug release pattern could be achieved by variation of polymers ratios which was optimized to match the target release profile. In comparison of in-vitro release studies for different controlled release formulations, F9 releases 98.54% of drug at the end of 12th hour and was considered as best formulation. Stability study has shown no significant change in the drug content analysis and in-vitro dissolution study of best formulation even after 6 months.
Keywords: Almotriptan, Controlled release, Dissolution profile, in-vitro drug release, Stability studies.
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Brunner, Martin, Ursula Hollenstein, Simon Delacher, Dorothea Jäger, Rainer Schmid, Edith Lackner, Apostoulos Georgopoulos, Hans Georg Eichler, and Markus Müller. "Distribution and Antimicrobial Activity of Ciprofloxacin in Human Soft Tissues." Antimicrobial Agents and Chemotherapy 43, no. 5 (May 1, 1999): 1307–9. http://dx.doi.org/10.1128/aac.43.5.1307.
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ABSTRACT Interstitial ciprofloxacin concentrations in soft tissues were measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum drug concentrations; the interstitium-to-serum concentration ratios ranged from 0.55 to 0.73. An in vitro simulation based on interstitial pharmacokinetics showed a substantially lower antimicrobial activity than did the simulation based on serum pharmacokinetics. Thus, ciprofloxacin concentrations at the site of effect may be subinhibitory although effective concentrations are attained in serum.
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Odongo, Charles Okot, Lydia Nakiyingi, Clovis Gatete Nkeramihigo, Daniel Seifu, and Kuteesa Ronald Bisaso. "Towards Improved Management of Tuberculous Bloodstream Infections: Pharmacokinetic Considerations with Suggestions for Better Treatment Outcomes." Antibiotics 11, no. 7 (July 5, 2022): 895. http://dx.doi.org/10.3390/antibiotics11070895.
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Mycobacterium tuberculosis is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target Cmax concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment.
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Robillard, Kevin R., Gary N. Y. Chan, Guijin Zhang, Charles la Porte, William Cameron, and Reina Bendayan. "Role of P-Glycoprotein in the Distribution of the HIV Protease Inhibitor Atazanavir in the Brain and Male Genital Tract." Antimicrobial Agents and Chemotherapy 58, no. 3 (December 30, 2013): 1713–22. http://dx.doi.org/10.1128/aac.02031-13.
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ABSTRACTThe blood-testis barrier and blood-brain barrier are responsible for protecting the male genital tract and central nervous system from xenobiotic exposure. In HIV-infected patients, low concentrations of antiretroviral drugs in cerebrospinal fluid and seminal fluid have been reported. One mechanism that may contribute to reduced concentrations is the expression of ATP-binding cassette drug efflux transporters, such as P-glycoprotein (P-gp). The objective of this study was to investigatein vivothe tissue distribution of the HIV protease inhibitor atazanavir in wild-type (WT) mice, P-gp/breast cancer resistance protein (Bcrp)-knockout (Mdr1a−/−,Mdr1b−/−, andAbcg2−/−triple-knockout [TKO]) mice, and Cyp3a−/−(Cyp) mice. WT mice and Cyp mice were pretreated with a P-gp/Bcrp inhibitor, elacridar (5 mg/kg of body weight), and the HIV protease inhibitor and boosting agent ritonavir (2 mg/kg intravenously [i.v.]), respectively. Atazanavir (10 mg/kg) was administered i.v. Atazanavir concentrations in plasma (Cplasma), brain (Cbrain), and testes (Ctestes) were quantified at various times by liquid chromatography-tandem mass spectrometry. In TKO mice, we demonstrated a significant increase in atazanavirCbrain/Cplasma(5.4-fold) andCtestes/Cplasma(4.6-fold) ratios compared to those in WT mice (P< 0.05). Elacridar-treated WT mice showed a significant increase in atazanavirCbrain/Cplasma(12.3-fold) andCtestes/Cplasma(13.5-fold) ratios compared to those in vehicle-treated WT mice. In Cyp mice pretreated with ritonavir, significant (P< 0.05) increases in atazanavirCbrain/Cplasma(1.8-fold) andCtestes/Cplasma(9.5-fold) ratios compared to those in vehicle-treated WT mice were observed. These data suggest that drug efflux transporters, i.e., P-gp, are involved in limiting the ability of atazanavir to permeate the rodent brain and genital tract. Since these transporters are known to be expressed in humans, they could contribute to the low cerebrospinal and seminal fluid antiretroviral concentrations reported in the clinic.
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Chigumira, Washington, Prosper Maposa, Louis L. Gadaga, Admire Dube, Dexter Tagwireyi, and Charles C. Maponga. "Preparation and Evaluation of Pralidoxime-Loaded PLGA Nanoparticles as Potential Carriers of the Drug across the Blood Brain Barrier." Journal of Nanomaterials 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/692672.
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Pralidoxime is an organophosphate antidote with poor central nervous system distribution due to a high polarity. In the present study, pralidoxime-loaded poly(lactic-co-glycolic acid) nanoparticles were prepared and evaluated as a potential delivery system of the drug into the central nervous system. The nanoparticles were prepared using double emulsion solvent evaporation method. Poly(lactic-co-glycolic acid) (PLGA) in ethyl acetate made the organic phase and pralidoxime in water made the aqueous phase. The system was stabilized by polyvinyl alcohol. Different drug/polymer ratios were used (1 : 1, 1 : 2, and 1 : 4) and the fabricated particles were characterized for encapsulation efficiency using UV-VIS Spectroscopy; particle size distribution, polydispersity index, and zeta potential using photon correlation spectroscopy; andin vitrodrug release profile using UV-VIS Spectroscopy. Mean particle sizes were 386.6 nm, 304.7 nm, and 322.8 nm, encapsulation efficiency was 28.58%, 51.91%, and 68.78%, and zeta potential was 5.04 mV, 3.31 mV, and 5.98 mV for particles with drug/polymer ratios 1 : 1, 1 : 2, and 1 : 4, respectively.In vitrodrug release profile changed from biphasic to monobasic as the drug/polymer ratio decreased from 1 : 1 to 1 : 4. Stable pralidoxime-loaded PLGA nanoparticles were produced using double emulsion solvent evaporation techniques.
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Nakanishi, Hajime, Nancy F. Cruz, Keiji Adachi, Louis Sokoloff, and Gerald A. Dienel. "Influence of Glucose Supply and Demand on Determination of Brain Glucose Content with Labeled Methylglucose." Journal of Cerebral Blood Flow & Metabolism 16, no. 3 (May 1996): 439–49. http://dx.doi.org/10.1097/00004647-199605000-00010.
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The equilibrium brain/plasma distribution ratio for 3- O-methyl-D-glucose (methylglucose) varies with plasma and tissue glucose contents and can be used to determine local glucose levels in brain. This ratio was previously found to rise as brain glucose concentration fell in response to lowered plasma glucose content. The ratios, however, differed with the same tissue glucose levels in conscious and pentobarbital-sedated rats, suggesting that changes in metabolic demand might alter the quantitative relationship between the methylglucose distribution ratio and brain glucose concentration. To examine this possibility, metabolic rate was varied by focal drug application, and hexose concentrations measured in treated and surrounding tissue. When tissue glucose levels were reduced by raised metabolic demand, methylglucose distribution ratios also fell. When brain glucose levels rose due to reduced consumption, the methylglucose distribution ratio also rose. Thus, in contrast to the inverse relationship between brain/plasma methylglucose ratio and brain glucose concentration when brain glucose content is altered secondarily to changes in plasma glucose level, changes in brain glucose content induced by altered glucose utilization cause the brain glucose level and methylglucose distribution ratio to rise and fall in a direct relationship. Determination of brain glucose content from methylglucose distribution ratios must take into account rates of glucose delivery and consumption.
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Tagger, Aaron Y., Joan Boux, and Jim A. Wright. "Hydroxy[14C]urea uptake by normal and transformed human cells: evidence for a mechanism of passive diffusion." Biochemistry and Cell Biology 65, no. 11 (November 1, 1987): 925–29. http://dx.doi.org/10.1139/o87-120.
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The antitumor agent hydroxyurea is a potent inhibitor of cell division and selectivity toxic for rapidly proliferating cells. This drug has been used in the treatment of human cancer and, since drug transport is an important aspect of drug action, we investigated the mechanism of hydroxy[14C]urea uptake by human diploid fibroblasts and their SV40-virus-transformed counterparts. Kinetic analysis of drug uptake, studies with metabolic inhibitors, and estimates of cell/medium distribution ratios and temperature coefficient (Q10) values indicated that hydroxyurea enters normal and SV40-virus-transformed human cells by a mechanism of diffusion.
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Blacklock, J. Bob, Donald C. Wright, Robert L. Dedrick, Ronald G. Blasberg, Robert J. Lutz, John L. Doppman, and Edward H. Oldfield. "Drug streaming during intra-arterial chemotherapy." Journal of Neurosurgery 64, no. 2 (February 1986): 284–91. http://dx.doi.org/10.3171/jns.1986.64.2.0284.
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✓ Treatment of brain tumors by intra-arterial (IA) chemotherapy is occasionally complicated by sites of focal toxicity in the brain and retina. A possible cause of focal toxicity is non-uniform drug delivery due to intravascular drug streaming. To investigate this phenomenon in vivo, the authors examined the distribution of drug delivery after internal carotid artery (ICA) infusion in rhesus monkeys. Carbon-14 (14C)-labeled iodoantipyrine was delivered into the ICA of eight monkeys at slow infusion rates (1% to 2% of ICA flow) or at fast infusion rates (20% of ICA flow) combined with additional techniques to promote mixing with ICA blood. Two monkeys received intravenous (IV) 14C-antipyrine. Uniformity of delivery was assessed by comparing high-to-low ratios of isotope concentration in four brain regions evaluated by quantitative autoradiography. There was striking non-uniformity of drug delivery in the slow IA infusion group, with as much as 13-fold differences in drug concentration in anatomically contiguous areas. The values of high-to-low concentration ratios (mean ± standard deviation) in individual autoradiographic planes were: 1) frontoparietal cortex: slow IA infusion 4.54 ± 2.07, fast IA infusion 1.71 ± 0.31, IV infusion 1.30 ± 0.174; 2) frontoparietal white matter: slow IA infusion 2.94 ± 1.45, fast IA infusion 1.59 ± 0.41, IV infusion 1.34 ± 0.21; 3) temporal cortex: slow IA infusion 5.43 ± 3.57, fast IA infusion 1.69 ± 0.24, IV infusion 1.67 ± 0.25; 4) basal ganglia: slow IA infusion 3.6 ± 2.9, fast IA infusion 1.18 ± 0.10, IV infusion 1.09 ± 0.04. Differences between concentration ratios after slow IA and fast IA infusion are significant (p < 0.01); those between fast IA and IV infusion are not significant. Intra-arterial drug administration at infusion rates analogous to those currently used clinically results in drug streaming with markedly heterogeneous drug deposition in the perfused hemisphere. This may cause suboptimal drug levels in the tumor, and toxic levels at sites within the perfused hemisphere. This effect can be abrogated by techniques that eliminate drug streaming.
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Mamada, Hideaki, Kazuhiko Iwamoto, Yukihiro Nomura, and Yoshihiro Uesawa. "Predicting blood-to-plasma concentration ratios of drugs from chemical structures and volumes of distribution in humans." Molecular Diversity 25, no. 3 (February 10, 2021): 1261–70. http://dx.doi.org/10.1007/s11030-021-10186-7.
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Abstract Despite their importance in determining the dosing regimen of drugs in the clinic, only a few studies have investigated methods for predicting blood-to-plasma concentration ratios (Rb). This study established an Rb prediction model incorporating typical human pharmacokinetics (PK) parameters. Experimental Rb values were compiled for 289 compounds, offering reliable predictions by expanding the applicability domain. Notably, it is the largest list of Rb values reported so far. Subsequently, human PK parameters calculated from plasma drug concentrations, including the volume of distribution (Vd), clearance, mean residence time, and plasma protein binding rate, as well as 2702 kinds of molecular descriptors, were used to construct quantitative structure–PK relationship models for Rb. Among the evaluated PK parameters, logVd correlated best with Rb (correlation coefficient of 0.47). Thus, in addition to molecular descriptors selected by XGBoost, logVd was employed to construct the prediction models. Among the analyzed algorithms, artificial neural networks gave the best results. Following optimization using six molecular descriptors and logVd, the model exhibited a correlation coefficient of 0.64 and a root-mean-square error of 0.205, which were superior to those previously reported for other Rb prediction methods. Since Vd values and chemical structures are known for most medications, the Rb prediction model described herein is expected to be valuable in clinical settings. Graphical abstract
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Singh, Ranjodh, Vanessa Bellat, Melinda Wang, Melanie E. Schweitzer, Y. Linda Wu, Ching-Hsuan Tung, Mark M. Souweidane, and Benedict Law. "Volume of distribution and clearance of peptide-based nanofiber after convection-enhanced delivery." Journal of Neurosurgery 129, no. 1 (July 2018): 10–18. http://dx.doi.org/10.3171/2017.2.jns162273.
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OBJECTIVEDrug clearance may be a limiting factor in the clinical application of convection-enhanced delivery (CED). Peptide-based nanofibers (NFPs) have a high aspect ratio, and NFPs loaded with drugs could potentially maintain effective drug concentrations for an extended period sufficient for cancer therapy. The objective of this study was to assess the volume of distribution (Vd) and clearance of variable lengths of NFPs when administered using CED.METHODSNFPs composed of multiple methoxypolyethylene glycol (mPEG)-conjugated constructs (mPEG2000-KLDLKLDLKLDL-K(FITC)-CONH2, for which FITC is fluorescein isothiocyanate) were assembled in an aqueous buffer. The NFPs were approximately 5 nm in width and were formulated into different lengths: 100 nm (NFP-100), 400 nm (NFP-400), and 1000 nm (NFP-1000). The NFP surface was covalently conjugated with multiple Cy5.5 fluorophores as the optical reporters to track the post-CED distribution. Forty-two 6- to 8-week-old Ntv-a;p53fl/fl mice underwent CED to the striatum. Animals were killed immediately, 24 hours or 72 hours after CED. The brains were extracted and sectioned for assessing NFP Vd to volume of infusion (Vi) ratio, and clearance using fluorescence microscopy.RESULTSCED of NFPs was well tolerated by all the animals. The average Vd/Vi ratios for NFP-100, NFP-400, NFP-1000, and unconjugated positive control (free Cy5.5) were 1.87, 2.47, 1.07, and 3.0, respectively, which were statistically different (p = 0.003). The percentages remaining of the original infusion volume at 24 hours for NFP-100, -400, and -1000 were 40%, 90%, and 74%, respectively. The percentages remaining at 72 hours for NFP-100, -400, and -1000 were 15%, 30%, and 46%, respectively. Unconjugated Cy5.5 was not detected at 24 or 72 hours after CED.CONCLUSIONSCED of NFPs is feasible with Vd/Vi ratios and clearance rates comparable to other nanocarriers. Of the 3 NFPs, NFP-400 appears to provide the best distribution and slowest clearance after 24 hours. NFP provides a dynamic theranostic platform, with the potential to deliver clinically efficacious drug payload to brain tumor after CED.
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Jansson, Rasmus, Ulf Bredberg, and Michael Ashton. "Prediction of Drug Tissue to Plasma Concentration Ratios Using a Measured Volume of Distribution in Combination With Lipophilicity." Journal of Pharmaceutical Sciences 97, no. 6 (June 2008): 2324–39. http://dx.doi.org/10.1002/jps.21130.
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Vine, W., M. W. Flye, and P. Jatlow. "Relationships of cyclosporine concentrations in serum, whole blood, and bile after renal and hepatic transplantation." Clinical Chemistry 32, no. 10 (October 1, 1986): 1828–31. http://dx.doi.org/10.1093/clinchem/32.10.1828.
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Abstract "Trough" (minimum inter-dose) cyclosporine concentrations were measured by liquid chromatography in samples of serum and whole blood or bile obtained from renal- and hepatic-transplant patients. Overall, concentrations in whole blood correlated poorly with concentrations in concurrently obtained serum. The poor correlation also held for individual patients over time. The degree of variability observed for individuals is especially disconcerting. Although cyclosporine measurements in whole blood may mitigate time- and temperature-dependent changes in the drug's distribution after collection, concentrations in serum separated after distribution are less dependent on the cellular mass in blood, and may better reflect the amount of drug available to receptor sites. This consideration may be particularly important in the postoperative period, when fluctuations in the cellular mass of blood are frequent. Concentrations of cyclosporine were also determined in concurrently collected bile and serum samples after liver transplantation. Concentrations of unchanged drug in bile were variably higher than those in serum. Bile/serum concentration ratios ranged from 65/1 to 4.6/1. It is postulated that bile/blood concentration ratios may reflect liver function.
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Saluja, Ronak, Tina Jiao, Liza Koshy, Matthew Cheung, and Kelvin K. W. Chan. "Comparing Manufacturer Submitted and Pan-Canadian Oncology Drug Review Reanalysed Incremental Cost-Effectiveness Ratios for Novel Oncology Drugs." Current Oncology 28, no. 1 (January 20, 2021): 606–18. http://dx.doi.org/10.3390/curroncol28010060.
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Background: To determine the magnitude of difference between manufacturer-submitted and pan-Canadian Oncology Drug Review (pCODR) calculated incremental cost-effectiveness ratios (ICERs), incremental cost (ΔC), and incremental effectiveness (ΔE); to examine whether there is a significant difference in the proportion of ICERs deemed cost-effective; to evaluate trends in the ICERs over time; and to identify methodological issues in manufacturer-submitted economic models. Methods: Economic guidance reports for all drug indications submitted from July 2011–November 2018 were extracted from the pCODR database. Cumulative distribution plots were constructed to compare the manufacturer-submitted economic values with both the pCODR lower- and upper-reanalyzed estimates. The proportion of drug reviews considered cost-effective at varying willingness-to-pay (WTP) thresholds by the manufacturer and pCODR were calculated. Manufacturer changes in ICERs over time from 2012 to 2018 were determined. Recurring methodological issues with manufacturer submissions were tallied. Results: There were 73 unique indications that were included. Manufacturer-submitted ICERs were consistently lower than pCODR estimates for most indications. Manufacturer-submitted ICERs were generally more cost-effective over a range of WTP thresholds. From 2012 to 2018, manufacturer and economic guidance panel (EGP) lower limit reanalyzed ICERs did not change significantly over time. However, EGP upper limit re-analyses did show decreasing cost-effectiveness (increasing ICERs). The two most common issues identified in the manufacturer-submitted models were related to survival time horizon and utility estimates. Conclusions: Manufacturers tend to overestimate the cost-effectiveness of their therapies when submitting economic models to pCODR. Although certain methodological issues are still common in manufacturer-submitted models, revision rates are high for most issues raised by pCODR.
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Bang, Young Yoon, Im-Sook Song, Min Seo Lee, Chang Ho Lim, Yong-Yeon Cho, Joo Young Lee, Han Chang Kang, and Hye Suk Lee. "Toxicokinetics of β-Amanitin in Mice and In Vitro Drug–Drug Interaction Potential." Pharmaceutics 14, no. 4 (April 1, 2022): 774. http://dx.doi.org/10.3390/pharmaceutics14040774.
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The toxicokinetics of β-amanitin, a toxic bicyclic octapeptide present abundantly in Amanitaceae mushrooms, was evaluated in mice after intravenous (iv) and oral administration. The area under plasma concentration curves (AUC) following iv injection increased in proportion to doses of 0.2, 0.4, and 0.8 mg/kg. β-amanitin disappeared rapidly from plasma with a half-life of 18.3–33.6 min, and 52.3% of the iv dose was recovered as a parent form. After oral administration, the AUC again increased in proportion with doses of 2, 5, and 10 mg/kg. Absolute bioavailability was 7.3–9.4%, which resulted in 72.4% of fecal recovery from orally administered β-amanitin. Tissue-to-plasma AUC ratios of orally administered β-amanitin were the highest in the intestine and stomach. It also readily distributed to kidney > spleen > lung > liver ≈ heart. Distribution to intestines, kidneys, and the liver is in agreement with previously reported target organs after acute amatoxin poisoning. In addition, β-amanitin weakly or negligibly inhibited major cytochrome P450 and 5′-diphospho-glucuronosyltransferase activities in human liver microsomes and suppressed drug transport functions in mammalian cells that overexpress transporters, suggesting the remote drug interaction potentials caused by β-amanitin exposure.
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Kunitsu, Yuki, Daiki Hira, Aya Morikochi, Tomohiro Ueda, Tetsuichiro Isono, Shin-ya Morita, and Tomohiro Terada. "Time until onset of acute kidney injury by combination therapy with “Triple Whammy” drugs obtained from Japanese Adverse Drug Event Report database." PLOS ONE 17, no. 2 (February 9, 2022): e0263682. http://dx.doi.org/10.1371/journal.pone.0263682.
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Acute kidney injury (AKI) associated with “Triple Whammy” drug therapy consisting of renin-angiotensin system inhibitors, diuretics, and nonsteroidal anti-inflammatory drugs (NSAIDs) has been reported. There have been no reports investigating “Triple Whammy” drug therapy and the time to AKI onset using adverse drug events report databases. The aim of this study was to determine the relationship between the time to AKI onset and treatment with “Triple Whammy” drug therapy. We analyzed AKI cases registered in the Japanese Adverse Drug Event Report database. The data were analyzed using the Kaplan–Meier approach, generalized Wilcoxon tests, and Weibull distribution. AKI was reported in 18,415 cases, of which 7,466 cases used Triple Whammy drugs. All combinations of Triple Whammy drugs were associated with significantly higher odds ratios for reporting AKI. In Weibull analysis, AKI onset was early for most combination patterns of Triple Whammy drugs. The Kaplan–Meier approach showed that the treatment duration to AKI onset was much shorter in cases using NSAIDs; median onsets, 8 days for triple combination, 7 days for NSAIDs added to renin-angiotensin system inhibitors, 9 days for NSAIDs added to diuretics, 6 days for diuretics added to NSAIDs, and 9 days for NSAIDs alone. AKI associated with Triple Whammy drugs is likely to occur in the early stages of treatment, especially with concomitant NSAIDs. Patients should be monitored for the occurrence of AKI within the first 2 weeks.
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Srisuwan, Yaowalak, and Prasong Srihanam. "Human Hair Keratin Microspheres Prepared by the Water-In-Oil Emulsion Solvent Diffusion Method for Hydrophilic Drug Carrier." Oriental Journal of Chemistry 35, no. 3 (May 18, 2019): 1112–16. http://dx.doi.org/10.13005/ojc/350326.
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Human hair keratin (HK) was prepared with reducing agent and used in solution to construct microspheres by the simple emulsion solvent diffusion method. The obtained microspheres were observing under scanning electron microscope (SEM). The shape, size distribution and content of microspheres were influenced by W:O ratios. A and 1% w/v keratin solution and 100 mL of oil phase were optimal conditions for fabrication of HK microspheres. The authors studied drug loading efficiency of the HK microspheres by using blue-dextran a model drug and found that the drug loading efficiency as well as releasing profile of blue-dextran were gradually increased by increasing keratin concentration. In conclusion, HK microspheres could be used as hydrophilic carrier molecules for drug delivery system application.
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Mor, N., B. Simon, and L. Heifets. "Bacteriostatic and bactericidal activities of benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis and Mycobacterium avium in human macrophages." Antimicrobial Agents and Chemotherapy 40, no. 6 (June 1996): 1482–85. http://dx.doi.org/10.1128/aac.40.6.1482.
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Inhibitory and bactericidal activities of KRM-1648 were determined against Mycobacterium tuberculosis and M. avium residing in human monocyte-derived macrophages and extracellular M. tuberculosis and M. avium. MICs and MBCs of KRM-1648 against intracellular and extracellular bacteria were substantially lower than those of rifampin. The MICs and MBCs of either drug against the intracellular bacteria were only twofold lower than or equal to the values found for extracellular bacteria. The prolonged effect of KRM-1648 found in this study is probably associated with high ratios of intracellular accumulation, which were 50- to 100-fold higher than that found for rifampin. Further studies on intracellular distribution of KRM-1648 and on the sites of actual interaction between the drug and bacteria residing in macrophages are necessary, as well as evaluation of combined effects of KRM-1648 with other drugs in long-term macrophage culture experiments.
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Mallory, Joel D., Anatoly B. Kolomeisky, and Oleg A. Igoshin. "Kinetic control of stationary flux ratios for a wide range of biochemical processes." Proceedings of the National Academy of Sciences 117, no. 16 (April 7, 2020): 8884–89. http://dx.doi.org/10.1073/pnas.1920873117.
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One of the most intriguing features of biological systems is their ability to regulate the steady-state fluxes of the underlying biochemical reactions; however, the regulatory mechanisms and their physicochemical properties are not fully understood. Fundamentally, flux regulation can be explained with a chemical kinetic formalism describing the transitions between discrete states, with the reaction rates defined by an underlying free energy landscape. Which features of the energy landscape affect the flux distribution? Here we prove that the ratios of the steady-state fluxes of quasi–first-order biochemical processes are invariant to energy perturbations of the discrete states and are only affected by the energy barriers. In other words, the nonequilibrium flux distribution is under kinetic and not thermodynamic control. We illustrate the generality of this result for three biological processes. For the network describing protein folding along competing pathways, the probabilities of proceeding via these pathways are shown to be invariant to the stability of the intermediates or to the presence of additional misfolded states. For the network describing protein synthesis, the error rate and the energy expenditure per peptide bond is proven to be independent of the stability of the intermediate states. For molecular motors such as myosin-V, the ratio of forward to backward steps and the number of adenosine 5′-triphosphate (ATP) molecules hydrolyzed per step is demonstrated to be invariant to energy perturbations of the intermediate states. These findings place important constraints on the ability of mutations and drug perturbations to affect the steady-state flux distribution for a wide class of biological processes.
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Darna, Bhikshapathi, and Sujitha Katuri. "Design and Characterization of Ceritinib Self-nanoemulsifying Drug Delivery Systems." International Journal of Pharmaceutical Sciences and Drug Research 13, no. 03 (March 30, 2020): 353–60. http://dx.doi.org/10.25004/ijpsdr.2021.130316.
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Objective: The main objective of the current study was to develop ceritinib SNEDDS for the improvement of solubility, permeability, and drug release. Methods: Solubility of ceritinib was studied in various oils, surfactants, and co-surfactants, and based on its maximum solubility, an oil, surfactant, and co-surfactant were chosen (captex355, tergitol, and propylene glycol) and mixed in varying ratios, the ratios with no phase separation, maximum transmittance and clear in appearance were identified and used for plotting pseudo tertiary phase diagram. Fifteen selfnanoemulsifying drug delivery systems (SNEDDS) formulations were selected from miscible regions of the pseudo ternary phase diagram subjected to thermodynamic stability testing. Formulations that passed stability testing were evaluated for % transmission, drug content, and in vitro drug release analysis. The final optimized formulation was analyzed for particle size, Z average, and zeta potential, followed by fourier transform infrared spectroscopy (FTIR) and SEM analysis. Results: Formulation F13 with maximum drug release of 98.9% in 60 minutes higher than 48 % of the pure drug is considered the optimized formulation. The particle size, Z average, and zeta potential of the ceritinib SNEDDS formulation F13 were 144 nm, 132 nm, and -7.2 mV, respectively. The FTIR and SEM studies do not indicate any drug excipient interaction and confirm uniform drug distribution. The formulation subjected to accelerated stability study is proved to be stable over six months. Conclusion: The results indicate that ceritinib SNEDDS formulations can be designed to enhance the solubility of ceritinib and increase its absorption rate and drug release.
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Wu, Zhimin, Manzhen Duan, Di Xiong, and Can Yang Zhang. "Mesoscale Simulations of pH-Responsive Amphiphilic Polymeric Micelles for Oral Drug Delivery." Pharmaceutics 11, no. 12 (November 20, 2019): 620. http://dx.doi.org/10.3390/pharmaceutics11120620.
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It is of great significance to study the structure property and self-assembly of amphiphilic block copolymer in order to effectively and efficiently design and prepare drug delivery systems. In this work, dissipative particle dynamics (DPD) simulation method was used to investigate the structure property and self-assembly ability of pH-responsive amphiphilic block copolymer poly(methyl methacrylate-co-methacrylic acid)-b-poly(aminoethyl methacrylate) (poly(MMA-co-MAA)-b-PAEMA). The effects of different block ratios (hydrophilic PAEMA segment and pH-sensitive PMAA segment) in copolymer on self-assembly and drug loading capacity including drug distribution were extensively investigated. The increase of hydrophilic PAEMA facilitated the formation of a typical core-shell structure as well as a hydrophobic PMAA segment. Furthermore, the optimal drug-carrier ratio was confirmed by an analysis of the drug distribution during the self-assembly process of block copolymer and model drug Ibuprofen (IBU). In addition, the drug distribution and nanostructure of IBU-loaded polymeric micelles (PMs) self-assembled from precise block copolymer (PMMA-b-PMAA-b-PAEMA) and block copolymer (poly(MMA-co-MAA)-b-PAEMA) with random pH-responsive/hydrophobic structure were evaluated, showing that almost all drug molecules were encapsulated into a core for a random copolymer compared to the analogue. The nanostructures of IBU-loaded PMs at different pH values were evaluated. The results displayed that the nanostructure was stable at pH < pKa and anomalous at pH > pKa which indicated drug release, suggesting that the PMs could be used in oral drug delivery. These findings proved that the amphiphilic block copolymer P(MMA30-co-MAA33)-b-PAEMA38 with random structure and pH-sensitivity might be a potential drug carrier. Moreover, DPD simulation shows potential to study the structure property of PMs self-assembled from amphiphilic block copolymer.
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Pena, Erik S., Elizabeth G. Graham-Gurysh, Eric M. Bachelder, and Kristy M. Ainslie. "Design of Biopolymer-Based Interstitial Therapies for the Treatment of Glioblastoma." International Journal of Molecular Sciences 22, no. 23 (December 6, 2021): 13160. http://dx.doi.org/10.3390/ijms222313160.
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Glioblastoma multiforme (GBM) is the most common form of primary brain cancer and has the highest morbidity rate and current treatments result in a bleak 5-year survival rate of 5.6%. Interstitial therapy is one option to increase survival. Drug delivery by interstitial therapy most commonly makes use of a polymer implant encapsulating a drug which releases as the polymer degrades. Interstitial therapy has been extensively studied as a treatment option for GBM as it provides several advantages over systemic administration of chemotherapeutics. Primarily, it can be applied behind the blood–brain barrier, increasing the number of possible chemotherapeutic candidates that can be used and reducing systemic levels of the therapy while concentrating it near the cancer source. With interstitial therapy, multiple drugs can be released locally into the brain at the site of resection as the polymer of the implant degrades, and the release profile of these drugs can be tailored to optimize combination therapy or maintain synergistic ratios. This can bypass the blood–brain barrier, alleviate systemic toxicity, and resolve drug resistance in the tumor. However, tailoring drug release requires appropriate consideration of the complex relationship between the drug, polymer, and formulation method. Drug physicochemical properties can result in intermolecular bonding with the polymeric matrix and affect drug distribution in the implant depending on the formulation method used. This review is focused on current works that have applied interstitial therapy towards GBM, discusses polymer and formulation methods, and provides design considerations for future implantable biodegradable materials.
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Yoon, Deok Yong, SeungHwan Lee, In-Jin Jang, Myeongjoong Kim, Heechan Lee, Seokuee Kim, Bongtae Kim, Geun Seog Song, and Su-jin Rhee. "Prediction of Drug–Drug Interaction Potential of Tegoprazan Using Physiologically Based Pharmacokinetic Modeling and Simulation." Pharmaceutics 13, no. 9 (September 16, 2021): 1489. http://dx.doi.org/10.3390/pharmaceutics13091489.
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This study aimed to develop a physiologically based pharmacokinetic (PBPK) model of tegoprazan and to predict the drug–drug interaction (DDI) potential between tegoprazan and cytochrome P450 (CYP) 3A4 perpetrators. The PBPK model of tegoprazan was developed using SimCYP Simulator® and verified by comparing the model-predicted pharmacokinetics (PKs) of tegoprazan with the observed data from phase 1 clinical studies, including DDI studies. DDIs between tegoprazan and three CYP3A4 perpetrators were predicted by simulating the difference in tegoprazan exposure with and without perpetrators, after multiple dosing for a clinically used dose range. The final PBPK model adequately predicted the biphasic distribution profiles of tegoprazan and DDI between tegoprazan and clarithromycin. All ratios of the predicted-to-observed PK parameters were between 0.5 and 2.0. In DDI simulation, systemic exposure to tegoprazan was expected to increase about threefold when co-administered with the maximum recommended dose of clarithromycin or ketoconazole. Meanwhile, tegoprazan exposure was expected to decrease to ~30% when rifampicin was co-administered. Based on the simulation by the PBPK model, it is suggested that the DDI potential be considered when tegoprazan is used with CYP3A4 perpetrator, as the acid suppression effect of tegoprazan is known to be associated with systemic exposure.
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McGee, Bryan, Reynaldo Dietze, David Jamil Hadad, Lucilia Pereira Dutra Molino, Ethel Leonor Noia Maciel, W. Henry Boom, Moises Palaci, John L. Johnson, and Charles A. Peloquin. "Population Pharmacokinetics of Linezolid in Adults with Pulmonary Tuberculosis." Antimicrobial Agents and Chemotherapy 53, no. 9 (June 29, 2009): 3981–84. http://dx.doi.org/10.1128/aac.01378-08.
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ABSTRACT Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h−1, 29.6 liters, and 0.25 h−1 (once daily) and 2.7 h−1, 32.1 liters, and 0.15 h−1 (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).
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Mayer, Lawrence D., Nicole Sadowski, Paul Tardi, Xiaowei Xie, Donna Cabral-Lilly, and Dennis Heller. "Quantitative Whole Body Autoradiography (QWBA) Analysis Reveals That CPX-351 Shifts the Exposure of Cytarabine (Cyt) and Daunorubicin (Daun) Away from Many Tissues While Providing Prolonged Exposure to Cytotoxic Drug Concentrations in the Bone Marrow Compared to Conventional Free Drug Administration." Blood 124, no. 21 (December 6, 2014): 3740. http://dx.doi.org/10.1182/blood.v124.21.3740.3740.
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Abstract Background: CPX-351 is a liposomal formulation co-encapsulating Cyt and Daun, that delivers the drugs in vivo at a 5:1 molar ratio shown to be synergistic preclinically. Clinically, CPX-351 has provided evidence of promising improvements in patient outcomes, most notably in elderly newly diagnosed high risk (secondary) AML and in unfavorable risk first relapse adult AML where statistically significant increases in overall survival where observed in two randomized, controlled Phase 2 studies. In patients, CPX-351 displays a volume of distribution equal to the plasma volume and first order elimination with a half-life of > 24h for both drugs while maintaining the circulating Cyt:Daun molar ratio near 5:1. This is in contrast to the two drugs as conventionally administered in non-liposomal (NL) aqueous solution form where very rapid drug elimination is observed. Comparison of tissue distribution over time between CPX-351 and NL Cyt:Daun was performed in rats to better understand the pharmacodynamic relationships for CPX-351 in the context of what is known for the non-liposomal (NL) drugs, particularly as it relates to tissues relevant to efficacy and drug toxicity. Methods: Duplicate batches utilizing either [14C]Daun or [14C]Cyt CPX-351 or saline solutions of like labeled Cyt+Daun were prepared. Long-Evans rats received single IV bolus doses of either 15 units/kg (15 mg/kg Cyt + 6.64 mg/kg Daun) CPX-351, or a saline solution of 300 mg/kg Cyt + 10 mg/kg Daun. These doses were selected based on allometric scaling to reflect the respective clinical doses of CPX-351 and non-infusional Cyt:Daun treatment regimens. Animals were sacrificed at the designated time points post-dose and were frozen in a dry-ice/hexane bath in preparation for QWBA procedures. The tissue distribution of test article-derived radioactivity was determined using QWBA. Exposure of Cyt and Daun to a wide range of tissues was estimated based on the tissue density of [14C]Cyt-derived or [14C]Daun-derived radioactivity from QWBA section images. Tissue drug exposure comparisons between CPX-351 and NL Cyt:Daun were performed using Cmax and AUC0-t values. Results: The rapid tissue distribution of Cyt and Daun following injection of the NL form of the combination was reflected by the recovery of <5% of either drug in the plasma 15 minutes after injection and tissue/plasma AUC0-t ratios that were >1 and >10 for [14C]Cyt and [14C]Daun, respectively, for the majority of tissues studied. In contrast, for CPX-351 virtually all of the injected Cyt and Daun was present in the plasma between 0.25-1.0 hours and corresponding tissue/plasma AUC0-t ratios in the majority of tissues were <0.05 and <0.2 for [14C]Cyt and [14C]Daun, respectively. These differences were readily apparent in the QWBA section images. For the NL form of the combination, [14C]Cyt and [14C]Daun were widely distributed throughout the body shortly after injection. Following CPX-351 administration, radioactivity was more limited to discreet tissues and organs. Distribution of Cyt into tissues after CPX-351 administration was reduced as well as much slower than after NL Cyt injection as reflected by markedly lower Cmax values in all non-vascular tissues as well as lower AUC values in a majority of tissues. Comparing [14C]Daun distribution for CPX-351 vs NL Daun revealed a slower removal from the blood/plasma compartment and gradual distribution to tissues for CPX-351 with a similar general tissue profile as for NL drug with the notable increases in exposure to spleen, liver, testis and bone marrow. Bone marrow levels of Cyt and Daun peaked at 24h post CPX-351 injection and persisted for several days at anti-leukemic concentrations; drug levels present in the marrow at 96h were well above the CPX-351 IC50 values previously observed with fresh AML patient blast samples. In contrast, bone marrow Cyt concentrations fell below detectable limits within 24h after administration of NL drug. Conclusions: CPX-351 shifts the exposure of Cyt and Daun away from most non-hematologic tissues compared to NL drug treatment. Importantly, CPX-351 accumulates and persists in the bone marrow for over 4 days at concentrations known to have anti-leukemic activity against AML blasts. Taken together, these results provide additional biologic rationale that support the clinical improvements in both efficacy and safety seen for CPX-351 in randomized trials compared to conventional Cyt + Daun treatment. Disclosures Mayer: Celator: Employment, Equity Ownership, Patents & Royalties. Sadowski:Xenobiotic Laboratories: Employment. Tardi:Celator Pharmaceuticals: Employment, Equity Ownership. Xie:Celator Pharmaceuticals: Employment, Equity Ownership. Cabral-Lilly:Ceator Pharmaceuticals: Employment, Equity Ownership. Heller:Xenobiotic Laboratories: Employment, Research Funding.
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Gontijo, Aline Vidal Lacerda, Julien Brillault, Nicolas Grégoire, Isabelle Lamarche, Patrice Gobin, William Couet, and Sandrine Marchand. "Biopharmaceutical Characterization of Nebulized Antimicrobial Agents in Rats: 1. Ciprofloxacin, Moxifloxacin, and Grepafloxacin." Antimicrobial Agents and Chemotherapy 58, no. 7 (May 5, 2014): 3942–49. http://dx.doi.org/10.1128/aac.02818-14.
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ABSTRACTThe aim of this study was to evaluate the biopharmaceutical characteristics of three fluoroquinolones (FQs), ciprofloxacin (CIP), moxifloxacin (MXF), and grepafloxacin (GRX), after delivery via a nebulized aerosol to rats. Bronchoalveolar lavages (BAL) were conducted 0.5, 2, 4, and 6 h after FQ intravenous administration and nebulized aerosol delivery to estimate epithelial lining fluid (ELF) drug concentrations. Plasma drug concentrations were also measured, and profiles of drug concentrations versus time after intravenous administration and nebulized aerosol delivery were virtually superimposable, attesting for rapid and complete systemic absorption of FQs. ELF drug concentrations were systematically higher than corresponding plasma drug concentrations, whatever the route of administration, and average ELF-to-unbound plasma drug concentration ratios post-distribution equilibrium did not change significantly between the ways of administration and were equal: 4.0 ± 5.3 for CIP, 12.6 ± 7.3 for MXF, and 19.1 ± 10.5 for GRX (means ± standard deviations). The impact of macrophage lysis on estimated ELF drug concentrations was significant for GRX but reduced for MXF and CIP; therefore, simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was only performed for the latter two drugs. The model was characterized by a fixed volume of ELF (VELF), passive diffusion clearance (QELF), and active efflux clearance (CLout) between plasma and ELF, indicating active efflux transport systems. In conclusion, this study demonstrates that ELF drug concentrations of these three FQs are several times higher than plasma drug concentrations, probably due to the presence of efflux transporters at the pulmonary barrier level, but no biopharmaceutical advantage of FQ nebulization was observed compared with intravenous administration.
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Marchand, Sandrine, Denis Frasca, Claire Dahyot-Fizelier, Céline Breheret, Olivier Mimoz, and William Couet. "Lung Microdialysis Study of Levofloxacin in Rats following Intravenous Infusion at Steady State." Antimicrobial Agents and Chemotherapy 52, no. 9 (June 30, 2008): 3074–77. http://dx.doi.org/10.1128/aac.00242-08.
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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.
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Balzarini, Jan, Maria-José Camarasa, Maria-Jesus Pérez-Pérez, Ana San-Félix, Sonsoles Velázquez, Carlo-Federico Perno, Erik De Clercq, John N. Anderson, and Anna Karlsson. "Exploitation of the Low Fidelity of Human Immunodeficiency Virus Type 1 (HIV-1) Reverse Transcriptase and the Nucleotide Composition Bias in the HIV-1 Genome To Alter the Drug Resistance Development of HIV." Journal of Virology 75, no. 13 (July 1, 2001): 5772–77. http://dx.doi.org/10.1128/jvi.75.13.5772-5777.2001.
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ABSTRACT The RNA genome of the lentivirus human immunodeficiency virus type 1 (HIV-1) is significantly richer in adenine nucleotides than the statistically equal distribution of the four different nucleotides that is expected. This compositional bias may be due to the guanine-to-adenine (G→A) nucleotide hypermutation of the HIV genome, which has been explained by dCTP pool imbalances during reverse transcription. The adenine nucleotide bias together with the poor fidelity of HIV-1 reverse transcriptase markedly enhances the genetic variation of HIV and may be responsible for the rapid emergence of drug-resistant HIV-1 strains. We have now attempted to counteract the normal mutational pattern of HIV-1 in response to anti-HIV-1 drugs by altering the endogenous deoxynucleoside triphosphate pool ratios with antimetabolites in virus-infected cell cultures. We showed that administration of these antimetabolic compounds resulted in an altered drug resistance pattern due to the reversal of the predominant mutational flow of HIV (G→A) to an adenine-to-guanine (A→G) nucleotide pattern in the intact HIV-1-infected lymphocyte cultures. Forcing the virus to change its inherent nucleotide bias may lead to better control of viral drug resistance development.
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Antonio, Nelson, Alessandra Diehl, Marcelo Niel, Sandra Pillon, Lilian Ratto, Maria Carolina Pinheiro, Dartiu Silveira, et al. "Sexual addiction in drug addicts: The impact of drug of choice and poly-addiction." Revista da Associação Médica Brasileira 63, no. 5 (May 2017): 414–21. http://dx.doi.org/10.1590/1806-9282.63.05.414.
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Summary Objective: To compare the risk of comorbid sexual addiction in a sample of individuals with a diagnosis of substance dependence, stratifying the sample by drug of choice as well as by mono versus polysubstance addiction. Method: All data were collected at Santa Casa de São Paulo, Brazil. The study sample comprised all alcohol or drug dependents admitted to the Addiction Treatment Unit between November 2013 and August 2014. A generalized linear model with a binomial distribution was performed to compare the odds of having a Sexual Addiction Screening Test (SAST) score greater than 6 points in the subgroups analyzed. Results: A total of 133 participants were included in our analysis, all reporting cocaine/crack and/or alcohol as drug of choice. Polysubstance addicts had a significant higher risk of a positive screening for sexual addiction compared to monosubstance addicts, age-sex adjusted odds ratios of sexual addiction being respectively 2.72 (95CI 1.1-6.71) and 0.37 (95CI 0.15-0.91). The odds of a SAST score greater than 6 was not statistically different between the cocaine/crack and alcohol groups, respectively 0.38 (95CI 0.14-1.02) and 2.67 (95CI 0.98-7.25). We found a significant relation between stronger drug addiction and greater levels of sexual addiction in the cocaine/crack group (p=0.0012), but not in the alcohol group. Conclusion: Our study reinforces the importance of assessing sexual behavior of drug addicts in clinical practice, especially considering users of multiple substances or with severe dependence.
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Faisalina, A. F., Fabio Sonvico, Paolo Colombo, A. A. Amirul, H. A. Wahab, and Mohamed Isa Abdul Majid. "Docetaxel-Loaded Poly(3HB-co-4HB) Biodegradable Nanoparticles: Impact of Copolymer Composition." Nanomaterials 10, no. 11 (October 26, 2020): 2123. http://dx.doi.org/10.3390/nano10112123.
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Polyhydroxyalkanoate (PHA) copolymers show a relatively higher in vivo degradation rate compared to other PHAs, thus, they receive a great deal of attention for a wide range of medical applications. Nanoparticles (NPs) loaded with poorly water-soluble anticancer drug docetaxel (DCX) were produced using poly(3-hydroxybutyrate-co-4-hydroxybutyrate), P(3HB-co-4HB), copolymers biosynthesised from Cupriavidus malaysiensis USMAA1020 isolated from the Malaysian environment. Three copolymers with different molar proportions of 4-hydroxybutirate (4HB) were used: 16% (PHB16), 30% (PHB30) and 70% (PHB70) 4HB-containing P(3HB-co-4HB). Blank and DCX-loaded nanoparticles were then characterized for their size and size distribution, surface charge, encapsulation efficiency and drug release. Preformulation studies showed that an optimised formulation could be achieved through the emulsification/solvent evaporation method using PHB70 with the addition of 1.0% PVA, as stabilizer and 0.03% VitE-TPGS, as surfactant. DCX-loaded PHB70 nanoparticles (DCX-PHB70) gave the desired particle size distribution in terms of average particle size around 150 nm and narrow particle size distribution (polydispersity index (PDI) below 0.100). The encapsulation efficiency result showed that at 30% w/w drug-to-polymer ratio: DCX- PHB16 NPs were able to encapsulate up to 42% of DCX; DCX-PHB30 NPs encapsulated up to 46% of DCX and DCX-PHB70 NPs encapsulated up to 50% of DCX within the nanoparticle system. Approximately 60% of DCX was released from the DCX-PHB70 NPs within 7 days for 5%, 10% and 20% of drug-to-polymer ratio while for the 30% and 40% drug-to-polymer ratios, an almost complete drug release (98%) after 7 days of incubation was observed.
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Rassu, Giovanna, Luca Ferraro, Barbara Pavan, Paolo Giunchedi, Elisabetta Gavini, and Alessandro Dalpiaz. "The Role of Combined Penetration Enhancers in Nasal Microspheres on In Vivo Drug Bioavailability." Pharmaceutics 10, no. 4 (October 26, 2018): 206. http://dx.doi.org/10.3390/pharmaceutics10040206.
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Microspheres based on both methyl-β-cyclodextrins and chitosan were prepared by spray-drying as nasal formulations of a model polar drug to analyze, firstly, how the composition of the carrier affects drug permeation across synthetic membranes and, secondly, how it induces systemic or brain delivery of the drug. Microparticles with different weight ratios of the two penetration enhancers (10–90, 50–50, 90–10) were characterized with respect to morphology, size, structural composition, water uptake, and the in vitro drug permeation profile. The leader formulation (weight ratio of 50–50) was then nasally administered to rats; systemic and cerebrospinal fluid (CSF) drug concentrations were analyzed by high performance liquid chromatography (HPLC) over time. Microspheres obtained with a single enhancer, methyl-β-cyclodextrins or chitosan, were administered in vivo as a comparison. The in vitro properties of combined microspheres appeared modified with regard to the polymeric matrix ratio. In vivo results suggest that the optimal drug distribution between CSF and bloodstream can be easily obtained by varying the amount of these two penetration enhancers studied in the matrix of nasal microspheres.
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Baral, Kshitis Chandra, Jae-Geun Song, Sang Hoon Lee, Rajiv Bajracharya, Godesi Sreenivasulu, Minkyoung Kim, Kyeong Lee, and Hyo-Kyung Han. "Enhanced Bioavailability of AC1497, a Novel Anticancer Drug Candidate, via a Self-Nanoemulsifying Drug Delivery System." Pharmaceutics 13, no. 8 (July 27, 2021): 1142. http://dx.doi.org/10.3390/pharmaceutics13081142.
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AC1497 is an effective dual inhibitor of malate dehydrogenase 1 and 2 targeting cancer metabolism. However, its poor aqueous solubility results in low bioavailability, limiting its clinical development. This study was conducted to develop an effective self-nanoemulsifying drug delivery system (SNEDDS) of AC1497 to improve its oral absorption. Based on the solubility of AC1497 in various oils, surfactants, and cosurfactants, Capryol 90, Kolliphor RH40, and Transcutol HP were selected as the components of SNEDDS. After testing various weight ratios of Capryol 90 (20–30%), Kolliphor RH40 (35–70%), and Transcutol HP (10–35%), SNEDDS-F4 containing 20% Capryol 90, 45% Kolliphor RH40, and 35% Transcutol HP was identified as an optimal SNEDDS with a narrow size distribution (17.8 ± 0.36 nm) and high encapsulation efficiency (93.6 ± 2.28%). Drug release from SNEDDS-F4 was rapid, with approximately 80% of AC1497 release in 10 min while the dissolution of the drug powder was minimal (<2%). Furthermore, SNEDDS-F4 significantly improved the oral absorption of AC1497 in rats. The maximum plasma concentration and area under the plasma concentration–time curve of AC1497 were, respectively 6.82- and 3.14-fold higher for SNEDDS-F4 than for the drug powder. In conclusion, SNEDDS-F4 with Capryol 90, Kolliphor RH40, and Transcutol HP (20:45:35, w/w) effectively improves the solubility and oral absorption of AC1497.
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Wang, Peng, Chao Huang, Zhaowei Meng, Wenjuan Zhang, Yongle Li, Xuefang Yu, Xin Du, et al. "No obvious association exists between red blood cell distribution width and thyroid function." Biomarkers in Medicine 13, no. 16 (November 2019): 1363–72. http://dx.doi.org/10.2217/bmm-2018-0476.
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Aim: We aimed to explore gender impacts on the associations between red blood cell distribution width (RDW) and thyroid function in the Chinese population. Methods/results: Gender impacts on the associations between RDW and thyroid function in 8424 males and 5198 females were investigated. RDW was found significantly lower in males than in females. An increasing trend of RDW along with aging was demonstrated in males. For females, an obvious decrease was shown during menopause period. From binary logistic regression, RDW displayed negative relationship with hypothyroidism in both genders as a single factor. However, if RDW was analyzed as a categorical variable (in RDW width quartiles) and as a continuous variable in models with covariates, all the odds ratios were negative, except for a weak-negative relationship with hypothyroidism in women in a continuous RDW model. Conclusion: The current study suggests that anisocytosis could be a contributing factor in thyroid dysfunction.
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Shu, Bai Li, Xu Ming Xue, Qi Meng Zhang, Ying Li Liu, Zong Hui Ma, Hua Li Nie, Li Min Zhu, and Ling Yun Du. "Preparation and Characterisation of TAM-PLGA Microspheres by Solvent Evaporation." Advanced Materials Research 194-196 (February 2011): 558–61. http://dx.doi.org/10.4028/www.scientific.net/amr.194-196.558.
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Uniformly sized microspheres of poly(d, l-lactic-co-glycolic) (PLGA) encapsulating tamoxifen(TAM) were successfully prepared by solvent evaporation. In this study three different polylactide-co-glycolides were used with differing lactide-glycolide ratios (50:50, 75:25, and 85:15, respectively). The sphere size distribution and morphology was analyzed using Laser Particle Size Analyzer and SEM. The drug loading and release in vitro of the microspheres were also investigated. The result showed that the microspheres have good spherical and better sustained release.
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Tucker, Elizabeth W., Beatriz Guglieri-Lopez, Alvaro A. Ordonez, Brittaney Ritchie, Mariah H. Klunk, Richa Sharma, Yong S. Chang, et al. "Noninvasive 11C-rifampin positron emission tomography reveals drug biodistribution in tuberculous meningitis." Science Translational Medicine 10, no. 470 (December 5, 2018): eaau0965. http://dx.doi.org/10.1126/scitranslmed.aau0965.
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Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.
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Wu, Mingxia, Hang Pan, Weiling Leng, Xiaotian Lei, Liu Chen, and Ziwen Liang. "Distribution of Microbes and Drug Susceptibility in Patients with Diabetic Foot Infections in Southwest China." Journal of Diabetes Research 2018 (August 5, 2018): 1–9. http://dx.doi.org/10.1155/2018/9817308.
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Objective. To investigate the microbial distribution and drug susceptibility among diabetic foot ulcers (DFUs) with different Wagner grades and between acute and chronic DFUs. Methods. We enrolled 428 DFU patients who were hospitalized and treated in the Southwest Hospital. We collected deep ulcer secretion for microbial culture and drug susceptibility tests and analyzed the results. We reexamined 67 patients with poor anti-infection efficacy and analyzed microbial species. Results: The 354 positive samples included 201 cases (56.8%) of single-pathogen infections and 153 cases (43.2%) of multiple-pathogen infections before antibiotic therapy. A total of 555 strains were cultivated, including 205 (36.9%) strains of gram-positive organisms (GPOs), 283 (51.0%) gram-negative bacilli (GNB), and 67 (12.1%) fungal strains. In terms of distribution, patients with different Wagner grades had different bacterial composition ratios (P<0.01). Patients with Wagner grades 3–5 mainly had GNB. The specimens from chronic ulcer wounds were primarily GNB (54.2%), whereas fungi accounted for 14.4% of the infections; the distribution was significantly different from that of acute ulcers (P<0.01). The susceptibility tests showed that the Staphylococcus genus was more susceptible to vancomycin, linezolid, and tigecycline. Tobramycin was the most effective drug (97%) for the treatment of Escherichia coli, followed by ertapenem (96.4%), imipenem (93.5%), and cefotetan (90%). Most of the remaining GNB were susceptible to antibiotics such as carbapenems, aminoglycosides, fluoroquinolones, ceftazidime, cefepime, and piperacillin-tazobactam (>63.2%). After antibiotic therapy, the positive rate of microbial culture was 52.2%, and the proportion of GNB and fungi increased to 68.9% and 20%. Conclusion. The distribution and types of bacteria in diabetic foot infection (DFI) patients varied with the different Wagner classification grades, courses of the ulcers, and antibiotic therapy. Multidrug resistance were increased, and the clinical treatment of DFIs should select the most suitable antibiotics based on the pathogen culture and drug susceptibility test results.
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Georgieva, Yana Zh, Bissera A. Pilicheva, Vesela Yu Kokova, Elisaveta G. Apostolova, and Margarita I. Kassarova. "Taste Masking of Enalapril Maleate by the Precipitation Method." Folia Medica 61, no. 3 (September 30, 2019): 426–34. http://dx.doi.org/10.3897/folmed.61.e39208.
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Background: Taste masking of bitter or unpleasant drugs is an important prerequisite to improve patient compliance, especially for children and elderly patients. We aimed at obtaining taste-masked microparticles intended for incorporation into orodispersible tablets (ODTs). We selected the precipitation method using enalapril maleate (ENA) as a model bitter-tasting drug and Eudragit EPO® as a pH sensitive polymer. Aim: The aim of this study was to obtain microparticles with enalapril maleate by the precipitation method in order to mask the bitter taste of the drug. Materials and methods: Nine models of enalapril maleate – Eudragit EPO® microparticles were prepared by the precipitation method at varied drug-polymer ratios. The models were characterized in terms of size, shape, production yield, drug content, encapsulation efficiency and moisture content. Fourier-transformed infrared spectroscopy, powder X-ray diffraction and differential scanning calorimetry were used to analyze possible interactions in the complex. In vitro drug release in simulated salivary fluid and in vivo taste evaluation in rats were realized to prove taste masking. Results: The particle size distribution varied from 266.9 µm to 410.9 µm. The shape of the resulting particles was irregular. The production yield varied from 23.6% to 78.2%. The drug content ranged between 2.3% to 4.8%, encapsulation efficiency increased from 1.6% to 9.0%. In vitro drug release data indicated significant taste masking. Conclusion: Some of the obtained microparticles by the precipitation method showed satisfactory taste masking efficiency, which proved the taste masking feasibility of this method.
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Matsuzawa, Yukimasa, Tadaichi Kitamura, Motofumi Suzuki, Yasuhiro Koyama, and Kazuyoshi Shigehara. "Prevalence, Genotype Distribution, and Predictors against HPV Infections Targeted by 2-, 4-, 9-Valent HPV Vaccines among Japanese Males." Vaccines 8, no. 2 (May 14, 2020): 221. http://dx.doi.org/10.3390/vaccines8020221.
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Objectives: Epidemiological reports of sexual life and human papilloma virus (HPV) infection among Japanese men are scarce, and the necessity of HPV vaccines for males is regarded as a controversial topic in Japan. The objective of this study is to determine the prevalence, genotype distribution, and risk factors against HPV infections targeted by bivalent (2v), quadrivalent (4v), and 9-valent (9v) HPV vaccines among Japanese male patients who visited our urological clinics. Material and Methods: The study population consisted of 798 males aged 20 to 95 years (mean ± standard deviation, 55.4 ± 19.5 years). We collected scraping samples from the glans penis using cotton swabs from all patients for genotyping of HPVs. We compared patients’ characteristics and detected HPV genotypes in order to determine the risk factors against HPV infections. Results: Of 798 participants, 198 participants (198/798; 24.8%) had at least one genotype of any HPV infection. The total number of detected HPV genotypes was 328. Of 328 genotypes, 30% (n = 99; 99/328) were 9v HPV genotypes. Most frequently detected types of high-risk HPV infection were type 52 (n = 40; 40/328; 12.2%). Number of lifetime sex partners (≥21) and present or history of sexually transmitted infections were found to be predictors of any HPV infection with adjusted odds ratios of 3.106 (95% confidence interval (CI), 1.593–6.509) and 1.894 (95% CI, 1.185–3.026), respectively. Age of sex initiation was a predictor of 2v and 4v HPV infections with adjusted odds ratios of 100 (95% CI, 1.013–25.673) and 2.676 (95% CI, 1.037–6.905), respectively. Number of lifetime sex partners (≥21) was a predictor of 9v HPVs with adjusted odds ratios of 2.397 (95% CI, 1.060–5.424). Conclusions: Approximately, a quarter of Japanese male patients who visited urological clinics were exposed to HPV. Moreover, from the perspective of our multivariate logistic regression analysis, some kinds of sexual behavior aggravate the risk of typical HPV genotypes infections.
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Cahusac, Peter M. B., and Solomon S. Senok. "Does Hyaluronidase Enhance Drug Penetration to Mechanoreceptors?" Skin Pharmacology and Physiology 33, no. 5 (2020): 253–60. http://dx.doi.org/10.1159/000510890.
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<b><i>Background:</i></b> The pharmacological study of mechanoreceptors embedded within tissue is hampered by tissue barriers to applied research drugs. <b><i>Methods:</i></b> Hyaluronidase increases the permeability of tissues and is used clinically to facilitate the distribution of injected drugs. An in vitro rat sinus hair preparation was used to determine whether hyaluronidase (1,500 or 3,000 IU/10 mL) had an effect on drug access to receptor sites on slowly adapting St I and St II mechanoreceptors. Electrical recordings were made from single mechanoreceptor units that were activated by trapezoid ramp stimuli. Cinnamaldehyde (500–1,500 μM) and capsazepine (100 μM) were used as test drugs. Changes in onset time and degree of depression of firing due to test drugs were compared to control experiments not employing hyaluronidase. <b><i>Results:</i></b> There were no statistical effects on any of the observed measures. Often the effects were opposite to those predicted. Using a likelihood approach, it was calculated that there was strong evidence (log-likelihood ratios from −0.5 to −6.5) to support a null effect over a facilitatory effect. There was no evidence of loss of integrity of mechanoreceptor mechanotransduction mechanisms following hyaluronidase applications. <b><i>Comparison with Existing Method:</i></b> The use of hyaluronidase does not facilitate drug access to receptors. <b><i>Conclusions:</i></b> In the in vitro sinus hair preparation, the addition of hyaluronidase does not allow easier access to slowly adapting mechanoreceptors within the follicle.
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Finazzi, Stefano, Giacomo Luci, Carlo Olivieri, Martin Langer, Giulia Mandelli, Alberto Corona, Bruno Viaggi, and Antonello Di Paolo. "Tissue Penetration of Antimicrobials in Intensive Care Unit Patients: A Systematic Review—Part I." Antibiotics 11, no. 9 (August 29, 2022): 1164. http://dx.doi.org/10.3390/antibiotics11091164.
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The challenging severity of some infections, especially in critically ill patients, makes the diffusion of antimicrobial drugs within tissues one of the cornerstones of chemotherapy. The knowledge of how antibacterial agents penetrate tissues may come from different sources: preclinical studies in animal models, phase I–III clinical trials and post-registration studies. However, the particular physiopathology of critically ill patients may significantly alter drug pharmacokinetics. Indeed, changes in interstitial volumes (the third space) and/or in glomerular filtration ratio may influence the achievement of bactericidal concentrations in peripheral compartments, while inflammation can alter the systemic distribution of some drugs. On the contrary, other antibacterial agents may reach high and effective concentrations thanks to the increased tissue accumulation of macrophages and neutrophils. Therefore, the present review explores the tissue distribution of beta-lactams and other antimicrobials acting on the cell wall and cytoplasmic membrane of bacteria in critically ill patients. A systematic search of articles was performed according to PRISMA guidelines, and tissue/plasma penetration ratios were collected. Results showed a highly variable passage of drugs within tissues, while large interindividual variability may represent a hurdle which must be overcome to achieve therapeutic concentrations in some compartments. To solve that issue, off-label dosing regimens could represent an effective solution in particular conditions.
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Farmoudeh, Ali, Anahita Rezaeiroshan, Mohammadreza Abbaspour, Ali Nokhodchi, and Pedram Ebrahimnejad. "Solid Dispersion Pellets: An Efficient Pharmaceutical Approach to Enrich the Solubility and Dissolution Rate of Deferasirox." BioMed Research International 2020 (June 24, 2020): 1–12. http://dx.doi.org/10.1155/2020/8583540.
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Deferasirox (DFX) is an oral iron-chelating agent and classified into class II of the Biopharmaceutics Classification System. Low bioavailability of the drug due to insufficient solubility in physiological fluids is the main drawback of DFX. The idea of the current study was to explore the potential of solid dispersion (SD) as an effective method to improve the dissolution rate of DFX in pellets. The SDs were made by the solvent evaporation technique using polyethylene glycol 4000 (PEG 4000) and polyvinylpyrrolidone K25 with different drug-to-carrier ratios. Then, the dispersion was milled and mixed with other components and the mixture layered on sugar-based cores by pan coating technique. The pellets were evaluated in terms of size distribution, morphology (SEM), and dissolution behaviour. Drug-polymer interactions were studied using differential scanning calorimetry (DSC), X-ray diffraction study (XRD), and Fourier transformation infrared (FTIR) spectroscopy. The pellets coated with SD showed a remarkable rise in the solubility of DFX than that of free drug-loaded pellets. The dispersion with PVP K25 showed a faster dissolution rate as compared to other mixtures. The DSC and XRD analysis indicated that the drug was in the amorphous state when dispersed in the polymer. The FTIR studies demonstrated any ruled out interaction between drug and polymer. The SEM showed smoothness on the surface of the pellets. It is resolved that the SD method considerably enriched the dissolution rate of DFX in pellets, which can also be utilized for other poorly water-soluble drugs.
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Souweidane, Mark M. "INSP-17. Augmented Drug Delivery for Pediatric Diffuse Midline Glioma using Convection Enhanced Delivery." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i189—i190. http://dx.doi.org/10.1093/neuonc/noac079.713.
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Abstract Convection enhanced delivery (CED), an alternative to systemic chemotherapy, spans nearly two decades of clinical experience. The application of CED in pediatric neuro-oncology has been mainly used in children with DMG. This exploratory period is highlighted by widely variable features including procedural technique, disease extent, device interface, infusion parameters, and therapeutic agent. This presentation is meant to critically assess if CED for DMG is a logical therapeutic strategy. Most convincing to the perpetuation of this platform is the reproducible demonstration of augmented drug delivery. Post-treatment ratios of intralesional to systemic drug concentrations consistently exceed 1000. CED in the brain stem satisfies a desirable goal of CNS drug delivery: achieving high target tissue drug concentrations while avoiding systemic exposure. Surgical targeting of the brain stem and cannula deployment are solidly established as safe and accurate. Catheter insertion complications such as clinically relevant hemorrhage, CNS infection, and neurological injury are exceptional. Likewise, targeting error is on a millimeter scale with infrequent need for catheter repositioning. The use of intrinsic MRI signals, direct drug labeling, and surrogate tracers have all been used for measuring distribution of the infusion. The experience using a radio-labelled theragnostic agent has provided detailed distribution and dosimetry information. Based on estimates of tumor and hence target volumes, a rationale goal is to reach volumes of distribution in the range of 15-25 cm3. Optimizing this goal has focused on surgical targeting, infusion duration, and multiple treatment plans. Computational predictive modeling is being employed as a preoperative adjunct for maximizing distribution. Experience in DMG thus far has been limited to feasibility and safety studies. There is a paucity of Phase 2 studies and hence outcome has not yet been rigorously tested. Anecdotal increase in survival and long-term survival has been reproducibly reported. Of particular interest are the occasional cases of children exhibiting late out-of-treatment field and even extra-CNS recurrence. Available data is convincing that CED should serve be further explored in future clinical trials designs for children with DMG. Important features of any Phase 2 study design however should include monitoring of drug distribution, measures of tumor coverage, early response monitoring techniques, and possibly combination with whole CNS axis treatment.
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Nicol, Melanie R., Fan Wang, Ambayo Richard, Olivie Carolyne Namuju, Katelyn A. Pastick, David R. Boulware, David B. Meya, and Robert Lukande. "88462 Fluconazole distribution in CNS and gynecological tissues in HIV-related cryptococcal meningitis decedents." Journal of Clinical and Translational Science 5, s1 (March 2021): 96. http://dx.doi.org/10.1017/cts.2021.648.
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ABSTRACT IMPACT: Plasma and CSF are not reliable estimates of drug exposure in tissue compartments relevant for treatment and prevention of infectious diseases. OBJECTIVES/GOALS: Globally, high dose fluconazole is widely used in the management of cryptococcal meningitis. While it is known to readily penetrate into cerebrospinal (CSF), less is known about drug concentrations in brain parenchymal tissues. Similarly, distribution of fluconazole into gynecological tissues has not been robustly characterized. METHODS/STUDY POPULATION: With informed consent from next-of-kin, we conducted autopsies within 24h of death for hospitalized Ugandans receiving fluconazole for treatment or secondary prophylaxis of cryptococcal meningitis. Dosing history was abstracted from medical chart and caregiver interviews. Fluconazole concentrations were determined using high-performance liquid chromatography- tandem mass spectrometry (LC-MS/MS) in plasma, CSF, 10 brain compartments (frontal, parietal, and occipital lobes, corpus callosum, globus pallidus, hippocampus, midbrain, medulla oblongata, spinal cord, and choroid plexus) and 4 female genital compartments (cervix, vagina, ovary, and uterus), depending on tissue availability. Descriptive statistics of tissue to plasma ratios were used to describe concentrations relative to plasma. RESULTS/ANTICIPATED RESULTS: Fluconazole concentrations were measured in available tissues of 21 individuals with detectable fluconazole in plasma. Daily doses of fluconazole were 200 mg (n=4), 400 mg (n=1), 800 mg (n=4), 1200 mg (n=9) or unknown (n=3). CSF concentrations (n=10) ranged from 93-1380% (median 100%) of plasma while brain concentrations (n=3) across all 10 compartments ranged from 45% to 89% (median 69%) of plasma. In the female genital tract, cervical concentrations (n=10) were 9-78% (median 65%) of plasma and in the 2 individuals with available tissue, concentrations in vaginal, ovarian, and uterine tissues were similar to cervix, ranging from 63-105% of plasma. DISCUSSION/SIGNIFICANCE OF FINDINGS: Measuring drug concentrations directly in tissues, the presumed site of action, improves estimates of drug efficacy. While fluconazole concentrations in CSF were similar to plasma, actual brain tissues were consistently lower. Concentrations were similar between upper and lower female genital tracts, but were consistently lower than plasma.
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Marchand, Sandrine, Claire Dahyot, Isabelle Lamarche, Elodie Plan, Olivier Mimoz, and William Couet. "Lack of Effect of Experimental Hypovolemia on Imipenem Muscle Distribution in Rats Assessed by Microdialysis." Antimicrobial Agents and Chemotherapy 49, no. 12 (December 2005): 4974–79. http://dx.doi.org/10.1128/aac.49.12.4974-4979.2005.
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ABSTRACT The aim of this study was to investigate the influence of hypovolemia on the distribution of imipenem in muscle extracellular fluid determined by microdialysis in awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Imipenem recoveries in muscle and blood were determined in each rat by retrodialysis by drug before drug administration. Hypovolemia was induced by removing 40% of the initial blood volume over 30 min. Imipenem was infused intravenously at a dose of 70 mg · kg−1 over 30 min, and microdialysis samples were collected for 120 min from hypovolemic (n = 8) and control (n = 8) rats. The decay of the free concentrations in blood and muscle with time were monoexponential, and the concentration profiles in muscle and blood were virtually superimposed in both groups. Accordingly, the ratios of the area under the concentration-time curve (AUC) for tissue (muscle) to the AUC for blood were always virtually equal to 1. Hypovolemia induced a 23% decrease in the clearance (P < 0.05) of imipenem, with no statistically significant alteration of its volume of distribution. This study showed that imipenem elimination was altered in hypovolemic rats, probably due to decreased renal blood flow, but its distribution characteristics were not. In particular, free imipenem concentrations in blood and muscle were always virtually identical.
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Marchand, Sandrine, Claire Dahyot, Isabelle Lamarche, Olivier Mimoz, and William Couet. "Microdialysis Study of Imipenem Distribution in Skeletal Muscle and Lung Extracellular Fluids of Noninfected Rats." Antimicrobial Agents and Chemotherapy 49, no. 6 (June 2005): 2356–61. http://dx.doi.org/10.1128/aac.49.6.2356-2361.2005.
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ABSTRACT The aim of this study was to investigate the imipenem distribution in muscle and lung interstitial fluids by microdialysis in rats and to compare the free concentrations in tissue with the free concentrations in blood. Microdialysis probes were inserted into the jugular vein, hind leg muscle, and lung. Imipenem recoveries in these three media were determined in each rat by retrodialysis by drug period before drug administration. Imipenem was infused intravenously at a dose of 120 mg · kg−1 over 30 min, and microdialysis samples were collected for 150 min. The whole study was conducted with nonhydrated rats (n = 4) and hydrated rats (n = 6) while the animals were under isoflurane anesthesia. The decay of free concentrations in blood, muscle, and lung with time were monoexponential; and the concentration profiles in these three media were virtually superimposed in both groups. Accordingly, the ratios of the area under the curve (AUC) for tissue (muscle or lung) to the AUC for blood were always virtually equal to 1. Compared to values previously determined with awake rats, clearance was reduced by 2 and 1.5 in nonhydrated and hydrated rats, respectively, but the volume of distribution was unchanged. By combining microdialysis in blood and tissues, it was possible to demonstrate that free imipenem concentrations were virtually identical in blood, muscle, and lung.
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Hornak, Joseph Patrik, and David Reynoso. "44. Antibiotic Class-Based Distribution and Analysis of Reported Beta-Lactam Allergies amongst Hospitalized Patients." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S45. http://dx.doi.org/10.1093/ofid/ofaa439.089.
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Abstract Background Reported β-lactam allergy (BLA) is very common, yet less than 10% of these patients exhibit true hypersensitivity. When faced with reported BLAs, physicians often choose alternative antibiotics which can be associated with C. difficile infection, drug-resistance development, poorer outcomes, & increased costs. Effective identification of these patients is necessary for subsequent, appropriate BLA “de-labeling.” Here, we conducted a single-center analysis of alternative antibiotic utilization amongst patients reporting BLA and compare the frequency of drug-resistant infections and C. difficile infection in allergic & non-allergic patients. Methods This is a retrospective review of adult patients hospitalized at The University of Texas Medical Branch from 1/1/2015 to 12/31/2019. Pooled electronic medical records were filtered by antibiotic orders and reported allergies to penicillins or cephalosporins. Patients with drug-resistant and/or C. difficile infection (CDI) were identified by ICD-10 codes. Microsoft Excel & MedCalc were used for statistical calculations. Results Data were available for 118,326 patients and 9.3% (11,982) reported a BLA, with the highest rates seen in those receiving aztreonam (85.9%, 530/617) & clindamycin (33.7%, 3949/11718). Amongst patients reporting BLA, high ratios-of-consumption (relative to all patients receiving antibiotics) were seen with aztreonam (7.0), clindamycin (2.7), cephalosporin/β-lactamase inhibitors (2.4), & daptomycin (2.1). Compared to the non-BLA population, BLA patients more frequently experienced MRSA infection (3.0% vs 1.5%, OR 1.99, 95% CI 1.79–2.23, p< 0.0001), β-lactam resistance (1.2% vs 0.6%, OR 2.07, 95% CI 1.72–2.49, p< 0.0001), and CDI (1.2% vs 0.7%, OR 1.85, 95% CI 1.54–2.23, p< 0.0001). Conclusion Our measured BLA rate matches approximate expectations near 10%. Moreover, these patients experienced significantly higher frequencies of drug-resistant bacterial infections and CDI. Targeted inpatient penicillin allergy testing stands to be particularly effective in those patients receiving disproportionately utilized alternative agents (e.g. aztreonam, clindamycin, daptomycin). β-lactam allergy “de-labeling” in these patients is likely a valuable antimicrobial stewardship target. Disclosures All Authors: No reported disclosures
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Awadhesh Kumar Pandey and Arun Kumar Dwivedi. "Recent advancement in wound healing dressing material." International Journal of Research in Pharmaceutical Sciences 10, no. 3 (August 25, 2019): 2572–77. http://dx.doi.org/10.26452/ijrps.v10i3.1512.
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Wounds have been occurring as long as the existence of life. Presently available advanced wound care products for dressing are beyond the reach of the majority Indian population, and they also do not completely fulfil the required benefits of therapeutic value. The dermal patch technology is the best-known and widely used approach for delivering drugs. It has been proven to be the fastest, easiest, safest and most economical way for drug delivery. The use of biodegradable polymers in wound management has been brought into prominence with new innovations in drug delivery system. Thus with a new dimension for the use of polymeric materials in or as wound healing, drug delivery devices involves incorporation of biodegradability into the drug delivery system. A number of degradable polymers are potentially useful for drug delivery including a variety of synthetic and natural substances such as Poly Lactic acid, Poly Crypolactone, Chitosen etc. Among all these Poly (lactic acid) (PLA) is the most readily biodegradable polymer in the surgical field. The biodegradable polymers have gained growing importance in the medical area, and these have been used in a wide number of applications in the human body, such as surgical sutures, controlled drug release systems, artificial skins, guides for nerves, veins and artificial arteries and orthopaedic devices. Biodegradable polymers have several physical and chemical characteristics, such as molecular mass average and distribution, glass transition and/or melting temperatures, monomer ratios and sequencing for copolymers. The knowledge of physicochemical characteristics of Poly Lactic acid polymers essential to understand its thermo-mechanical performance. In order to achieve appropriate wound healing, sustained release of the drug from the bio-degradable patch is necessary. So the assessment of the interaction between the drug and polymer is indispensable.
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Patil, Madhoosudan, Brock Matter, Yogendra Raol, David Bourne, Ryan Kelley, and Uday Kompella. "Brain Distribution and Metabolism of Flupirtine, a Nonopioid Analgesic Drug with Antiseizure Effects, in Neonatal Rats." Pharmaceutics 10, no. 4 (December 16, 2018): 281. http://dx.doi.org/10.3390/pharmaceutics10040281.
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Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing. An LC-MS/MS assay was developed to quantify flupirtine and D-13223. Flupirtine was delivered to all tissues assessed, with the highest area under the concentration vs. time curve (AUC0–24h) in liver (488 µg·h/g tissue) and the lowest in spleen (82 µg·h/g tissue). Flupirtine reached the brain, including the hippocampus and cortex, within 1 h of dosing and persisted at 24 h. Flupirtine AUC in various brain regions was approximately 195 µg·h/g tissue. The half-life of flupirtine in various tissues ranged from 3.1 to 5.2 h. D-13223 was formed in vivo and detected in all tissues assessed, with the concentrations being the highest in the liver. Incubation of isolated neonatal rat liver, heart, kidney, lung, spleen, whole eye, serum, or whole brain with flupirtine for 3 h at 37 °C formed D-13223 in all tissues, except serum. D-13223 formation was the highest in isolated liver tissue. Tissue partition coefficients based on isolated tissue uptake correlated well with in vivo tissue:serum drug exposure ratios. Thus, flupirtine reaches the target brain tissues from the systemic route in neonatal rats, and brain tissue forms the active metabolite D-13223.